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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | De novo lupus nephritis during treatment with belimumab.
In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting.
Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3-151.2).
We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046).
Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.
pmc Rheumatology key messages
Irrespective of prior renal involvement, belimumab treatment may not adequately protect against lupus nephritis.
Concomitant antimalarial therapy along with belimumab was implied to protect against development of lupus nephritis.
Our observations call for vigilance with regard to evolving renal disease during belimumab therapy.
Introduction
SLE is a chronic, multisystem autoimmune disease with unmet needs, such as delayed diagnosis, premature atherosclerosis, drug-associated organ damage and a prominent impairment of health-related quality of life [1]. The wide range of manifestations and serological findings pose challenges with regard to diagnosis and treatment. Today, standard-of-care (SoC) therapy includes glucocorticoids, antimalarials, immunosuppressants and biologic agents, e.g. belimumab (BLM) and rituximab (RTX). The selection of drugs is mainly based on the afflicted organ systems and the organ-specific or global disease activity [2]. LN is a manifestation of SLE with a potentially life-threatening course [3].
BLM is a recombinant human IgG1-λ monoclonal antibody that specifically binds the soluble form of B cell activating factor (BAFF). The efficacy of BLM has been demonstrated to date in five placebo-controlled phase III trials and several observational studies [4]. Although post hoc analysis of clinical trials of BLM showed superiority of BLM over placebo in preventing renal flares [5] and a systematic review suggested an overall promising effect of BAFF inhibition on renal outcomes [6], development of LN during BLM treatment has also been reported [7–10]. Clinical trials of BLM in LN, either as an add-on therapy to SoC or in combination with RTX, are underway [11–13] and the BLISS-LN trial recently demonstrated superiority of addition of BLM to SoC for active LN over SoC alone [14].
We herein report cases of de novo LN during treatment with BLM observed in our academic practices, and cases of LN flares in patients with a history of renal SLE at the time of BLM initiation. We further aimed at identifying factors or risk phenotypes that are associated with the development of LN, in order to contribute to optimized monitoring during treatment with BLM.
Methods
Patients
Patients, classified with SLE according to the 1982 ACR [15] and/or 2012 SLICC [16] criteria, receiving BLM 10 mg/kg intravenously at week 0, 2, 4 and thereafter every fourth week from its approval in 2011 until 31 December 2017 in the Day Care Units of four Swedish academic rheumatology centres (Linköping, Lund, Stockholm and Uppsala) and one academic centre in Leeds, UK, were followed longitudinally within the frame of observational research programmes, and were included in the present report (n = 95). BLM was given as an add-on to background SoC, with no change in SoC implemented unless clinically indicated. None of these patients were given cyclophosphamide, RTX or other B cell depleting agents during treatment with BLM. No patient selection was applied other than consent to participate in the study. Sixty-six of these patients (69.5%) had no history of renal involvement until BLM initiation. As a comparator group to the non-renal SLE cases exposed to BLM, we included 66 non-renal SLE cases from Linköping and Stockholm, individually matched for age and sex, with similar serological profiles (anti-dsDNA positivity, low complement protein 3 and/or 4), who were also followed longitudinally; no selection other than matched serology and age at baseline was applied. Kidney biopsy was performed in the case of a suspected new onset of LN during follow-up. Patient characteristics are detailed in Table 1.
Table 1 Patient characteristics
Item Belimumab-treated SLE Non-renal SLE comparators P-value
Total Non-renal
Background variables
Number of cases, n 95 66 66
Age, mean (s.d.), years 42.2 (14.2) 42.2 (15.2) 43.4 (16.0) 0.152
Females, n (%) 89 (93.7) 63 (95.5) 63 (95.5) NA
Current tobacco smoking, n (%) 11 (12.5); n = 88 9 (15.0); n = 60 14 (21.2) 0.367
Former tobacco smoking, n (%) 25 (28.4); n = 88 14 (23.3); n = 60 23 (34.8) 0.047
Caucasian, n (%) 86 (90.5) 59 (89.4) 64 (97.0) NA
African, n (%) 6 (6.3) 5 (7.6) 0 (0.0) NA
Asian, n (%) 2 (2.1) 2 (3.0) 2 (3.0) NA
Hispanic, n (%) 1 (1.1) 0 (0.0) 0 (0.0) NA
Diabetes until enrolment, n (%) 3 (3.2) 0 (0.0) 0 (0.0) NA
Hypertension until enrolment, n (%) 23 (24.2) 9 (13.6) 14 (21.2) 0.332
Disease variables at enrolment
Duration of SLE, mean (s.d.), years 11.4 (9.3) 10.5 (9.1) 9.8 (11.1)d 0.529
SLEDAI-2K score, mean (s.d.) 9.3 (5.9) 8.2 (4.7) 4.9 (3.7) <0.001
SDI score, median (IQR) 1 (0–1); n = 93 0 (0–1); n = 64 0 (0–2) 0.594
Serological activitya, n (%) 68 (71.6) 47 (71.2) 50 (75.8) 0.250
Anti-dsDNA positive, n (%) 50 (52.6) 33 (50.0) 34 (51.5) 1.000
Low complement, n (%) 57 (60.0) 40 (60.6) 41 (62.1) 1.000
Anti-Smith positive, n (%) 24 (25.3) 16 (24.2) 14 (21.2) 0.832
Main reasons for belimumab
General, n (%) 4 (4.2) 3 (4.5) NA NA
Mucocutaneous, n (%) 55 (57.9) 39 (59.1) NA NA
Musculoskeletal, n (%) 54 (56.8) 39 (59.1) NA NA
Haematological, n (%) 12 (12.6) 8 (12.1) NA NA
Cardiorespiratory, n (%) 6 (6.3) 4 (6.1) NA NA
Renal, n (%) 9 (9.5) 0 (0.0) NA NA
Neurological, n (%) 5 (9.5) 2 (3.0) NA NA
Immunological, n (%) 3 (3.2) 2 (3.0) NA NA
Ongoing concomitant treatments
Daily prednisolone doseb, mean (s.d.), mg 11.3 (9.4) 11.1 (9.4) 7.3 (12.1)e 0.004
Antimalarial agents, n (%) 67 (70.5) 45 (68.2) 36 (54.5) 0.137
Immunosuppressantsc, n (%) 58 (61.1) 40 (60.6) 21 (31.8) 0.002
Azathioprine, n (%) 27 (28.4) 17 (25.8) 6 (9.1) 0.013
Methotrexate, n (%) 14 (14.7) 11 (16.7) 8 (12.1) 0.629
Mycophenolate mofetil/sodium, n (%) 14 (14.7) 11 (16.7) 3 (4.5) 0.057
Other immunosuppressants, n (%) 4 (6.8) 2 (3.0) 5 (7.6) 0.375
In cases of missing values, the total number of available observations (n) is indicated. P-values are derived from comparisons between non-renal SLE patients who were treated with belimumab and individually matched for age and sex non-renal SLE comparators who were not treated with belimumab, using Wilcoxon’s signed rank test for continues variables and McNemar’s test for dichotomous variables, or the χ2 test in cases of missing values in one of the two groups. Significant P-values are indicated in bold. aAnti-dsDNA positivity and/or low complement levels. bAt the time of belimumab initiation or enrolment for the comparators. cExcluding antimalarial agents. dMedian (IQR): 6.4 (0.5–13.4) years. eMedian (IQR): 5.0 (0.0–10.0) mg. IQR: interquartile range; NA: not applicable or not available; SDI: SLICC/ACR Damage Index.
Definitions
We defined de novo LN as a new onset of significant proteinuria, defined as a urinary protein-to-creatinine ratio or protein excretion in 24-h urine collection corresponding to >0.5 g/day, combined with renal histology consistent with LN according to the WHO and/or 2003 International Society of Nephrology/Renal Pathology Society classification [17], in patients who previously had not met the ACR criterion for renal disorder [15].
Global SLE disease activity was evaluated using the SLEDAI-2K [18], and organ damage using the SLICC/ACR Damage Index (SDI) [19]. For SLEDAI-2K scores, laboratory and serological items were assessed based on results from routine tests at the local university hospital laboratories.
Statistics
Comparisons between matched non-renal SLE patients who received BLM vs those who did not were performed using Wilcoxon’s signed rank test for continuous and McNemar’s test for dichotomous variables. The occurrence of de novo LN or LN flares during follow-up was illustrated using Kaplan–Meier curves, and the pairwise log-rank (Mantel–Cox) test was employed to compare the de novo LN distributions between BLM exposed vs not exposed non-renal SLE patients. Contingency between unrelated dichotomous variables was tested using Fisher’s exact test. Proportional hazards (Cox) regression was used to investigate factors and disease phenotypes associated with LN development during therapy. P-values<0.05 were considered statistically significant. IBM SPSS version 25 software (IBM Corp., Armonk, NY, USA) was used for statistical analyses and GraphPad Prism 7 (GraphPad Software Inc., La Jolla, CA, USA) for construction of graphs.
Ethical considerations
The study complied with the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from all patients. The study protocol was approved by regional ethics review boards.
Results
Outcome of cases without prior LN
As shown in Table 1, non-renal SLE patients who were selected for treatment with BLM had comparable serological profiles, disease duration and SDI scores but higher baseline SLEDAI-2K scores [mean (s.d.): 8.2 (4.7)] than age- and sex-matched non-renal SLE controls [4.9 (3.7); P < 0.001]. Accordingly, they were on higher daily prednisolone doses [11.1 (9.4) vs 7.3 (12.1) mg; P = 0.004] and a higher proportion within BLM-treated non-renal SLE patients used immunosuppressants (60.6%) compared with the controls (31.8%; P = 0.002), but the proportions of patients using antimalarial agents did not differ significantly (P = 0.137). Use of immunosuppressants and antimalarials for the controls during the entire follow-up period is delineated in Supplementary Figs S1 and S2 (available at Rheumatology online), respectively.
Six patients (9.1%) developed a biopsy-proven de novo LN in the BLM-treated non-renal SLE group after a median follow-up time of 7.4 (IQR: 2.7–22.2) months. Among the comparators, two individuals (3.0%) developed de novo LN, one class III and one class IV after 21 and 50 months, respectively.
In the six patients who developed de novo LN, all Caucasians, BLM was primarily initiated for active mucocutaneous and/or musculoskeletal disease. All had positive anti-dsDNA levels and were hypocomplementaemic at baseline. At BLM initiation, SLEDAI-2K scores ranged from 6 to 23, and the daily prednisolone dose from 7.5 to 30 mg. Only 2/6 patients were on concomitant treatment with antimalarials. The renal histopathology in 4/6 subjects was consistent with proliferative LN (class III or IV), whereas the two remaining cases showed membranous LN (class V) in combination with class II. Detailed information is shown in Supplementary Table S1, available at Rheumatology online.
As illustrated in Fig. 1A, non-renal SLE patients treated with BLM showed a higher frequency of and/or shorter time to de novo LN compared with non-renal SLE patients who did not receive BLM (hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012). This association between BLM treatment and de novo LN development remained significant after adjustment for SLEDAI-2K scores (HR: 8.3; 95% CI: 1.2, 57.0; P = 0.031), while no such association was seen for SLEDAI-2K scores as a co-variate in the same model (HR: 1.1; 95% CI: 0.9, 1.2; P = 0.362). The Kaplan–Meier curve in Fig. 1B illustrates the course of BLM-treated patients with and without a history of renal SLE at BLM initiation, as well as the non-renal comparators, until the time of LN development or the last available evaluation.
Fig. 1 Development of LN in BLM-treated patients and unexposed comparators
(A) Bar graph showing proportions of patients who developed de novo LN within the BLM-treated non-renal patient subgroup (red) and age- and sex-matched comparators not exposed to BLM (blue). The forest plot above illustrates the result from Cox regression analysis, with the dark blue circle representing the HR and the whiskers representing the 95% CI. (B) Kaplan–Meier curve illustrating the course of BLM-treated cases with (green) and without (red) a history of LN at the time of treatment initiation, and the non-renal SLE comparators (blue), until the time of LN development or the last available follow-up evaluation. BLM: belimumab; HR: hazard ratio.
Next, we selected patients not exposed to BLM with baseline SLEDAI-2K scores >4, which yielded a control group with comparable SLEDAI-2K scores [8.5 (3.2); n = 25] to the non-renal BLM group. None of the patients within this group had developed LN after a mean follow-up of 126.5 (37.8) months.
Outcome of cases with previous LN
Among the 29/95 BLM-treated patients with LN prior to enrolment, but quiescent renal disease at the time of BLM initiation, two cases (6.9%) of LN flare were observed after 1 and 9 months (Fig. 1B). One of these patients underwent a renal biopsy that showed a proliferative LN (class IV); prior to BLM treatment, this patient had a history of class IV nephritis that later shifted to class V in two subsequent biopsies. The second patient presented with heavy proteinuria, haematuria and hypertension, indicating renal flare. Therefore, a clinical decision was made not to wait for a biopsy and instead to promptly initiate induction therapy with pulsed cyclophosphamide.
Associations between anti-dsDNA seroconversion and LN development
Of patients with positive anti-dsDNA levels at baseline and available follow-up data, no seroconversion was observed among those who developed LN (n = 8) in the BLM-treated group (n = 46) or de novo LN (n = 6) in the BLM-treated non-renal SLE group (n = 30), while 15 and 13 patients seroconverted among those who did not develop LN (n = 38; P = 0.040) or de novo LN (n = 24; P = 0.024), respectively. Of patients with low complement levels at baseline, one among those who developed de novo LN showed normalization during follow-up; no significant association between C3/C4 normalization and LN development was observed.
Predictors of LN development
The following variables were investigated using univariable Cox regression analysis: age at baseline, SLE disease duration, baseline SLEDAI-2K score, anti-dsDNA positivity, low complement (C3 and/or C4), serological activity (anti-dsDNA positivity and/or hypocomplementaemia), anti-Smith positivity, SDI score, current or former tobacco smoking, daily prednisolone dose, use of antimalarial agents, concomitant use of immunosuppressants, comorbid hypertension and diabetes, and history of renal involvement when all BLM-treated cases were analysed. From these variables, only use of antimalarial agents was negatively associated with development of LN when all BLM-treated patients were considered (coefficient: −0.6; HR: 0.2; 95% CI: 0.05, 0.86; P = 0.031) and with de novo LN when non-renal cases were considered (coefficient: −1.7; HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046).
Discussion
In our real-life setting of BLM-treated subjects, 9% of patients with no renal history developed de novo LN and 7% of patients with prior LN relapsed during treatment. Using age- and sex-matched non-renal comparators with similar serological profiles and a long follow-up, we showed that use of BLM was associated with an increased frequency of de novo LN. Interestingly, our data indicated that concomitant use of antimalarial agents along with BLM may be protective.
In 2014, de novo LN during BLM treatment was first reported in a serologically active middle-aged woman with relapsing serositis, resistant to conventional therapies, and unacceptable doses of corticosteroids [7]. Later, three patients who developed LN over the first year of BLM therapy were observed among 195 patients in 10 centres, mainly American [8]. Staveri et al. reported de novo LN shortly after BLM initiation in two women who had a moderately active non-renal SLE at baseline; one was anti-dsDNA negative [9]. Finally, one case of de novo LN was observed among 23 patients (4%) treated with BLM in a Spanish setting [10].
It is important to highlight that the majority of patients chosen for biologic therapy had a severe disease course, and had failed conventional disease-modifying non-biologic drugs, including the patients who developed de novo LN, of whom 5/6 had a long-standing disease (>7 years). A possible explanation for the development of de novo LN might be a more aggressive disease, as reflected by higher SLEDAI-2K scores and prednisolone doses in these patients; however, neither these features nor SDI scores, also a proxy for severe disease course, were associated with LN development. The non-renal SLE comparators were carefully selected to have similar serological profiles and age at enrolment, and were individually matched with the BLM-treated non-renal SLE patients. However, they had lower levels of disease activity, lower prednisolone doses and fewer patients required immunosuppressants. This reflects that the majority of patients in the comparator group were in a quiescent phase of their disease at the time of enrolment, but could also mirror an overall milder disease phenotype. Nevertheless, they were followed for a longer time compared with the BLM-treated patients, and the observed association between BLM and de novo LN was still present after adjustment for disease activity. Notably, in a subgroup of the comparators comprising 25 patients with comparable degree of activity to the BLM-treated group, none developed de novo LN during follow-up. The reasons behind the observed associations are not clear. Awareness of the steroid-sparing effects of belimumab may have contributed to rapid tapering of glucocorticoid doses, which in turn unveiled renal activity. Belimumab binds to the soluble counterpart of BAFF, a molecule implicated in the pathogenesis of LN [20, 21], and has been shown to alter absolute and relative numbers of B cell subsets, mainly B cells of early developmental stages [22, 23]. However, the long-term consequences of BAFF inhibition, e.g. regarding B cell subsets with regulatory properties, have yet to be determined. Such long-term effects on subsets of B cells could potentially increase the susceptibility of these patients to develop a more severe or organ-specific (renal) phenotype. Accumulating evidence indicates that B cells exert regulatory properties through production of IL-10 [24]. Hence, our recent observation of decreasing serum IL-10 levels during BLM treatment [25] may be suggestive of a regulatory B cell downregulation, collectively warranting granular survey of BLM-mediated effects on the B cell repertoire.
Another interesting finding was that concomitant use of antimalarial agents along with BLM was implied to be protective against the development of de novo LN or LN relapse. Although no firm conclusions can be drawn due to the relatively low number of patients and the known non-adherence of patients to antimalarials, this association is in line with the known beneficial effects of antimalarials that include prevention of renal flares [26] and is also of particular importance in light of a recent report that showed that decreasing levels of IgG and IgA anticardiolipin antibodies in BLM-treated patients were solely observed among those receiving antimalarials [27]. The mechanistic explanation for such a synergy remains to be elucidated. SLE patients using antimalarials have been shown to have lower BAFF levels compared with non-users [28]; while BLM binds to circulating BAFF, antimalarials are likely to hamper type I IFN-mediated BAFF excretion, potentially contributing to additive neutralization. Furthermore, antimalarials also bind nucleic acids, impeding Toll-like receptor activation and therefore innate immune responses, and inhibit loading of antigen into MHC and antigen presentation to T cells, both constituting further explanations for the additional benefit in patients in whom B cells are inhibited [29].
The observational design of our study constituted a limitation, yet the cases represent real-life use of BLM in our academic practices. The vast majority of study participants were of Caucasian origin, reflecting the patient population in Sweden and the UK, and the findings cannot be directly extrapolated to other populations, in particular African/African American or Asian patients. Another limitation was the relatively low number of patients who were enrolled and those who developed de novo LN and LN relapse, limiting the power in statistical analyses. Lastly, non-adherence assessment for background therapies was not performed.
Although firm conclusions cannot be drawn, our observations imply that BLM may not be sufficient for the prevention of LN and suggest close monitoring of BLM-treated patients for signs of evolving renal disease. Concomitant use of antimalarial agents may exert synergistic effects along with BLM with regard to renal outcomes, a finding that warrants corroboration in other settings. Investigation of the long-term effects of BAFF inhibition on B cell subsets with regulatory properties is merited.
Supplementary Material
keaa796_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Professor Elisabet Svenungsson for kindly reviewing the manuscript.
Funding: This work was supported by grants from the Alfred Österlund’s Foundation, the Anna-Greta Crafoord Foundation, the Greta and Johan Kock’s Foundation, the Gustafsson Foundation, the King Gustaf V and Queen Victoria’s Freemasons Foundation, the King Gustaf V’s 80-year Anniversary Foundation, the Professor Nanna Svartz Foundation, the Region Östergötland (ALF grants), the Selander Foundation, the Skåne University Hospital and the Medical Faculty of Lund University, the Swedish Research Council, the Swedish Rheumatism Association, and the Swedish Society of Medicine (the Ingegerd Johansson donation).
Disclosure statement: I.P. has received research funding from GlaxoSmithKline and Elli Lilly and Company, and honoraria from Gilead Sciences, GlaxoSmithKline and Novartis. E.M.V. has received honoraria and research grant support from Roche, GlaxoSmithKline and AstraZeneca. The other authors have declared no conflict of interest. The funders had no role in the design of the study; in the analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Data availability statement
The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.
Supplementary data
Supplementary data are available at Rheumatology online. | BELIMUMAB, HYDROXYCHLOROQUINE, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33341888 | 18,694,286 | 2021-09-01 |
What was the administration route of drug 'BELIMUMAB'? | De novo lupus nephritis during treatment with belimumab.
In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting.
Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0-34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3-151.2).
We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7-22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046).
Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.
pmc Rheumatology key messages
Irrespective of prior renal involvement, belimumab treatment may not adequately protect against lupus nephritis.
Concomitant antimalarial therapy along with belimumab was implied to protect against development of lupus nephritis.
Our observations call for vigilance with regard to evolving renal disease during belimumab therapy.
Introduction
SLE is a chronic, multisystem autoimmune disease with unmet needs, such as delayed diagnosis, premature atherosclerosis, drug-associated organ damage and a prominent impairment of health-related quality of life [1]. The wide range of manifestations and serological findings pose challenges with regard to diagnosis and treatment. Today, standard-of-care (SoC) therapy includes glucocorticoids, antimalarials, immunosuppressants and biologic agents, e.g. belimumab (BLM) and rituximab (RTX). The selection of drugs is mainly based on the afflicted organ systems and the organ-specific or global disease activity [2]. LN is a manifestation of SLE with a potentially life-threatening course [3].
BLM is a recombinant human IgG1-λ monoclonal antibody that specifically binds the soluble form of B cell activating factor (BAFF). The efficacy of BLM has been demonstrated to date in five placebo-controlled phase III trials and several observational studies [4]. Although post hoc analysis of clinical trials of BLM showed superiority of BLM over placebo in preventing renal flares [5] and a systematic review suggested an overall promising effect of BAFF inhibition on renal outcomes [6], development of LN during BLM treatment has also been reported [7–10]. Clinical trials of BLM in LN, either as an add-on therapy to SoC or in combination with RTX, are underway [11–13] and the BLISS-LN trial recently demonstrated superiority of addition of BLM to SoC for active LN over SoC alone [14].
We herein report cases of de novo LN during treatment with BLM observed in our academic practices, and cases of LN flares in patients with a history of renal SLE at the time of BLM initiation. We further aimed at identifying factors or risk phenotypes that are associated with the development of LN, in order to contribute to optimized monitoring during treatment with BLM.
Methods
Patients
Patients, classified with SLE according to the 1982 ACR [15] and/or 2012 SLICC [16] criteria, receiving BLM 10 mg/kg intravenously at week 0, 2, 4 and thereafter every fourth week from its approval in 2011 until 31 December 2017 in the Day Care Units of four Swedish academic rheumatology centres (Linköping, Lund, Stockholm and Uppsala) and one academic centre in Leeds, UK, were followed longitudinally within the frame of observational research programmes, and were included in the present report (n = 95). BLM was given as an add-on to background SoC, with no change in SoC implemented unless clinically indicated. None of these patients were given cyclophosphamide, RTX or other B cell depleting agents during treatment with BLM. No patient selection was applied other than consent to participate in the study. Sixty-six of these patients (69.5%) had no history of renal involvement until BLM initiation. As a comparator group to the non-renal SLE cases exposed to BLM, we included 66 non-renal SLE cases from Linköping and Stockholm, individually matched for age and sex, with similar serological profiles (anti-dsDNA positivity, low complement protein 3 and/or 4), who were also followed longitudinally; no selection other than matched serology and age at baseline was applied. Kidney biopsy was performed in the case of a suspected new onset of LN during follow-up. Patient characteristics are detailed in Table 1.
Table 1 Patient characteristics
Item Belimumab-treated SLE Non-renal SLE comparators P-value
Total Non-renal
Background variables
Number of cases, n 95 66 66
Age, mean (s.d.), years 42.2 (14.2) 42.2 (15.2) 43.4 (16.0) 0.152
Females, n (%) 89 (93.7) 63 (95.5) 63 (95.5) NA
Current tobacco smoking, n (%) 11 (12.5); n = 88 9 (15.0); n = 60 14 (21.2) 0.367
Former tobacco smoking, n (%) 25 (28.4); n = 88 14 (23.3); n = 60 23 (34.8) 0.047
Caucasian, n (%) 86 (90.5) 59 (89.4) 64 (97.0) NA
African, n (%) 6 (6.3) 5 (7.6) 0 (0.0) NA
Asian, n (%) 2 (2.1) 2 (3.0) 2 (3.0) NA
Hispanic, n (%) 1 (1.1) 0 (0.0) 0 (0.0) NA
Diabetes until enrolment, n (%) 3 (3.2) 0 (0.0) 0 (0.0) NA
Hypertension until enrolment, n (%) 23 (24.2) 9 (13.6) 14 (21.2) 0.332
Disease variables at enrolment
Duration of SLE, mean (s.d.), years 11.4 (9.3) 10.5 (9.1) 9.8 (11.1)d 0.529
SLEDAI-2K score, mean (s.d.) 9.3 (5.9) 8.2 (4.7) 4.9 (3.7) <0.001
SDI score, median (IQR) 1 (0–1); n = 93 0 (0–1); n = 64 0 (0–2) 0.594
Serological activitya, n (%) 68 (71.6) 47 (71.2) 50 (75.8) 0.250
Anti-dsDNA positive, n (%) 50 (52.6) 33 (50.0) 34 (51.5) 1.000
Low complement, n (%) 57 (60.0) 40 (60.6) 41 (62.1) 1.000
Anti-Smith positive, n (%) 24 (25.3) 16 (24.2) 14 (21.2) 0.832
Main reasons for belimumab
General, n (%) 4 (4.2) 3 (4.5) NA NA
Mucocutaneous, n (%) 55 (57.9) 39 (59.1) NA NA
Musculoskeletal, n (%) 54 (56.8) 39 (59.1) NA NA
Haematological, n (%) 12 (12.6) 8 (12.1) NA NA
Cardiorespiratory, n (%) 6 (6.3) 4 (6.1) NA NA
Renal, n (%) 9 (9.5) 0 (0.0) NA NA
Neurological, n (%) 5 (9.5) 2 (3.0) NA NA
Immunological, n (%) 3 (3.2) 2 (3.0) NA NA
Ongoing concomitant treatments
Daily prednisolone doseb, mean (s.d.), mg 11.3 (9.4) 11.1 (9.4) 7.3 (12.1)e 0.004
Antimalarial agents, n (%) 67 (70.5) 45 (68.2) 36 (54.5) 0.137
Immunosuppressantsc, n (%) 58 (61.1) 40 (60.6) 21 (31.8) 0.002
Azathioprine, n (%) 27 (28.4) 17 (25.8) 6 (9.1) 0.013
Methotrexate, n (%) 14 (14.7) 11 (16.7) 8 (12.1) 0.629
Mycophenolate mofetil/sodium, n (%) 14 (14.7) 11 (16.7) 3 (4.5) 0.057
Other immunosuppressants, n (%) 4 (6.8) 2 (3.0) 5 (7.6) 0.375
In cases of missing values, the total number of available observations (n) is indicated. P-values are derived from comparisons between non-renal SLE patients who were treated with belimumab and individually matched for age and sex non-renal SLE comparators who were not treated with belimumab, using Wilcoxon’s signed rank test for continues variables and McNemar’s test for dichotomous variables, or the χ2 test in cases of missing values in one of the two groups. Significant P-values are indicated in bold. aAnti-dsDNA positivity and/or low complement levels. bAt the time of belimumab initiation or enrolment for the comparators. cExcluding antimalarial agents. dMedian (IQR): 6.4 (0.5–13.4) years. eMedian (IQR): 5.0 (0.0–10.0) mg. IQR: interquartile range; NA: not applicable or not available; SDI: SLICC/ACR Damage Index.
Definitions
We defined de novo LN as a new onset of significant proteinuria, defined as a urinary protein-to-creatinine ratio or protein excretion in 24-h urine collection corresponding to >0.5 g/day, combined with renal histology consistent with LN according to the WHO and/or 2003 International Society of Nephrology/Renal Pathology Society classification [17], in patients who previously had not met the ACR criterion for renal disorder [15].
Global SLE disease activity was evaluated using the SLEDAI-2K [18], and organ damage using the SLICC/ACR Damage Index (SDI) [19]. For SLEDAI-2K scores, laboratory and serological items were assessed based on results from routine tests at the local university hospital laboratories.
Statistics
Comparisons between matched non-renal SLE patients who received BLM vs those who did not were performed using Wilcoxon’s signed rank test for continuous and McNemar’s test for dichotomous variables. The occurrence of de novo LN or LN flares during follow-up was illustrated using Kaplan–Meier curves, and the pairwise log-rank (Mantel–Cox) test was employed to compare the de novo LN distributions between BLM exposed vs not exposed non-renal SLE patients. Contingency between unrelated dichotomous variables was tested using Fisher’s exact test. Proportional hazards (Cox) regression was used to investigate factors and disease phenotypes associated with LN development during therapy. P-values<0.05 were considered statistically significant. IBM SPSS version 25 software (IBM Corp., Armonk, NY, USA) was used for statistical analyses and GraphPad Prism 7 (GraphPad Software Inc., La Jolla, CA, USA) for construction of graphs.
Ethical considerations
The study complied with the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from all patients. The study protocol was approved by regional ethics review boards.
Results
Outcome of cases without prior LN
As shown in Table 1, non-renal SLE patients who were selected for treatment with BLM had comparable serological profiles, disease duration and SDI scores but higher baseline SLEDAI-2K scores [mean (s.d.): 8.2 (4.7)] than age- and sex-matched non-renal SLE controls [4.9 (3.7); P < 0.001]. Accordingly, they were on higher daily prednisolone doses [11.1 (9.4) vs 7.3 (12.1) mg; P = 0.004] and a higher proportion within BLM-treated non-renal SLE patients used immunosuppressants (60.6%) compared with the controls (31.8%; P = 0.002), but the proportions of patients using antimalarial agents did not differ significantly (P = 0.137). Use of immunosuppressants and antimalarials for the controls during the entire follow-up period is delineated in Supplementary Figs S1 and S2 (available at Rheumatology online), respectively.
Six patients (9.1%) developed a biopsy-proven de novo LN in the BLM-treated non-renal SLE group after a median follow-up time of 7.4 (IQR: 2.7–22.2) months. Among the comparators, two individuals (3.0%) developed de novo LN, one class III and one class IV after 21 and 50 months, respectively.
In the six patients who developed de novo LN, all Caucasians, BLM was primarily initiated for active mucocutaneous and/or musculoskeletal disease. All had positive anti-dsDNA levels and were hypocomplementaemic at baseline. At BLM initiation, SLEDAI-2K scores ranged from 6 to 23, and the daily prednisolone dose from 7.5 to 30 mg. Only 2/6 patients were on concomitant treatment with antimalarials. The renal histopathology in 4/6 subjects was consistent with proliferative LN (class III or IV), whereas the two remaining cases showed membranous LN (class V) in combination with class II. Detailed information is shown in Supplementary Table S1, available at Rheumatology online.
As illustrated in Fig. 1A, non-renal SLE patients treated with BLM showed a higher frequency of and/or shorter time to de novo LN compared with non-renal SLE patients who did not receive BLM (hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012). This association between BLM treatment and de novo LN development remained significant after adjustment for SLEDAI-2K scores (HR: 8.3; 95% CI: 1.2, 57.0; P = 0.031), while no such association was seen for SLEDAI-2K scores as a co-variate in the same model (HR: 1.1; 95% CI: 0.9, 1.2; P = 0.362). The Kaplan–Meier curve in Fig. 1B illustrates the course of BLM-treated patients with and without a history of renal SLE at BLM initiation, as well as the non-renal comparators, until the time of LN development or the last available evaluation.
Fig. 1 Development of LN in BLM-treated patients and unexposed comparators
(A) Bar graph showing proportions of patients who developed de novo LN within the BLM-treated non-renal patient subgroup (red) and age- and sex-matched comparators not exposed to BLM (blue). The forest plot above illustrates the result from Cox regression analysis, with the dark blue circle representing the HR and the whiskers representing the 95% CI. (B) Kaplan–Meier curve illustrating the course of BLM-treated cases with (green) and without (red) a history of LN at the time of treatment initiation, and the non-renal SLE comparators (blue), until the time of LN development or the last available follow-up evaluation. BLM: belimumab; HR: hazard ratio.
Next, we selected patients not exposed to BLM with baseline SLEDAI-2K scores >4, which yielded a control group with comparable SLEDAI-2K scores [8.5 (3.2); n = 25] to the non-renal BLM group. None of the patients within this group had developed LN after a mean follow-up of 126.5 (37.8) months.
Outcome of cases with previous LN
Among the 29/95 BLM-treated patients with LN prior to enrolment, but quiescent renal disease at the time of BLM initiation, two cases (6.9%) of LN flare were observed after 1 and 9 months (Fig. 1B). One of these patients underwent a renal biopsy that showed a proliferative LN (class IV); prior to BLM treatment, this patient had a history of class IV nephritis that later shifted to class V in two subsequent biopsies. The second patient presented with heavy proteinuria, haematuria and hypertension, indicating renal flare. Therefore, a clinical decision was made not to wait for a biopsy and instead to promptly initiate induction therapy with pulsed cyclophosphamide.
Associations between anti-dsDNA seroconversion and LN development
Of patients with positive anti-dsDNA levels at baseline and available follow-up data, no seroconversion was observed among those who developed LN (n = 8) in the BLM-treated group (n = 46) or de novo LN (n = 6) in the BLM-treated non-renal SLE group (n = 30), while 15 and 13 patients seroconverted among those who did not develop LN (n = 38; P = 0.040) or de novo LN (n = 24; P = 0.024), respectively. Of patients with low complement levels at baseline, one among those who developed de novo LN showed normalization during follow-up; no significant association between C3/C4 normalization and LN development was observed.
Predictors of LN development
The following variables were investigated using univariable Cox regression analysis: age at baseline, SLE disease duration, baseline SLEDAI-2K score, anti-dsDNA positivity, low complement (C3 and/or C4), serological activity (anti-dsDNA positivity and/or hypocomplementaemia), anti-Smith positivity, SDI score, current or former tobacco smoking, daily prednisolone dose, use of antimalarial agents, concomitant use of immunosuppressants, comorbid hypertension and diabetes, and history of renal involvement when all BLM-treated cases were analysed. From these variables, only use of antimalarial agents was negatively associated with development of LN when all BLM-treated patients were considered (coefficient: −0.6; HR: 0.2; 95% CI: 0.05, 0.86; P = 0.031) and with de novo LN when non-renal cases were considered (coefficient: −1.7; HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046).
Discussion
In our real-life setting of BLM-treated subjects, 9% of patients with no renal history developed de novo LN and 7% of patients with prior LN relapsed during treatment. Using age- and sex-matched non-renal comparators with similar serological profiles and a long follow-up, we showed that use of BLM was associated with an increased frequency of de novo LN. Interestingly, our data indicated that concomitant use of antimalarial agents along with BLM may be protective.
In 2014, de novo LN during BLM treatment was first reported in a serologically active middle-aged woman with relapsing serositis, resistant to conventional therapies, and unacceptable doses of corticosteroids [7]. Later, three patients who developed LN over the first year of BLM therapy were observed among 195 patients in 10 centres, mainly American [8]. Staveri et al. reported de novo LN shortly after BLM initiation in two women who had a moderately active non-renal SLE at baseline; one was anti-dsDNA negative [9]. Finally, one case of de novo LN was observed among 23 patients (4%) treated with BLM in a Spanish setting [10].
It is important to highlight that the majority of patients chosen for biologic therapy had a severe disease course, and had failed conventional disease-modifying non-biologic drugs, including the patients who developed de novo LN, of whom 5/6 had a long-standing disease (>7 years). A possible explanation for the development of de novo LN might be a more aggressive disease, as reflected by higher SLEDAI-2K scores and prednisolone doses in these patients; however, neither these features nor SDI scores, also a proxy for severe disease course, were associated with LN development. The non-renal SLE comparators were carefully selected to have similar serological profiles and age at enrolment, and were individually matched with the BLM-treated non-renal SLE patients. However, they had lower levels of disease activity, lower prednisolone doses and fewer patients required immunosuppressants. This reflects that the majority of patients in the comparator group were in a quiescent phase of their disease at the time of enrolment, but could also mirror an overall milder disease phenotype. Nevertheless, they were followed for a longer time compared with the BLM-treated patients, and the observed association between BLM and de novo LN was still present after adjustment for disease activity. Notably, in a subgroup of the comparators comprising 25 patients with comparable degree of activity to the BLM-treated group, none developed de novo LN during follow-up. The reasons behind the observed associations are not clear. Awareness of the steroid-sparing effects of belimumab may have contributed to rapid tapering of glucocorticoid doses, which in turn unveiled renal activity. Belimumab binds to the soluble counterpart of BAFF, a molecule implicated in the pathogenesis of LN [20, 21], and has been shown to alter absolute and relative numbers of B cell subsets, mainly B cells of early developmental stages [22, 23]. However, the long-term consequences of BAFF inhibition, e.g. regarding B cell subsets with regulatory properties, have yet to be determined. Such long-term effects on subsets of B cells could potentially increase the susceptibility of these patients to develop a more severe or organ-specific (renal) phenotype. Accumulating evidence indicates that B cells exert regulatory properties through production of IL-10 [24]. Hence, our recent observation of decreasing serum IL-10 levels during BLM treatment [25] may be suggestive of a regulatory B cell downregulation, collectively warranting granular survey of BLM-mediated effects on the B cell repertoire.
Another interesting finding was that concomitant use of antimalarial agents along with BLM was implied to be protective against the development of de novo LN or LN relapse. Although no firm conclusions can be drawn due to the relatively low number of patients and the known non-adherence of patients to antimalarials, this association is in line with the known beneficial effects of antimalarials that include prevention of renal flares [26] and is also of particular importance in light of a recent report that showed that decreasing levels of IgG and IgA anticardiolipin antibodies in BLM-treated patients were solely observed among those receiving antimalarials [27]. The mechanistic explanation for such a synergy remains to be elucidated. SLE patients using antimalarials have been shown to have lower BAFF levels compared with non-users [28]; while BLM binds to circulating BAFF, antimalarials are likely to hamper type I IFN-mediated BAFF excretion, potentially contributing to additive neutralization. Furthermore, antimalarials also bind nucleic acids, impeding Toll-like receptor activation and therefore innate immune responses, and inhibit loading of antigen into MHC and antigen presentation to T cells, both constituting further explanations for the additional benefit in patients in whom B cells are inhibited [29].
The observational design of our study constituted a limitation, yet the cases represent real-life use of BLM in our academic practices. The vast majority of study participants were of Caucasian origin, reflecting the patient population in Sweden and the UK, and the findings cannot be directly extrapolated to other populations, in particular African/African American or Asian patients. Another limitation was the relatively low number of patients who were enrolled and those who developed de novo LN and LN relapse, limiting the power in statistical analyses. Lastly, non-adherence assessment for background therapies was not performed.
Although firm conclusions cannot be drawn, our observations imply that BLM may not be sufficient for the prevention of LN and suggest close monitoring of BLM-treated patients for signs of evolving renal disease. Concomitant use of antimalarial agents may exert synergistic effects along with BLM with regard to renal outcomes, a finding that warrants corroboration in other settings. Investigation of the long-term effects of BAFF inhibition on B cell subsets with regulatory properties is merited.
Supplementary Material
keaa796_Supplementary_Data Click here for additional data file.
Acknowledgements
We thank Professor Elisabet Svenungsson for kindly reviewing the manuscript.
Funding: This work was supported by grants from the Alfred Österlund’s Foundation, the Anna-Greta Crafoord Foundation, the Greta and Johan Kock’s Foundation, the Gustafsson Foundation, the King Gustaf V and Queen Victoria’s Freemasons Foundation, the King Gustaf V’s 80-year Anniversary Foundation, the Professor Nanna Svartz Foundation, the Region Östergötland (ALF grants), the Selander Foundation, the Skåne University Hospital and the Medical Faculty of Lund University, the Swedish Research Council, the Swedish Rheumatism Association, and the Swedish Society of Medicine (the Ingegerd Johansson donation).
Disclosure statement: I.P. has received research funding from GlaxoSmithKline and Elli Lilly and Company, and honoraria from Gilead Sciences, GlaxoSmithKline and Novartis. E.M.V. has received honoraria and research grant support from Roche, GlaxoSmithKline and AstraZeneca. The other authors have declared no conflict of interest. The funders had no role in the design of the study; in the analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Data availability statement
The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.
Supplementary data
Supplementary data are available at Rheumatology online. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33341888 | 18,692,184 | 2021-09-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cellulitis'. | Safe and Effective Chin Augmentation With the Hyaluronic Acid Injectable Filler, VYC-20L.
VYC-20L is a hyaluronic acid soft tissue filler with lidocaine designed to restore facial volume.
Evaluate the safety and effectiveness of VYC-20L in patients with chin retrusion.
Adults with chin retrusion were randomized (3:1) to receive VYC-20L in the chin at study onset (treatment group) or 6 months later (control group). The primary effectiveness end point was ≥1-point improvement on the Allergan Chin Retrusion Scale (ACRS) from baseline at Month 6. Safety assessments included injection site responses (ISRs) and adverse events (AEs).
VYC-20L was administered to 192 participants (treatment group, n = 144; control group, n = 48). At Month 6, significantly more participants had an ACRS response in the treatment versus control group (56.3% vs 27.5%; p = .0019). Effectiveness was also demonstrated by the proportion of participants with improved/much improved Global Aesthetic Improvement Scale scores and responses on the FACE-Q Satisfaction with Chin questionnaire and FACE-Q Psychological Wellbeing module. Treatment benefit remained evident at Month 12. Most common ISRs were tenderness (81.1%) and firmness (75.1%). One participant (0.5%) discontinued the study due to 2 treatment-related serious AEs of facial cellulitis and injection site inflammation, both resolved without sequelae.
VYC-20L significantly improved an ACRS response and was generally safe and well tolerated.
Hyaluronic acid (HA) injectable gels are a proven treatment for facial rejuvenation with an established record of safety and effectiveness.1 In 2018, more than 2.1 million HA injectable filler procedures were performed in the United States—a 48% increase over the past decade.2,3 The FDA has approved a range of dermal and subcutaneous indications for HA injectable fillers, including facial wrinkles, folds, lip augmentation, and cheeks.4 One such product, VYC-20L (Juvéderm Voluma XC; Allergan plc, Dublin, Ireland), which is a 20-mg/mL HA gel with lidocaine, was specifically designed for volumizing and has demonstrated effectiveness in restoring age-related volume deficit to the midface.5 Compared with HA gels designed for correction of wrinkles and folds, VYC-20L improved qualities of lift and projection to the midface.
In addition to the midface, the chin area is another facial region where lift and projection are important aspects of volumizing. The chin is defined by the labiomental crease (superiorly), the oral commissures (laterally), and the submental cervical crease (inferiorly). The shape and projection of the chin contribute to a “well-balanced and harmonious” face.6 For both men and women, good chin projection and a youthful jawline are considered the standards of beauty7 and can influence an individual's psychosocial well-being.8 Although congenital elements are the predominant factor in chin aesthetics, aging can result in bony resorption and produce sagging9 as well as laxity and droop in the chin area.10 In addition, aging can result in lumps, bulges, and depressions in the prejowl sulci.11
VYC-20L is a temporary HA soft tissue filler developed to provide a safe, minimally invasive method to restore facial volume, which is also reversible by hyaluronidase in case of adverse events (AEs) requiring treatment.5,12 It is currently indicated in the United States for injection into the subcutaneous and/or supraperiosteal space of the midface to add volume in the cheek area and is approved in other countries for facial volumizing, including the chin and prejowl sulci.5,12–16 As the chin and prejowl sulci are high-mobility areas, VYC-20L represents an ideal option for its volumizing and lifting capabilities. This study was designed to collect effectiveness and safety data for VYC-20L in participants seeking to correct volume deficit and retrusion in the chin and prejowl sulci.
Methods
Study Design
This multicenter, randomized, evaluator-blinded, delayed treatment-controlled study was designed to evaluate the safety and effectiveness of VYC-20L injectable gel for correction of chin volume deficit. A no-treatment control was used because there were no FDA-approved soft tissue fillers for chin augmentation at the time of the study. Participants were randomized in a 3:1 ratio either to have treatment with VYC-20L (treatment group) or a 6-month control period, followed by optional treatment (control group). At the Month 12 visit, participants in the treatment group had the option of receiving repeat treatment, with routine follow-up visits for safety and effectiveness through 1 month after repeat treatment. Treated control group participants were only followed for safety, and no effectiveness measures were performed. Participants underwent a touch-up treatment 30 days after initial treatment to achieve optimal correction if needed. The study was conducted at 14 sites in the United States, each of which had a treating investigator (TI) and at least one blinded evaluating investigator (EI).
The TIs performed the treatments and monitored participant safety throughout the study. Blinded EIs performed all effectiveness assessments. For treatment, the TI used 27 G 1/2 -inch needles for supraperiosteal and/or subcutaneous injections into the pogonion, menton, and prejowl sulci; 25 G 1½-inch cannulas were permitted for supraperiosteal and/or subcutaneous injections in the menton and prejowl sulci. An appropriate injection volume for the chin and chin area was determined by the TI but was not to exceed a maximum total volume of 4.0 mL for initial and touch-up treatments combined and 4.0 mL for repeat treatment. After each treatment, participants completed a daily safety diary for up to 30 days. Visits for both effectiveness and safety occurred at months 1, 3, 6, 9, and 12 after the last treatment.
Participants were required to be aged 22 or older and desire chin augmentation to correct moderate or severe chin retrusion (Grades 2 or 3 on the validated 5-point photonumeric Allergan Chin Retrusion Scale [ACRS]) as determined by a live assessment by both the EI and TI. Participants were ineligible if they had undergone cosmetic facial plastic surgery, tissue grafting, or tissue augmentation with silicone, fat, or permanent dermal fillers; had clinically significant malocclusion (severe overbite); had dentures; any device covering the palate; tattoos; piercings; facial hair; or scars that would interfere with visual assessment of the chin area. Mandatory facial treatment washout periods before study entry were 36 months for semipermanent dermal fillers, 24 months for dermal fillers in the chin or jaw area, 12 months for dermal fillers in the lips or perioral area, and 6 months for mesotherapy, botulinum toxin below the subnasale, or cosmetic treatment (laser, photomodulation, intense pulsed light, radiofrequency, dermabrasion, chemical peel, liposuction, lipolysis, or other ablative procedures). Applicable institutional review boards approved the study protocol, and all participants provided written informed consent before study enrolment (www.clinicaltrials.gov, identifier NCT02833077).
Response Measures and Statistics
The primary end point was based on the EI's blinded assessment of overall chin retrusion using ACRS grades defined as none (0), minimal (1), moderate (2), severe (3), and extreme (4) (See Supplemental Digital Content, Table S1, http://links.lww.com/DSS/A543). The primary effectiveness measure used a profile-view image cropped to include only the participant's lower face for ACRS assessment, which is based on the relationship between facial anatomical landmarks. Photograph assessments, rather than live assessments, facilitated consistent head positioning and were intended to help raters assess the relationship between landmarks. A participant showing ≥1-point improvement (decrease) in an ACRS score compared with baseline was considered a responder. The primary evaluation timepoint for efficacy was Month 6 after last treatment for participants in the treatment group and Month 6 after randomization for participants in the control group (untreated). The primary effectiveness end point was met if the treatment group responder rate was statistically greater (>50%) than the control group at Month 6 based on a 2-sided Fisher's exact test with a 5% significance level.
The Global Aesthetic Improvement Scale (GAIS), as well as the Satisfaction with Chin and Psychosocial Well-Being modules of the FACE-Q questionnaire, was used for assessment of secondary effectiveness end points. For the GAIS, responder rates for the treatment group (with 95% exact confidence intervals [CIs]) were based on EI and participant assessments. A “responder” was a participant who showed improvement (i.e., improved or much improved) on the overall aesthetic assessment in the chin area at the Month 6 visit. For the Satisfaction with Chin module of the FACE-Q questionnaire, the change from baseline to Month 6 visit in overall scores and a 2-sided paired t-test at the 5% level were used to demonstrate that the mean overall satisfaction score at the Month 6 visit was statistically greater than baseline for the treatment group. Volume change from baseline was measured by a blinded Canfield image analysis technician from three-dimensional (3D) imaging of the participant's facial profile pretreatment and post-treatment for both the treatment and control groups at the 6 Month visit.
Participants
A total of 221 participants were enrolled in the study, with an average of 14 (range 11–21) per investigational site. A total of 192 participants were randomized after 29 participants were screen failures, resulting in 144 in the treatment group and 48 in the control group. One hundred sixty-nine participants (88.0%) completed the Month 6 visit and 167 participants (87.0%) completed the study, with 25 participants (13.0%) discontinuing after randomization. Eighty-eight participants received touch-up treatment and 74 received repeat treatment. For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment. All initial and touch-up treatments occurred between June 28, 2016, and January 25, 2018, and all repeat treatments occurred between July 11, 2017, and August 23, 2018. The treatment and control groups were similar in terms of all demographic and baseline characteristics (See Supplemental Digital Content, Table S2, http://links.lww.com/DSS/A544). Among the 192 enrolled participants, the majority were women (88.5%) and White (81.8%), with a median age at study entry of 52 years (range, 22–80) and mean body mass index of 25.0 kg/m2. Fitzpatrick skin types were I/II (34.9%), III/IV (52.1%), and V/VI (13.0%).
Treatment
Anesthesia was administered to 75.0% (108/144) of participants in the treatment group, with the most common being topical (69.4%, 75/108; median duration 29.0 minutes) while ice was less common (34.3%, 37/108; median duration 15.0 minutes). The primary plane of injection used during the initial treatment was supraperiosteal (99.3%), followed by subcutaneous (63.0%). At touch-up and repeat treatments, the most common injection planes were also supraperiosteal (90.9% and 100.0%, respectively) and subcutaneous (53.4% and 59.5%, respectively). Planes and techniques were similar for the treated control participants. 99.3% of treatment group participants were treated in the pogonion, 77.8% in the menton, and 87.5% in the prejowl sulci. At the touch-up visit, 78.4% of treatment group participants were treated in the pogonion, 52.3% in the menton, and 65.9% in the prejowl sulci. At the repeat treatment visit, 93.2% were treated in the pogonion, 56.8% in the menton, and 66.2% in the prejowl sulci.
Needles were used for 100% of participants, and cannulas were used for 25.0% at initial treatment. There were no cannula/needle malfunctions. Treatment administration was similar for the treated control participants. Treating investigators rated ease of injection and product moldability on an 11-point scale, difficult (0) to easy (10), and stiff (0) to moldable (10), respectively. A total of 66.0% and 21.5% of participants were scored as 10 and 9, respectively, for ease of injection, whereas 62.5% and 20.8% of participants were scored as 10 and 9, respectively, for product moldability.
In the treatment group, 144 participants received initial treatment, 88 received touch-up treatment, and 74 received repeat treatment (Table 1). For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment, with injection volumes similar to the treatment group. The median total initial injection volume was 2.2 mL (range, 0.7–4.0 mL) for the treatment group (initial treatment and touch-up combined) and 2.8 mL (range, 1.3–4.0 mL) for the treated control group (initial treatment and touch-up combined). The median total injection volume for repeat treatment was 1.2 mL (range, 0.2–4.0 mL).
TABLE 1. Injection Volumes (Safety Population)
Total Volume Injected Treatment (N = 144) Control (N = 48)
Initial treatment volume (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 1.9 (0.6) 2.1 (0.6)
Median (range) 2 (0.7–4.0) 2 (1.0–3.8)
Initial/touch-up treatment volume combined (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 2.6 (1.0) 2.7 (0.8)
Median (range) 2.2 (0.7–4.0) 2.8 (1.3–4.0)
Repeat treatment volume (mL)
Received treatment, n (%) 74 (51.4) 0 (0.0)
Mean (SD) 1.4 (0.8) N/A
Median (range) 1.2 (0.2–4.0) N/A
For the control group, data after receiving initial treatment at Month 6 are included.
Results
Effectiveness
The primary efficacy end point was met with 56.3% ACRS responders (photograph assessment) at Month 6, which was greater than 50% and significantly greater than the responder rate for the untreated control group (27.5%, p = .0019) (Table 2). In addition, the ACRS responder rate in the treatment group was 70.1% at Month 1, 57.6% at Month 12, and 73.9% at Month 1 after repeat treatment (See Supplemental Digital Content, Figure S1, http://links.lww.com/DSS/A539). The median ACRS scores improved by a median of 1 point from a baseline score of 3 in the treatment group, whereas the control group remained at a score of 2.5. Notably, the Month 6 responder rate from the EI live assessment was markedly higher than results from the photograph assessment with 91.8% for the treatment group and 23.3% for the control group, a difference of 68.42% (p < .0001).
TABLE 2. Allergan Chin Retrusion Scale Results at Month 6 (Modified Intent-to-Treat Population)
Treatment (N = 144) Control (N = 48)
Month 6
Total participants, n* 126 40
Responder, n (%) 71 (56.3) 11 (27.5)
Nonresponder, n (%) 55 (43.7) 29 (72.5)
95% CI (%)† (47.23–65.16) (14.60–43.89)
Versus control
Responder rate difference, % 28.85
95% CI (%)‡ 11.16–45.60
p-value§ 0.0019
For the untreated control group, data before receiving initial treatment at Month 6 are included.
* Participants with analysis values at baseline and the specified visit.
† 95% CI is based on the exact binomial distribution.
‡ 95% exact CI for the responder rate difference is presented.
§ p-value is based on 2-sided Fisher's exact test comparing the responder rate between treated and untreated control.
On the GAIS, EIs rated 91.2% (114/125) as “improved” or “much improved” in the treatment group and 19.5% (8/41) in the untreated control group at Month 6 (See Supplemental Digital Content, Figure S2, http://links.lww.com/DSS/A540). The treatment group responder rate remained high from Month 1 (94.0%) through Month 12 (91.2%) along with an increase at Month 1 after repeat treatment (98.6%; 70/71). The percentage of responders rated as “much improved” in the treatment group was notably high, with 61.6% at Month 6, 41.6% at Month 12, and 77.5% at Month 1 after repeat treatment. The participant self-evaluation on the GAIS was consistent with the EI assessments with most participants in the treatment group (87.3%; 110/126) rating as “improved” or “much improved” at Month 6. The treatment group responder rate remained high from Month 1 (95.5%) through Month 12 (82.4%) and was 97.1% at Month 1 after repeat treatment, similar to EI assessments. In addition, the mean change in chin volume assessed by 3D digital imaging showed a similar trend with (+)2.6 mL at Month 1, 2.4 mL Month 6, 2.2 cc at Month 12, and 3.9 cc at Month 1 after repeat treatment in the treatment group and 0.1 cc in the untreated control group.
The FACE-Q Satisfaction with Chin overall mean score for the treatment group was 34.9 at baseline and improved by a mean of 35.6 to a score of 71.3 at Month 6 (p < .001), whereas the mean score worsened by a mean of 3.3 from a baseline score of 35.1 for the untreated control group (See Supplemental Digital Content, Figure S3, http://links.lww.com/DSS/A541). The mean scores remained high from Month 1 (74.8) to Month 12 (66.4) and at Month 1 after repeat treatment (77.5).
The FACE-Q Psychological Well-Being overall mean score was 69.9 at baseline and improved by a mean of 15.4 at Month 6 for the treatment group, whereas the mean score worsened by a mean of −5.3 from 72.3 at Month 6 in the untreated control group (See Supplemental Digital Content, Figure S4, http://links.lww.com/DSS/A542). Most treatment group participants reported that they definitely/somewhat agree with each of the 10 individual FACE-Q Psychological Well-Being items at all timepoints, indicating positive well-being.
Safety
For initial/touch-up treatment, 14 treated participants (7.7%) had 20 treatment-related AEs (Table 3) while 3 (4.1%) had 7 treatment-related AEs after repeat treatment (See Supplemental Digital Content, Table S3, http://links.lww.com/DSS/A545). During the repeat treatment period, an injection site mass occurred in 2 participants (2.7%). The most common treatment-related AEs for the initial/touch-up treatment period were injection site erythema (1.6%, 3/182 participants) and injection site pain (1.6%, 3/182 participants). There were no deaths or unanticipated adverse effects. Facial sensation assessments found that treatment did not reduce chin area sensitivity at any timepoint throughout the study.
TABLE 3. Common Treatment-Related Adverse Events (AEs) After Initial/Touch-Up Treatment
Event, n Onset (d) Duration (d) Severity Resolution
Injection site abscess 6 9 Moderate Resolved w/o sequelae
Gingival pain 1 2 Moderate Resolved w/o sequelae
Acne cystic 6 134 Mild Resolved w/o sequelae
Injection site cellulitis 7 36 Severe Resolved w/o sequelae
Injection site inflammation 7 153 Severe Resolved w/o sequelae
w/o, without.
The type and frequency of injection site responses (ISRs) were similar in treatment group participants and treated control participants and are considered to be commonly reported events after treatment with HA soft tissue fillers (See Supplemental Digital Content, Table S4, http://links.lww.com/DSS/A546). Overall, 167 treated participants (92.3%) reported at least 1 ISR after initial treatment, 86 (82.7%) after touch-up treatment, and 55 (75.3%) after repeat treatment. The most frequently reported ISRs after initial treatment included tenderness to touch (81.8%), firmness (75.1%), and swelling (68.5%). Similar results were seen after repeat treatment, where the most common ISRs were also tenderness to touch (71.2%), firmness (69.9%), and swelling (58.9%). Most ISRs were mild or moderate in severity after initial, touch-up, and repeat treatment and resolved within 1 week based on total days from first to last occurrence according to the diaries. Participants assessed procedural pain (pain during injection) immediately after completion of each treatment on an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) and reported minimal pain, with a mean score of 2.3 for the treatment group at each treatment (initial, touch-up, and repeat).
Most treatment-related AEs were mild or moderate in severity (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 2.7% (5/182) of participants had mild treatment-related AEs and 4.4% (8/182) had moderate AEs. For repeat treatment, 4.1% (3/74) of participants had mild and 1.4% (1/74) moderate AEs. Two participants (1.1%) had 3 severe treatment-related AEs, including injection site inflammation and cellulitis in one participant and injection site induration in another participant.
Most treatment-related AEs resolved within 1 week (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 3 participants (1.6%) had 4 treatment-related AEs that lasted longer than 30 days. The first participant had injection site inflammation that lasted 153 days and injection site cellulitis that lasted 36 days. Treatment consisted of antibiotics, anti-inflammatories, and hyaluronidase. These 2 events were considered to be serious AEs. A second participant had injection site erythema that lasted 264 days. A third participant had an acne cyst that lasted 134 days. For repeat treatment, 1 participant (1.4%) had an injection site mass that lasted 42 days. Most treatment-related AEs began within 7 days of treatment. There were no treatment-related AEs that began >30 days after repeat treatment. All treatment-related AEs resolved without sequelae during the study period.
A lower incidence of ISRs was observed for injections with a cannula than without a cannula after initial touch-up and repeat treatments (See Supplemental Digital Content, Table S6, http://links.lww.com/DSS/A548). For initial/touch-up treatment with a cannula, 2 treated participants (4.5%) had 2 treatment-related AEs; without a cannula, 12 treated participants (8.7%) had 18 treatment-related AEs. For repeat treatment with a cannula, there were no treatment-related AEs; without a cannula, 3 treated participants (5.6%) had 7 treatment-related AEs.
Discussion
Although the primary end point was met, the ACRS responder rate of 56.3% was lower than expected. Comparatively, the midface study met its primary end point at Month 6, with 85.6% of treated participants having a clinically meaningful improvement.5 A possible reason for this discrepancy is the markedly higher injection volumes used in the midface study. This study used lower volumes, more closely representative of volumes used in real-world clinical practice. Another potential reason for this discrepancy is the different methods of evaluation. The midface study relied on live assessments, taking into account overall improvement. This study's assessment was limited to 2-dimensional cropped photographs, possibly obscuring a treatment effect because it relates to the whole face. This hypothesis is supported by the notably higher responder rate of 91.8% observed from the EI live assessments, which are more in line with the high responses observed with the GAIS and FACE-Q measures. Another supportive observation is the control responder rate at Month 6, which was observably lower in this study compared with the midface study, 27.5% versus 38.9%, respectively, indicating a lower false-positive rate.5 Although photograph assessments, rather than live assessments, were intended to help raters more consistently assess the relationship between landmarks, the use of cropped photographs as a primary measure may represent a study limitation. Other study limitations may have included the single-blind design, which left participants and injectors unblinded, and that control data were only available through month 6, although data could still be compared with baseline beyond Month 6.
VYC-20L was well tolerated, with most treatment-related AEs being ISRs of mild to moderate severity. Notably, there was an overall decrease in the number of AEs with repeat treatment compared with initial/touch-up treatment. One possibility is the lower volume injected during repeat treatment. Lower AE rates are commonly observed after repeat treatment. In addition, a lower number of AEs were associated with the use of cannulas versus needle injection, which is likely due to the ability of cannulas to assist injectors in avoiding sharp trauma and bruising,4,17,18 although there may be confounding factors as patients were not randomized to a needle or cannula. In a retrospective study of 50 patients treated with VYC 20L administered by a cannula, 8% of patients experienced procedure-related ecchymosis, which was self-limiting and nonserious.19 In a study that compared needle versus cannula in the treatment of nasolabial folds found the use of a cannula had significantly fewer AEs (pain, edema, redness, and hematoma) while maintaining similar efficacy to needle injection.17
One patient experienced 2 serious AEs related to the treatment, injection site cellulitis and injection site inflammation, which resolved without sequelae. The patient experienced severe inflammation beginning 7 days after touch-up treatment. She was admitted to the hospital for treatment with intravenous antibiotics and drainage of the abscess. Cultures of the abscess were negative for gram-positive and gram-negative bacteria. This type of event has been previously reported, although they are not typically observed in prospective clinical studies, in part due to their relatively low incidence.20 The etiology of late-onset inflammation and nodules after soft tissue filler treatment is not well understood and has been attributed to hypersensitivity, foreign body reaction, injection placement, infection, and biofilm development.21
Several soft tissue fillers have been previously reported in the literature for use in chin augmentation19,22–25; VYC-25L (Juvéderm Volux; Allergan plc) being the first HA soft tissue filler designed for chin augmentation and systematically investigated in a randomized controlled clinical trial for safety and effectiveness.25 Similar to VYC-20L, objective and subjective measures for VYC-25L showed sustained clinically meaningful benefits through Month 12, with comparable safety profiles where the incidence of ISRs and AEs were consistent for HA soft tissue fillers. The mean change from baseline to Month 12 in the glabella-subnasale-pogonion angle was 1.28°, and investigator and participant assessments on the GAIS at Month 12 were 83.5% and 77.2%, respectively. FACE-Q Satisfaction with Chin module and Psychological Well-Being module mean scores showed continued improvement over baseline (41.4 and 65.3, respectively) at Month 12 (61.6 and 74.4).
Conclusions
VYC-20L treatment is safe and effective when injected in the chin and prejowl sulci to treat chin retrusion, with results lasting through 1 year.
Acknowledgments
The authors sincerely thank the patients who participated in this study and acknowledge the additional investigators and staff who contributed to the study conduct, including Jeffrey Dover, MD; Todd Schlesinger, MD; Leslie Baumann, MD; Mitchel Goldman, MD; Dee Anna Glaser, MD; Jeanine Downie, MD; Valerie Callender, MD; Edwin Williams, MD; and William P. Werschler, MD.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.dermatologicsurgery.org).
This study was sponsored by Allergan plc, Dublin, Ireland. Medical writing assistance was provided to the authors by W. Kim of Allergan plc, Irvine, CA. All authors met the ICMJE authorship criteria. Neither honoraria nor any other form of compensation was provided for authorship. K. Beer, J. Kaufman-Janette, D. Bank, and S. Dayan have received funding as an investigator, consultant, and trainer for Allergan. B. Biesman has received consulting fees and research funding from Allergan. W. Kim, S. Chawla, and A. Schumacher are employees of Allergan plc and may own stock in the company. | HYALURONIC ACID, LIDOCAINE | DrugsGivenReaction | CC BY-NC-ND | 33347003 | 18,840,355 | 2021-01-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Injection site inflammation'. | Safe and Effective Chin Augmentation With the Hyaluronic Acid Injectable Filler, VYC-20L.
VYC-20L is a hyaluronic acid soft tissue filler with lidocaine designed to restore facial volume.
Evaluate the safety and effectiveness of VYC-20L in patients with chin retrusion.
Adults with chin retrusion were randomized (3:1) to receive VYC-20L in the chin at study onset (treatment group) or 6 months later (control group). The primary effectiveness end point was ≥1-point improvement on the Allergan Chin Retrusion Scale (ACRS) from baseline at Month 6. Safety assessments included injection site responses (ISRs) and adverse events (AEs).
VYC-20L was administered to 192 participants (treatment group, n = 144; control group, n = 48). At Month 6, significantly more participants had an ACRS response in the treatment versus control group (56.3% vs 27.5%; p = .0019). Effectiveness was also demonstrated by the proportion of participants with improved/much improved Global Aesthetic Improvement Scale scores and responses on the FACE-Q Satisfaction with Chin questionnaire and FACE-Q Psychological Wellbeing module. Treatment benefit remained evident at Month 12. Most common ISRs were tenderness (81.1%) and firmness (75.1%). One participant (0.5%) discontinued the study due to 2 treatment-related serious AEs of facial cellulitis and injection site inflammation, both resolved without sequelae.
VYC-20L significantly improved an ACRS response and was generally safe and well tolerated.
Hyaluronic acid (HA) injectable gels are a proven treatment for facial rejuvenation with an established record of safety and effectiveness.1 In 2018, more than 2.1 million HA injectable filler procedures were performed in the United States—a 48% increase over the past decade.2,3 The FDA has approved a range of dermal and subcutaneous indications for HA injectable fillers, including facial wrinkles, folds, lip augmentation, and cheeks.4 One such product, VYC-20L (Juvéderm Voluma XC; Allergan plc, Dublin, Ireland), which is a 20-mg/mL HA gel with lidocaine, was specifically designed for volumizing and has demonstrated effectiveness in restoring age-related volume deficit to the midface.5 Compared with HA gels designed for correction of wrinkles and folds, VYC-20L improved qualities of lift and projection to the midface.
In addition to the midface, the chin area is another facial region where lift and projection are important aspects of volumizing. The chin is defined by the labiomental crease (superiorly), the oral commissures (laterally), and the submental cervical crease (inferiorly). The shape and projection of the chin contribute to a “well-balanced and harmonious” face.6 For both men and women, good chin projection and a youthful jawline are considered the standards of beauty7 and can influence an individual's psychosocial well-being.8 Although congenital elements are the predominant factor in chin aesthetics, aging can result in bony resorption and produce sagging9 as well as laxity and droop in the chin area.10 In addition, aging can result in lumps, bulges, and depressions in the prejowl sulci.11
VYC-20L is a temporary HA soft tissue filler developed to provide a safe, minimally invasive method to restore facial volume, which is also reversible by hyaluronidase in case of adverse events (AEs) requiring treatment.5,12 It is currently indicated in the United States for injection into the subcutaneous and/or supraperiosteal space of the midface to add volume in the cheek area and is approved in other countries for facial volumizing, including the chin and prejowl sulci.5,12–16 As the chin and prejowl sulci are high-mobility areas, VYC-20L represents an ideal option for its volumizing and lifting capabilities. This study was designed to collect effectiveness and safety data for VYC-20L in participants seeking to correct volume deficit and retrusion in the chin and prejowl sulci.
Methods
Study Design
This multicenter, randomized, evaluator-blinded, delayed treatment-controlled study was designed to evaluate the safety and effectiveness of VYC-20L injectable gel for correction of chin volume deficit. A no-treatment control was used because there were no FDA-approved soft tissue fillers for chin augmentation at the time of the study. Participants were randomized in a 3:1 ratio either to have treatment with VYC-20L (treatment group) or a 6-month control period, followed by optional treatment (control group). At the Month 12 visit, participants in the treatment group had the option of receiving repeat treatment, with routine follow-up visits for safety and effectiveness through 1 month after repeat treatment. Treated control group participants were only followed for safety, and no effectiveness measures were performed. Participants underwent a touch-up treatment 30 days after initial treatment to achieve optimal correction if needed. The study was conducted at 14 sites in the United States, each of which had a treating investigator (TI) and at least one blinded evaluating investigator (EI).
The TIs performed the treatments and monitored participant safety throughout the study. Blinded EIs performed all effectiveness assessments. For treatment, the TI used 27 G 1/2 -inch needles for supraperiosteal and/or subcutaneous injections into the pogonion, menton, and prejowl sulci; 25 G 1½-inch cannulas were permitted for supraperiosteal and/or subcutaneous injections in the menton and prejowl sulci. An appropriate injection volume for the chin and chin area was determined by the TI but was not to exceed a maximum total volume of 4.0 mL for initial and touch-up treatments combined and 4.0 mL for repeat treatment. After each treatment, participants completed a daily safety diary for up to 30 days. Visits for both effectiveness and safety occurred at months 1, 3, 6, 9, and 12 after the last treatment.
Participants were required to be aged 22 or older and desire chin augmentation to correct moderate or severe chin retrusion (Grades 2 or 3 on the validated 5-point photonumeric Allergan Chin Retrusion Scale [ACRS]) as determined by a live assessment by both the EI and TI. Participants were ineligible if they had undergone cosmetic facial plastic surgery, tissue grafting, or tissue augmentation with silicone, fat, or permanent dermal fillers; had clinically significant malocclusion (severe overbite); had dentures; any device covering the palate; tattoos; piercings; facial hair; or scars that would interfere with visual assessment of the chin area. Mandatory facial treatment washout periods before study entry were 36 months for semipermanent dermal fillers, 24 months for dermal fillers in the chin or jaw area, 12 months for dermal fillers in the lips or perioral area, and 6 months for mesotherapy, botulinum toxin below the subnasale, or cosmetic treatment (laser, photomodulation, intense pulsed light, radiofrequency, dermabrasion, chemical peel, liposuction, lipolysis, or other ablative procedures). Applicable institutional review boards approved the study protocol, and all participants provided written informed consent before study enrolment (www.clinicaltrials.gov, identifier NCT02833077).
Response Measures and Statistics
The primary end point was based on the EI's blinded assessment of overall chin retrusion using ACRS grades defined as none (0), minimal (1), moderate (2), severe (3), and extreme (4) (See Supplemental Digital Content, Table S1, http://links.lww.com/DSS/A543). The primary effectiveness measure used a profile-view image cropped to include only the participant's lower face for ACRS assessment, which is based on the relationship between facial anatomical landmarks. Photograph assessments, rather than live assessments, facilitated consistent head positioning and were intended to help raters assess the relationship between landmarks. A participant showing ≥1-point improvement (decrease) in an ACRS score compared with baseline was considered a responder. The primary evaluation timepoint for efficacy was Month 6 after last treatment for participants in the treatment group and Month 6 after randomization for participants in the control group (untreated). The primary effectiveness end point was met if the treatment group responder rate was statistically greater (>50%) than the control group at Month 6 based on a 2-sided Fisher's exact test with a 5% significance level.
The Global Aesthetic Improvement Scale (GAIS), as well as the Satisfaction with Chin and Psychosocial Well-Being modules of the FACE-Q questionnaire, was used for assessment of secondary effectiveness end points. For the GAIS, responder rates for the treatment group (with 95% exact confidence intervals [CIs]) were based on EI and participant assessments. A “responder” was a participant who showed improvement (i.e., improved or much improved) on the overall aesthetic assessment in the chin area at the Month 6 visit. For the Satisfaction with Chin module of the FACE-Q questionnaire, the change from baseline to Month 6 visit in overall scores and a 2-sided paired t-test at the 5% level were used to demonstrate that the mean overall satisfaction score at the Month 6 visit was statistically greater than baseline for the treatment group. Volume change from baseline was measured by a blinded Canfield image analysis technician from three-dimensional (3D) imaging of the participant's facial profile pretreatment and post-treatment for both the treatment and control groups at the 6 Month visit.
Participants
A total of 221 participants were enrolled in the study, with an average of 14 (range 11–21) per investigational site. A total of 192 participants were randomized after 29 participants were screen failures, resulting in 144 in the treatment group and 48 in the control group. One hundred sixty-nine participants (88.0%) completed the Month 6 visit and 167 participants (87.0%) completed the study, with 25 participants (13.0%) discontinuing after randomization. Eighty-eight participants received touch-up treatment and 74 received repeat treatment. For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment. All initial and touch-up treatments occurred between June 28, 2016, and January 25, 2018, and all repeat treatments occurred between July 11, 2017, and August 23, 2018. The treatment and control groups were similar in terms of all demographic and baseline characteristics (See Supplemental Digital Content, Table S2, http://links.lww.com/DSS/A544). Among the 192 enrolled participants, the majority were women (88.5%) and White (81.8%), with a median age at study entry of 52 years (range, 22–80) and mean body mass index of 25.0 kg/m2. Fitzpatrick skin types were I/II (34.9%), III/IV (52.1%), and V/VI (13.0%).
Treatment
Anesthesia was administered to 75.0% (108/144) of participants in the treatment group, with the most common being topical (69.4%, 75/108; median duration 29.0 minutes) while ice was less common (34.3%, 37/108; median duration 15.0 minutes). The primary plane of injection used during the initial treatment was supraperiosteal (99.3%), followed by subcutaneous (63.0%). At touch-up and repeat treatments, the most common injection planes were also supraperiosteal (90.9% and 100.0%, respectively) and subcutaneous (53.4% and 59.5%, respectively). Planes and techniques were similar for the treated control participants. 99.3% of treatment group participants were treated in the pogonion, 77.8% in the menton, and 87.5% in the prejowl sulci. At the touch-up visit, 78.4% of treatment group participants were treated in the pogonion, 52.3% in the menton, and 65.9% in the prejowl sulci. At the repeat treatment visit, 93.2% were treated in the pogonion, 56.8% in the menton, and 66.2% in the prejowl sulci.
Needles were used for 100% of participants, and cannulas were used for 25.0% at initial treatment. There were no cannula/needle malfunctions. Treatment administration was similar for the treated control participants. Treating investigators rated ease of injection and product moldability on an 11-point scale, difficult (0) to easy (10), and stiff (0) to moldable (10), respectively. A total of 66.0% and 21.5% of participants were scored as 10 and 9, respectively, for ease of injection, whereas 62.5% and 20.8% of participants were scored as 10 and 9, respectively, for product moldability.
In the treatment group, 144 participants received initial treatment, 88 received touch-up treatment, and 74 received repeat treatment (Table 1). For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment, with injection volumes similar to the treatment group. The median total initial injection volume was 2.2 mL (range, 0.7–4.0 mL) for the treatment group (initial treatment and touch-up combined) and 2.8 mL (range, 1.3–4.0 mL) for the treated control group (initial treatment and touch-up combined). The median total injection volume for repeat treatment was 1.2 mL (range, 0.2–4.0 mL).
TABLE 1. Injection Volumes (Safety Population)
Total Volume Injected Treatment (N = 144) Control (N = 48)
Initial treatment volume (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 1.9 (0.6) 2.1 (0.6)
Median (range) 2 (0.7–4.0) 2 (1.0–3.8)
Initial/touch-up treatment volume combined (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 2.6 (1.0) 2.7 (0.8)
Median (range) 2.2 (0.7–4.0) 2.8 (1.3–4.0)
Repeat treatment volume (mL)
Received treatment, n (%) 74 (51.4) 0 (0.0)
Mean (SD) 1.4 (0.8) N/A
Median (range) 1.2 (0.2–4.0) N/A
For the control group, data after receiving initial treatment at Month 6 are included.
Results
Effectiveness
The primary efficacy end point was met with 56.3% ACRS responders (photograph assessment) at Month 6, which was greater than 50% and significantly greater than the responder rate for the untreated control group (27.5%, p = .0019) (Table 2). In addition, the ACRS responder rate in the treatment group was 70.1% at Month 1, 57.6% at Month 12, and 73.9% at Month 1 after repeat treatment (See Supplemental Digital Content, Figure S1, http://links.lww.com/DSS/A539). The median ACRS scores improved by a median of 1 point from a baseline score of 3 in the treatment group, whereas the control group remained at a score of 2.5. Notably, the Month 6 responder rate from the EI live assessment was markedly higher than results from the photograph assessment with 91.8% for the treatment group and 23.3% for the control group, a difference of 68.42% (p < .0001).
TABLE 2. Allergan Chin Retrusion Scale Results at Month 6 (Modified Intent-to-Treat Population)
Treatment (N = 144) Control (N = 48)
Month 6
Total participants, n* 126 40
Responder, n (%) 71 (56.3) 11 (27.5)
Nonresponder, n (%) 55 (43.7) 29 (72.5)
95% CI (%)† (47.23–65.16) (14.60–43.89)
Versus control
Responder rate difference, % 28.85
95% CI (%)‡ 11.16–45.60
p-value§ 0.0019
For the untreated control group, data before receiving initial treatment at Month 6 are included.
* Participants with analysis values at baseline and the specified visit.
† 95% CI is based on the exact binomial distribution.
‡ 95% exact CI for the responder rate difference is presented.
§ p-value is based on 2-sided Fisher's exact test comparing the responder rate between treated and untreated control.
On the GAIS, EIs rated 91.2% (114/125) as “improved” or “much improved” in the treatment group and 19.5% (8/41) in the untreated control group at Month 6 (See Supplemental Digital Content, Figure S2, http://links.lww.com/DSS/A540). The treatment group responder rate remained high from Month 1 (94.0%) through Month 12 (91.2%) along with an increase at Month 1 after repeat treatment (98.6%; 70/71). The percentage of responders rated as “much improved” in the treatment group was notably high, with 61.6% at Month 6, 41.6% at Month 12, and 77.5% at Month 1 after repeat treatment. The participant self-evaluation on the GAIS was consistent with the EI assessments with most participants in the treatment group (87.3%; 110/126) rating as “improved” or “much improved” at Month 6. The treatment group responder rate remained high from Month 1 (95.5%) through Month 12 (82.4%) and was 97.1% at Month 1 after repeat treatment, similar to EI assessments. In addition, the mean change in chin volume assessed by 3D digital imaging showed a similar trend with (+)2.6 mL at Month 1, 2.4 mL Month 6, 2.2 cc at Month 12, and 3.9 cc at Month 1 after repeat treatment in the treatment group and 0.1 cc in the untreated control group.
The FACE-Q Satisfaction with Chin overall mean score for the treatment group was 34.9 at baseline and improved by a mean of 35.6 to a score of 71.3 at Month 6 (p < .001), whereas the mean score worsened by a mean of 3.3 from a baseline score of 35.1 for the untreated control group (See Supplemental Digital Content, Figure S3, http://links.lww.com/DSS/A541). The mean scores remained high from Month 1 (74.8) to Month 12 (66.4) and at Month 1 after repeat treatment (77.5).
The FACE-Q Psychological Well-Being overall mean score was 69.9 at baseline and improved by a mean of 15.4 at Month 6 for the treatment group, whereas the mean score worsened by a mean of −5.3 from 72.3 at Month 6 in the untreated control group (See Supplemental Digital Content, Figure S4, http://links.lww.com/DSS/A542). Most treatment group participants reported that they definitely/somewhat agree with each of the 10 individual FACE-Q Psychological Well-Being items at all timepoints, indicating positive well-being.
Safety
For initial/touch-up treatment, 14 treated participants (7.7%) had 20 treatment-related AEs (Table 3) while 3 (4.1%) had 7 treatment-related AEs after repeat treatment (See Supplemental Digital Content, Table S3, http://links.lww.com/DSS/A545). During the repeat treatment period, an injection site mass occurred in 2 participants (2.7%). The most common treatment-related AEs for the initial/touch-up treatment period were injection site erythema (1.6%, 3/182 participants) and injection site pain (1.6%, 3/182 participants). There were no deaths or unanticipated adverse effects. Facial sensation assessments found that treatment did not reduce chin area sensitivity at any timepoint throughout the study.
TABLE 3. Common Treatment-Related Adverse Events (AEs) After Initial/Touch-Up Treatment
Event, n Onset (d) Duration (d) Severity Resolution
Injection site abscess 6 9 Moderate Resolved w/o sequelae
Gingival pain 1 2 Moderate Resolved w/o sequelae
Acne cystic 6 134 Mild Resolved w/o sequelae
Injection site cellulitis 7 36 Severe Resolved w/o sequelae
Injection site inflammation 7 153 Severe Resolved w/o sequelae
w/o, without.
The type and frequency of injection site responses (ISRs) were similar in treatment group participants and treated control participants and are considered to be commonly reported events after treatment with HA soft tissue fillers (See Supplemental Digital Content, Table S4, http://links.lww.com/DSS/A546). Overall, 167 treated participants (92.3%) reported at least 1 ISR after initial treatment, 86 (82.7%) after touch-up treatment, and 55 (75.3%) after repeat treatment. The most frequently reported ISRs after initial treatment included tenderness to touch (81.8%), firmness (75.1%), and swelling (68.5%). Similar results were seen after repeat treatment, where the most common ISRs were also tenderness to touch (71.2%), firmness (69.9%), and swelling (58.9%). Most ISRs were mild or moderate in severity after initial, touch-up, and repeat treatment and resolved within 1 week based on total days from first to last occurrence according to the diaries. Participants assessed procedural pain (pain during injection) immediately after completion of each treatment on an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) and reported minimal pain, with a mean score of 2.3 for the treatment group at each treatment (initial, touch-up, and repeat).
Most treatment-related AEs were mild or moderate in severity (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 2.7% (5/182) of participants had mild treatment-related AEs and 4.4% (8/182) had moderate AEs. For repeat treatment, 4.1% (3/74) of participants had mild and 1.4% (1/74) moderate AEs. Two participants (1.1%) had 3 severe treatment-related AEs, including injection site inflammation and cellulitis in one participant and injection site induration in another participant.
Most treatment-related AEs resolved within 1 week (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 3 participants (1.6%) had 4 treatment-related AEs that lasted longer than 30 days. The first participant had injection site inflammation that lasted 153 days and injection site cellulitis that lasted 36 days. Treatment consisted of antibiotics, anti-inflammatories, and hyaluronidase. These 2 events were considered to be serious AEs. A second participant had injection site erythema that lasted 264 days. A third participant had an acne cyst that lasted 134 days. For repeat treatment, 1 participant (1.4%) had an injection site mass that lasted 42 days. Most treatment-related AEs began within 7 days of treatment. There were no treatment-related AEs that began >30 days after repeat treatment. All treatment-related AEs resolved without sequelae during the study period.
A lower incidence of ISRs was observed for injections with a cannula than without a cannula after initial touch-up and repeat treatments (See Supplemental Digital Content, Table S6, http://links.lww.com/DSS/A548). For initial/touch-up treatment with a cannula, 2 treated participants (4.5%) had 2 treatment-related AEs; without a cannula, 12 treated participants (8.7%) had 18 treatment-related AEs. For repeat treatment with a cannula, there were no treatment-related AEs; without a cannula, 3 treated participants (5.6%) had 7 treatment-related AEs.
Discussion
Although the primary end point was met, the ACRS responder rate of 56.3% was lower than expected. Comparatively, the midface study met its primary end point at Month 6, with 85.6% of treated participants having a clinically meaningful improvement.5 A possible reason for this discrepancy is the markedly higher injection volumes used in the midface study. This study used lower volumes, more closely representative of volumes used in real-world clinical practice. Another potential reason for this discrepancy is the different methods of evaluation. The midface study relied on live assessments, taking into account overall improvement. This study's assessment was limited to 2-dimensional cropped photographs, possibly obscuring a treatment effect because it relates to the whole face. This hypothesis is supported by the notably higher responder rate of 91.8% observed from the EI live assessments, which are more in line with the high responses observed with the GAIS and FACE-Q measures. Another supportive observation is the control responder rate at Month 6, which was observably lower in this study compared with the midface study, 27.5% versus 38.9%, respectively, indicating a lower false-positive rate.5 Although photograph assessments, rather than live assessments, were intended to help raters more consistently assess the relationship between landmarks, the use of cropped photographs as a primary measure may represent a study limitation. Other study limitations may have included the single-blind design, which left participants and injectors unblinded, and that control data were only available through month 6, although data could still be compared with baseline beyond Month 6.
VYC-20L was well tolerated, with most treatment-related AEs being ISRs of mild to moderate severity. Notably, there was an overall decrease in the number of AEs with repeat treatment compared with initial/touch-up treatment. One possibility is the lower volume injected during repeat treatment. Lower AE rates are commonly observed after repeat treatment. In addition, a lower number of AEs were associated with the use of cannulas versus needle injection, which is likely due to the ability of cannulas to assist injectors in avoiding sharp trauma and bruising,4,17,18 although there may be confounding factors as patients were not randomized to a needle or cannula. In a retrospective study of 50 patients treated with VYC 20L administered by a cannula, 8% of patients experienced procedure-related ecchymosis, which was self-limiting and nonserious.19 In a study that compared needle versus cannula in the treatment of nasolabial folds found the use of a cannula had significantly fewer AEs (pain, edema, redness, and hematoma) while maintaining similar efficacy to needle injection.17
One patient experienced 2 serious AEs related to the treatment, injection site cellulitis and injection site inflammation, which resolved without sequelae. The patient experienced severe inflammation beginning 7 days after touch-up treatment. She was admitted to the hospital for treatment with intravenous antibiotics and drainage of the abscess. Cultures of the abscess were negative for gram-positive and gram-negative bacteria. This type of event has been previously reported, although they are not typically observed in prospective clinical studies, in part due to their relatively low incidence.20 The etiology of late-onset inflammation and nodules after soft tissue filler treatment is not well understood and has been attributed to hypersensitivity, foreign body reaction, injection placement, infection, and biofilm development.21
Several soft tissue fillers have been previously reported in the literature for use in chin augmentation19,22–25; VYC-25L (Juvéderm Volux; Allergan plc) being the first HA soft tissue filler designed for chin augmentation and systematically investigated in a randomized controlled clinical trial for safety and effectiveness.25 Similar to VYC-20L, objective and subjective measures for VYC-25L showed sustained clinically meaningful benefits through Month 12, with comparable safety profiles where the incidence of ISRs and AEs were consistent for HA soft tissue fillers. The mean change from baseline to Month 12 in the glabella-subnasale-pogonion angle was 1.28°, and investigator and participant assessments on the GAIS at Month 12 were 83.5% and 77.2%, respectively. FACE-Q Satisfaction with Chin module and Psychological Well-Being module mean scores showed continued improvement over baseline (41.4 and 65.3, respectively) at Month 12 (61.6 and 74.4).
Conclusions
VYC-20L treatment is safe and effective when injected in the chin and prejowl sulci to treat chin retrusion, with results lasting through 1 year.
Acknowledgments
The authors sincerely thank the patients who participated in this study and acknowledge the additional investigators and staff who contributed to the study conduct, including Jeffrey Dover, MD; Todd Schlesinger, MD; Leslie Baumann, MD; Mitchel Goldman, MD; Dee Anna Glaser, MD; Jeanine Downie, MD; Valerie Callender, MD; Edwin Williams, MD; and William P. Werschler, MD.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.dermatologicsurgery.org).
This study was sponsored by Allergan plc, Dublin, Ireland. Medical writing assistance was provided to the authors by W. Kim of Allergan plc, Irvine, CA. All authors met the ICMJE authorship criteria. Neither honoraria nor any other form of compensation was provided for authorship. K. Beer, J. Kaufman-Janette, D. Bank, and S. Dayan have received funding as an investigator, consultant, and trainer for Allergan. B. Biesman has received consulting fees and research funding from Allergan. W. Kim, S. Chawla, and A. Schumacher are employees of Allergan plc and may own stock in the company. | HYALURONIC ACID, LIDOCAINE | DrugsGivenReaction | CC BY-NC-ND | 33347003 | 18,840,355 | 2021-01-01 |
What was the dosage of drug 'HYALURONIC ACID'? | Safe and Effective Chin Augmentation With the Hyaluronic Acid Injectable Filler, VYC-20L.
VYC-20L is a hyaluronic acid soft tissue filler with lidocaine designed to restore facial volume.
Evaluate the safety and effectiveness of VYC-20L in patients with chin retrusion.
Adults with chin retrusion were randomized (3:1) to receive VYC-20L in the chin at study onset (treatment group) or 6 months later (control group). The primary effectiveness end point was ≥1-point improvement on the Allergan Chin Retrusion Scale (ACRS) from baseline at Month 6. Safety assessments included injection site responses (ISRs) and adverse events (AEs).
VYC-20L was administered to 192 participants (treatment group, n = 144; control group, n = 48). At Month 6, significantly more participants had an ACRS response in the treatment versus control group (56.3% vs 27.5%; p = .0019). Effectiveness was also demonstrated by the proportion of participants with improved/much improved Global Aesthetic Improvement Scale scores and responses on the FACE-Q Satisfaction with Chin questionnaire and FACE-Q Psychological Wellbeing module. Treatment benefit remained evident at Month 12. Most common ISRs were tenderness (81.1%) and firmness (75.1%). One participant (0.5%) discontinued the study due to 2 treatment-related serious AEs of facial cellulitis and injection site inflammation, both resolved without sequelae.
VYC-20L significantly improved an ACRS response and was generally safe and well tolerated.
Hyaluronic acid (HA) injectable gels are a proven treatment for facial rejuvenation with an established record of safety and effectiveness.1 In 2018, more than 2.1 million HA injectable filler procedures were performed in the United States—a 48% increase over the past decade.2,3 The FDA has approved a range of dermal and subcutaneous indications for HA injectable fillers, including facial wrinkles, folds, lip augmentation, and cheeks.4 One such product, VYC-20L (Juvéderm Voluma XC; Allergan plc, Dublin, Ireland), which is a 20-mg/mL HA gel with lidocaine, was specifically designed for volumizing and has demonstrated effectiveness in restoring age-related volume deficit to the midface.5 Compared with HA gels designed for correction of wrinkles and folds, VYC-20L improved qualities of lift and projection to the midface.
In addition to the midface, the chin area is another facial region where lift and projection are important aspects of volumizing. The chin is defined by the labiomental crease (superiorly), the oral commissures (laterally), and the submental cervical crease (inferiorly). The shape and projection of the chin contribute to a “well-balanced and harmonious” face.6 For both men and women, good chin projection and a youthful jawline are considered the standards of beauty7 and can influence an individual's psychosocial well-being.8 Although congenital elements are the predominant factor in chin aesthetics, aging can result in bony resorption and produce sagging9 as well as laxity and droop in the chin area.10 In addition, aging can result in lumps, bulges, and depressions in the prejowl sulci.11
VYC-20L is a temporary HA soft tissue filler developed to provide a safe, minimally invasive method to restore facial volume, which is also reversible by hyaluronidase in case of adverse events (AEs) requiring treatment.5,12 It is currently indicated in the United States for injection into the subcutaneous and/or supraperiosteal space of the midface to add volume in the cheek area and is approved in other countries for facial volumizing, including the chin and prejowl sulci.5,12–16 As the chin and prejowl sulci are high-mobility areas, VYC-20L represents an ideal option for its volumizing and lifting capabilities. This study was designed to collect effectiveness and safety data for VYC-20L in participants seeking to correct volume deficit and retrusion in the chin and prejowl sulci.
Methods
Study Design
This multicenter, randomized, evaluator-blinded, delayed treatment-controlled study was designed to evaluate the safety and effectiveness of VYC-20L injectable gel for correction of chin volume deficit. A no-treatment control was used because there were no FDA-approved soft tissue fillers for chin augmentation at the time of the study. Participants were randomized in a 3:1 ratio either to have treatment with VYC-20L (treatment group) or a 6-month control period, followed by optional treatment (control group). At the Month 12 visit, participants in the treatment group had the option of receiving repeat treatment, with routine follow-up visits for safety and effectiveness through 1 month after repeat treatment. Treated control group participants were only followed for safety, and no effectiveness measures were performed. Participants underwent a touch-up treatment 30 days after initial treatment to achieve optimal correction if needed. The study was conducted at 14 sites in the United States, each of which had a treating investigator (TI) and at least one blinded evaluating investigator (EI).
The TIs performed the treatments and monitored participant safety throughout the study. Blinded EIs performed all effectiveness assessments. For treatment, the TI used 27 G 1/2 -inch needles for supraperiosteal and/or subcutaneous injections into the pogonion, menton, and prejowl sulci; 25 G 1½-inch cannulas were permitted for supraperiosteal and/or subcutaneous injections in the menton and prejowl sulci. An appropriate injection volume for the chin and chin area was determined by the TI but was not to exceed a maximum total volume of 4.0 mL for initial and touch-up treatments combined and 4.0 mL for repeat treatment. After each treatment, participants completed a daily safety diary for up to 30 days. Visits for both effectiveness and safety occurred at months 1, 3, 6, 9, and 12 after the last treatment.
Participants were required to be aged 22 or older and desire chin augmentation to correct moderate or severe chin retrusion (Grades 2 or 3 on the validated 5-point photonumeric Allergan Chin Retrusion Scale [ACRS]) as determined by a live assessment by both the EI and TI. Participants were ineligible if they had undergone cosmetic facial plastic surgery, tissue grafting, or tissue augmentation with silicone, fat, or permanent dermal fillers; had clinically significant malocclusion (severe overbite); had dentures; any device covering the palate; tattoos; piercings; facial hair; or scars that would interfere with visual assessment of the chin area. Mandatory facial treatment washout periods before study entry were 36 months for semipermanent dermal fillers, 24 months for dermal fillers in the chin or jaw area, 12 months for dermal fillers in the lips or perioral area, and 6 months for mesotherapy, botulinum toxin below the subnasale, or cosmetic treatment (laser, photomodulation, intense pulsed light, radiofrequency, dermabrasion, chemical peel, liposuction, lipolysis, or other ablative procedures). Applicable institutional review boards approved the study protocol, and all participants provided written informed consent before study enrolment (www.clinicaltrials.gov, identifier NCT02833077).
Response Measures and Statistics
The primary end point was based on the EI's blinded assessment of overall chin retrusion using ACRS grades defined as none (0), minimal (1), moderate (2), severe (3), and extreme (4) (See Supplemental Digital Content, Table S1, http://links.lww.com/DSS/A543). The primary effectiveness measure used a profile-view image cropped to include only the participant's lower face for ACRS assessment, which is based on the relationship between facial anatomical landmarks. Photograph assessments, rather than live assessments, facilitated consistent head positioning and were intended to help raters assess the relationship between landmarks. A participant showing ≥1-point improvement (decrease) in an ACRS score compared with baseline was considered a responder. The primary evaluation timepoint for efficacy was Month 6 after last treatment for participants in the treatment group and Month 6 after randomization for participants in the control group (untreated). The primary effectiveness end point was met if the treatment group responder rate was statistically greater (>50%) than the control group at Month 6 based on a 2-sided Fisher's exact test with a 5% significance level.
The Global Aesthetic Improvement Scale (GAIS), as well as the Satisfaction with Chin and Psychosocial Well-Being modules of the FACE-Q questionnaire, was used for assessment of secondary effectiveness end points. For the GAIS, responder rates for the treatment group (with 95% exact confidence intervals [CIs]) were based on EI and participant assessments. A “responder” was a participant who showed improvement (i.e., improved or much improved) on the overall aesthetic assessment in the chin area at the Month 6 visit. For the Satisfaction with Chin module of the FACE-Q questionnaire, the change from baseline to Month 6 visit in overall scores and a 2-sided paired t-test at the 5% level were used to demonstrate that the mean overall satisfaction score at the Month 6 visit was statistically greater than baseline for the treatment group. Volume change from baseline was measured by a blinded Canfield image analysis technician from three-dimensional (3D) imaging of the participant's facial profile pretreatment and post-treatment for both the treatment and control groups at the 6 Month visit.
Participants
A total of 221 participants were enrolled in the study, with an average of 14 (range 11–21) per investigational site. A total of 192 participants were randomized after 29 participants were screen failures, resulting in 144 in the treatment group and 48 in the control group. One hundred sixty-nine participants (88.0%) completed the Month 6 visit and 167 participants (87.0%) completed the study, with 25 participants (13.0%) discontinuing after randomization. Eighty-eight participants received touch-up treatment and 74 received repeat treatment. For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment. All initial and touch-up treatments occurred between June 28, 2016, and January 25, 2018, and all repeat treatments occurred between July 11, 2017, and August 23, 2018. The treatment and control groups were similar in terms of all demographic and baseline characteristics (See Supplemental Digital Content, Table S2, http://links.lww.com/DSS/A544). Among the 192 enrolled participants, the majority were women (88.5%) and White (81.8%), with a median age at study entry of 52 years (range, 22–80) and mean body mass index of 25.0 kg/m2. Fitzpatrick skin types were I/II (34.9%), III/IV (52.1%), and V/VI (13.0%).
Treatment
Anesthesia was administered to 75.0% (108/144) of participants in the treatment group, with the most common being topical (69.4%, 75/108; median duration 29.0 minutes) while ice was less common (34.3%, 37/108; median duration 15.0 minutes). The primary plane of injection used during the initial treatment was supraperiosteal (99.3%), followed by subcutaneous (63.0%). At touch-up and repeat treatments, the most common injection planes were also supraperiosteal (90.9% and 100.0%, respectively) and subcutaneous (53.4% and 59.5%, respectively). Planes and techniques were similar for the treated control participants. 99.3% of treatment group participants were treated in the pogonion, 77.8% in the menton, and 87.5% in the prejowl sulci. At the touch-up visit, 78.4% of treatment group participants were treated in the pogonion, 52.3% in the menton, and 65.9% in the prejowl sulci. At the repeat treatment visit, 93.2% were treated in the pogonion, 56.8% in the menton, and 66.2% in the prejowl sulci.
Needles were used for 100% of participants, and cannulas were used for 25.0% at initial treatment. There were no cannula/needle malfunctions. Treatment administration was similar for the treated control participants. Treating investigators rated ease of injection and product moldability on an 11-point scale, difficult (0) to easy (10), and stiff (0) to moldable (10), respectively. A total of 66.0% and 21.5% of participants were scored as 10 and 9, respectively, for ease of injection, whereas 62.5% and 20.8% of participants were scored as 10 and 9, respectively, for product moldability.
In the treatment group, 144 participants received initial treatment, 88 received touch-up treatment, and 74 received repeat treatment (Table 1). For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment, with injection volumes similar to the treatment group. The median total initial injection volume was 2.2 mL (range, 0.7–4.0 mL) for the treatment group (initial treatment and touch-up combined) and 2.8 mL (range, 1.3–4.0 mL) for the treated control group (initial treatment and touch-up combined). The median total injection volume for repeat treatment was 1.2 mL (range, 0.2–4.0 mL).
TABLE 1. Injection Volumes (Safety Population)
Total Volume Injected Treatment (N = 144) Control (N = 48)
Initial treatment volume (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 1.9 (0.6) 2.1 (0.6)
Median (range) 2 (0.7–4.0) 2 (1.0–3.8)
Initial/touch-up treatment volume combined (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 2.6 (1.0) 2.7 (0.8)
Median (range) 2.2 (0.7–4.0) 2.8 (1.3–4.0)
Repeat treatment volume (mL)
Received treatment, n (%) 74 (51.4) 0 (0.0)
Mean (SD) 1.4 (0.8) N/A
Median (range) 1.2 (0.2–4.0) N/A
For the control group, data after receiving initial treatment at Month 6 are included.
Results
Effectiveness
The primary efficacy end point was met with 56.3% ACRS responders (photograph assessment) at Month 6, which was greater than 50% and significantly greater than the responder rate for the untreated control group (27.5%, p = .0019) (Table 2). In addition, the ACRS responder rate in the treatment group was 70.1% at Month 1, 57.6% at Month 12, and 73.9% at Month 1 after repeat treatment (See Supplemental Digital Content, Figure S1, http://links.lww.com/DSS/A539). The median ACRS scores improved by a median of 1 point from a baseline score of 3 in the treatment group, whereas the control group remained at a score of 2.5. Notably, the Month 6 responder rate from the EI live assessment was markedly higher than results from the photograph assessment with 91.8% for the treatment group and 23.3% for the control group, a difference of 68.42% (p < .0001).
TABLE 2. Allergan Chin Retrusion Scale Results at Month 6 (Modified Intent-to-Treat Population)
Treatment (N = 144) Control (N = 48)
Month 6
Total participants, n* 126 40
Responder, n (%) 71 (56.3) 11 (27.5)
Nonresponder, n (%) 55 (43.7) 29 (72.5)
95% CI (%)† (47.23–65.16) (14.60–43.89)
Versus control
Responder rate difference, % 28.85
95% CI (%)‡ 11.16–45.60
p-value§ 0.0019
For the untreated control group, data before receiving initial treatment at Month 6 are included.
* Participants with analysis values at baseline and the specified visit.
† 95% CI is based on the exact binomial distribution.
‡ 95% exact CI for the responder rate difference is presented.
§ p-value is based on 2-sided Fisher's exact test comparing the responder rate between treated and untreated control.
On the GAIS, EIs rated 91.2% (114/125) as “improved” or “much improved” in the treatment group and 19.5% (8/41) in the untreated control group at Month 6 (See Supplemental Digital Content, Figure S2, http://links.lww.com/DSS/A540). The treatment group responder rate remained high from Month 1 (94.0%) through Month 12 (91.2%) along with an increase at Month 1 after repeat treatment (98.6%; 70/71). The percentage of responders rated as “much improved” in the treatment group was notably high, with 61.6% at Month 6, 41.6% at Month 12, and 77.5% at Month 1 after repeat treatment. The participant self-evaluation on the GAIS was consistent with the EI assessments with most participants in the treatment group (87.3%; 110/126) rating as “improved” or “much improved” at Month 6. The treatment group responder rate remained high from Month 1 (95.5%) through Month 12 (82.4%) and was 97.1% at Month 1 after repeat treatment, similar to EI assessments. In addition, the mean change in chin volume assessed by 3D digital imaging showed a similar trend with (+)2.6 mL at Month 1, 2.4 mL Month 6, 2.2 cc at Month 12, and 3.9 cc at Month 1 after repeat treatment in the treatment group and 0.1 cc in the untreated control group.
The FACE-Q Satisfaction with Chin overall mean score for the treatment group was 34.9 at baseline and improved by a mean of 35.6 to a score of 71.3 at Month 6 (p < .001), whereas the mean score worsened by a mean of 3.3 from a baseline score of 35.1 for the untreated control group (See Supplemental Digital Content, Figure S3, http://links.lww.com/DSS/A541). The mean scores remained high from Month 1 (74.8) to Month 12 (66.4) and at Month 1 after repeat treatment (77.5).
The FACE-Q Psychological Well-Being overall mean score was 69.9 at baseline and improved by a mean of 15.4 at Month 6 for the treatment group, whereas the mean score worsened by a mean of −5.3 from 72.3 at Month 6 in the untreated control group (See Supplemental Digital Content, Figure S4, http://links.lww.com/DSS/A542). Most treatment group participants reported that they definitely/somewhat agree with each of the 10 individual FACE-Q Psychological Well-Being items at all timepoints, indicating positive well-being.
Safety
For initial/touch-up treatment, 14 treated participants (7.7%) had 20 treatment-related AEs (Table 3) while 3 (4.1%) had 7 treatment-related AEs after repeat treatment (See Supplemental Digital Content, Table S3, http://links.lww.com/DSS/A545). During the repeat treatment period, an injection site mass occurred in 2 participants (2.7%). The most common treatment-related AEs for the initial/touch-up treatment period were injection site erythema (1.6%, 3/182 participants) and injection site pain (1.6%, 3/182 participants). There were no deaths or unanticipated adverse effects. Facial sensation assessments found that treatment did not reduce chin area sensitivity at any timepoint throughout the study.
TABLE 3. Common Treatment-Related Adverse Events (AEs) After Initial/Touch-Up Treatment
Event, n Onset (d) Duration (d) Severity Resolution
Injection site abscess 6 9 Moderate Resolved w/o sequelae
Gingival pain 1 2 Moderate Resolved w/o sequelae
Acne cystic 6 134 Mild Resolved w/o sequelae
Injection site cellulitis 7 36 Severe Resolved w/o sequelae
Injection site inflammation 7 153 Severe Resolved w/o sequelae
w/o, without.
The type and frequency of injection site responses (ISRs) were similar in treatment group participants and treated control participants and are considered to be commonly reported events after treatment with HA soft tissue fillers (See Supplemental Digital Content, Table S4, http://links.lww.com/DSS/A546). Overall, 167 treated participants (92.3%) reported at least 1 ISR after initial treatment, 86 (82.7%) after touch-up treatment, and 55 (75.3%) after repeat treatment. The most frequently reported ISRs after initial treatment included tenderness to touch (81.8%), firmness (75.1%), and swelling (68.5%). Similar results were seen after repeat treatment, where the most common ISRs were also tenderness to touch (71.2%), firmness (69.9%), and swelling (58.9%). Most ISRs were mild or moderate in severity after initial, touch-up, and repeat treatment and resolved within 1 week based on total days from first to last occurrence according to the diaries. Participants assessed procedural pain (pain during injection) immediately after completion of each treatment on an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) and reported minimal pain, with a mean score of 2.3 for the treatment group at each treatment (initial, touch-up, and repeat).
Most treatment-related AEs were mild or moderate in severity (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 2.7% (5/182) of participants had mild treatment-related AEs and 4.4% (8/182) had moderate AEs. For repeat treatment, 4.1% (3/74) of participants had mild and 1.4% (1/74) moderate AEs. Two participants (1.1%) had 3 severe treatment-related AEs, including injection site inflammation and cellulitis in one participant and injection site induration in another participant.
Most treatment-related AEs resolved within 1 week (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 3 participants (1.6%) had 4 treatment-related AEs that lasted longer than 30 days. The first participant had injection site inflammation that lasted 153 days and injection site cellulitis that lasted 36 days. Treatment consisted of antibiotics, anti-inflammatories, and hyaluronidase. These 2 events were considered to be serious AEs. A second participant had injection site erythema that lasted 264 days. A third participant had an acne cyst that lasted 134 days. For repeat treatment, 1 participant (1.4%) had an injection site mass that lasted 42 days. Most treatment-related AEs began within 7 days of treatment. There were no treatment-related AEs that began >30 days after repeat treatment. All treatment-related AEs resolved without sequelae during the study period.
A lower incidence of ISRs was observed for injections with a cannula than without a cannula after initial touch-up and repeat treatments (See Supplemental Digital Content, Table S6, http://links.lww.com/DSS/A548). For initial/touch-up treatment with a cannula, 2 treated participants (4.5%) had 2 treatment-related AEs; without a cannula, 12 treated participants (8.7%) had 18 treatment-related AEs. For repeat treatment with a cannula, there were no treatment-related AEs; without a cannula, 3 treated participants (5.6%) had 7 treatment-related AEs.
Discussion
Although the primary end point was met, the ACRS responder rate of 56.3% was lower than expected. Comparatively, the midface study met its primary end point at Month 6, with 85.6% of treated participants having a clinically meaningful improvement.5 A possible reason for this discrepancy is the markedly higher injection volumes used in the midface study. This study used lower volumes, more closely representative of volumes used in real-world clinical practice. Another potential reason for this discrepancy is the different methods of evaluation. The midface study relied on live assessments, taking into account overall improvement. This study's assessment was limited to 2-dimensional cropped photographs, possibly obscuring a treatment effect because it relates to the whole face. This hypothesis is supported by the notably higher responder rate of 91.8% observed from the EI live assessments, which are more in line with the high responses observed with the GAIS and FACE-Q measures. Another supportive observation is the control responder rate at Month 6, which was observably lower in this study compared with the midface study, 27.5% versus 38.9%, respectively, indicating a lower false-positive rate.5 Although photograph assessments, rather than live assessments, were intended to help raters more consistently assess the relationship between landmarks, the use of cropped photographs as a primary measure may represent a study limitation. Other study limitations may have included the single-blind design, which left participants and injectors unblinded, and that control data were only available through month 6, although data could still be compared with baseline beyond Month 6.
VYC-20L was well tolerated, with most treatment-related AEs being ISRs of mild to moderate severity. Notably, there was an overall decrease in the number of AEs with repeat treatment compared with initial/touch-up treatment. One possibility is the lower volume injected during repeat treatment. Lower AE rates are commonly observed after repeat treatment. In addition, a lower number of AEs were associated with the use of cannulas versus needle injection, which is likely due to the ability of cannulas to assist injectors in avoiding sharp trauma and bruising,4,17,18 although there may be confounding factors as patients were not randomized to a needle or cannula. In a retrospective study of 50 patients treated with VYC 20L administered by a cannula, 8% of patients experienced procedure-related ecchymosis, which was self-limiting and nonserious.19 In a study that compared needle versus cannula in the treatment of nasolabial folds found the use of a cannula had significantly fewer AEs (pain, edema, redness, and hematoma) while maintaining similar efficacy to needle injection.17
One patient experienced 2 serious AEs related to the treatment, injection site cellulitis and injection site inflammation, which resolved without sequelae. The patient experienced severe inflammation beginning 7 days after touch-up treatment. She was admitted to the hospital for treatment with intravenous antibiotics and drainage of the abscess. Cultures of the abscess were negative for gram-positive and gram-negative bacteria. This type of event has been previously reported, although they are not typically observed in prospective clinical studies, in part due to their relatively low incidence.20 The etiology of late-onset inflammation and nodules after soft tissue filler treatment is not well understood and has been attributed to hypersensitivity, foreign body reaction, injection placement, infection, and biofilm development.21
Several soft tissue fillers have been previously reported in the literature for use in chin augmentation19,22–25; VYC-25L (Juvéderm Volux; Allergan plc) being the first HA soft tissue filler designed for chin augmentation and systematically investigated in a randomized controlled clinical trial for safety and effectiveness.25 Similar to VYC-20L, objective and subjective measures for VYC-25L showed sustained clinically meaningful benefits through Month 12, with comparable safety profiles where the incidence of ISRs and AEs were consistent for HA soft tissue fillers. The mean change from baseline to Month 12 in the glabella-subnasale-pogonion angle was 1.28°, and investigator and participant assessments on the GAIS at Month 12 were 83.5% and 77.2%, respectively. FACE-Q Satisfaction with Chin module and Psychological Well-Being module mean scores showed continued improvement over baseline (41.4 and 65.3, respectively) at Month 12 (61.6 and 74.4).
Conclusions
VYC-20L treatment is safe and effective when injected in the chin and prejowl sulci to treat chin retrusion, with results lasting through 1 year.
Acknowledgments
The authors sincerely thank the patients who participated in this study and acknowledge the additional investigators and staff who contributed to the study conduct, including Jeffrey Dover, MD; Todd Schlesinger, MD; Leslie Baumann, MD; Mitchel Goldman, MD; Dee Anna Glaser, MD; Jeanine Downie, MD; Valerie Callender, MD; Edwin Williams, MD; and William P. Werschler, MD.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.dermatologicsurgery.org).
This study was sponsored by Allergan plc, Dublin, Ireland. Medical writing assistance was provided to the authors by W. Kim of Allergan plc, Irvine, CA. All authors met the ICMJE authorship criteria. Neither honoraria nor any other form of compensation was provided for authorship. K. Beer, J. Kaufman-Janette, D. Bank, and S. Dayan have received funding as an investigator, consultant, and trainer for Allergan. B. Biesman has received consulting fees and research funding from Allergan. W. Kim, S. Chawla, and A. Schumacher are employees of Allergan plc and may own stock in the company. | VYC?20L (HYALURONIC ACID SOFT TISSUE FILLER WITH LIDOCAINE) | DrugDosageText | CC BY-NC-ND | 33347003 | 18,840,355 | 2021-01-01 |
What was the dosage of drug 'LIDOCAINE'? | Safe and Effective Chin Augmentation With the Hyaluronic Acid Injectable Filler, VYC-20L.
VYC-20L is a hyaluronic acid soft tissue filler with lidocaine designed to restore facial volume.
Evaluate the safety and effectiveness of VYC-20L in patients with chin retrusion.
Adults with chin retrusion were randomized (3:1) to receive VYC-20L in the chin at study onset (treatment group) or 6 months later (control group). The primary effectiveness end point was ≥1-point improvement on the Allergan Chin Retrusion Scale (ACRS) from baseline at Month 6. Safety assessments included injection site responses (ISRs) and adverse events (AEs).
VYC-20L was administered to 192 participants (treatment group, n = 144; control group, n = 48). At Month 6, significantly more participants had an ACRS response in the treatment versus control group (56.3% vs 27.5%; p = .0019). Effectiveness was also demonstrated by the proportion of participants with improved/much improved Global Aesthetic Improvement Scale scores and responses on the FACE-Q Satisfaction with Chin questionnaire and FACE-Q Psychological Wellbeing module. Treatment benefit remained evident at Month 12. Most common ISRs were tenderness (81.1%) and firmness (75.1%). One participant (0.5%) discontinued the study due to 2 treatment-related serious AEs of facial cellulitis and injection site inflammation, both resolved without sequelae.
VYC-20L significantly improved an ACRS response and was generally safe and well tolerated.
Hyaluronic acid (HA) injectable gels are a proven treatment for facial rejuvenation with an established record of safety and effectiveness.1 In 2018, more than 2.1 million HA injectable filler procedures were performed in the United States—a 48% increase over the past decade.2,3 The FDA has approved a range of dermal and subcutaneous indications for HA injectable fillers, including facial wrinkles, folds, lip augmentation, and cheeks.4 One such product, VYC-20L (Juvéderm Voluma XC; Allergan plc, Dublin, Ireland), which is a 20-mg/mL HA gel with lidocaine, was specifically designed for volumizing and has demonstrated effectiveness in restoring age-related volume deficit to the midface.5 Compared with HA gels designed for correction of wrinkles and folds, VYC-20L improved qualities of lift and projection to the midface.
In addition to the midface, the chin area is another facial region where lift and projection are important aspects of volumizing. The chin is defined by the labiomental crease (superiorly), the oral commissures (laterally), and the submental cervical crease (inferiorly). The shape and projection of the chin contribute to a “well-balanced and harmonious” face.6 For both men and women, good chin projection and a youthful jawline are considered the standards of beauty7 and can influence an individual's psychosocial well-being.8 Although congenital elements are the predominant factor in chin aesthetics, aging can result in bony resorption and produce sagging9 as well as laxity and droop in the chin area.10 In addition, aging can result in lumps, bulges, and depressions in the prejowl sulci.11
VYC-20L is a temporary HA soft tissue filler developed to provide a safe, minimally invasive method to restore facial volume, which is also reversible by hyaluronidase in case of adverse events (AEs) requiring treatment.5,12 It is currently indicated in the United States for injection into the subcutaneous and/or supraperiosteal space of the midface to add volume in the cheek area and is approved in other countries for facial volumizing, including the chin and prejowl sulci.5,12–16 As the chin and prejowl sulci are high-mobility areas, VYC-20L represents an ideal option for its volumizing and lifting capabilities. This study was designed to collect effectiveness and safety data for VYC-20L in participants seeking to correct volume deficit and retrusion in the chin and prejowl sulci.
Methods
Study Design
This multicenter, randomized, evaluator-blinded, delayed treatment-controlled study was designed to evaluate the safety and effectiveness of VYC-20L injectable gel for correction of chin volume deficit. A no-treatment control was used because there were no FDA-approved soft tissue fillers for chin augmentation at the time of the study. Participants were randomized in a 3:1 ratio either to have treatment with VYC-20L (treatment group) or a 6-month control period, followed by optional treatment (control group). At the Month 12 visit, participants in the treatment group had the option of receiving repeat treatment, with routine follow-up visits for safety and effectiveness through 1 month after repeat treatment. Treated control group participants were only followed for safety, and no effectiveness measures were performed. Participants underwent a touch-up treatment 30 days after initial treatment to achieve optimal correction if needed. The study was conducted at 14 sites in the United States, each of which had a treating investigator (TI) and at least one blinded evaluating investigator (EI).
The TIs performed the treatments and monitored participant safety throughout the study. Blinded EIs performed all effectiveness assessments. For treatment, the TI used 27 G 1/2 -inch needles for supraperiosteal and/or subcutaneous injections into the pogonion, menton, and prejowl sulci; 25 G 1½-inch cannulas were permitted for supraperiosteal and/or subcutaneous injections in the menton and prejowl sulci. An appropriate injection volume for the chin and chin area was determined by the TI but was not to exceed a maximum total volume of 4.0 mL for initial and touch-up treatments combined and 4.0 mL for repeat treatment. After each treatment, participants completed a daily safety diary for up to 30 days. Visits for both effectiveness and safety occurred at months 1, 3, 6, 9, and 12 after the last treatment.
Participants were required to be aged 22 or older and desire chin augmentation to correct moderate or severe chin retrusion (Grades 2 or 3 on the validated 5-point photonumeric Allergan Chin Retrusion Scale [ACRS]) as determined by a live assessment by both the EI and TI. Participants were ineligible if they had undergone cosmetic facial plastic surgery, tissue grafting, or tissue augmentation with silicone, fat, or permanent dermal fillers; had clinically significant malocclusion (severe overbite); had dentures; any device covering the palate; tattoos; piercings; facial hair; or scars that would interfere with visual assessment of the chin area. Mandatory facial treatment washout periods before study entry were 36 months for semipermanent dermal fillers, 24 months for dermal fillers in the chin or jaw area, 12 months for dermal fillers in the lips or perioral area, and 6 months for mesotherapy, botulinum toxin below the subnasale, or cosmetic treatment (laser, photomodulation, intense pulsed light, radiofrequency, dermabrasion, chemical peel, liposuction, lipolysis, or other ablative procedures). Applicable institutional review boards approved the study protocol, and all participants provided written informed consent before study enrolment (www.clinicaltrials.gov, identifier NCT02833077).
Response Measures and Statistics
The primary end point was based on the EI's blinded assessment of overall chin retrusion using ACRS grades defined as none (0), minimal (1), moderate (2), severe (3), and extreme (4) (See Supplemental Digital Content, Table S1, http://links.lww.com/DSS/A543). The primary effectiveness measure used a profile-view image cropped to include only the participant's lower face for ACRS assessment, which is based on the relationship between facial anatomical landmarks. Photograph assessments, rather than live assessments, facilitated consistent head positioning and were intended to help raters assess the relationship between landmarks. A participant showing ≥1-point improvement (decrease) in an ACRS score compared with baseline was considered a responder. The primary evaluation timepoint for efficacy was Month 6 after last treatment for participants in the treatment group and Month 6 after randomization for participants in the control group (untreated). The primary effectiveness end point was met if the treatment group responder rate was statistically greater (>50%) than the control group at Month 6 based on a 2-sided Fisher's exact test with a 5% significance level.
The Global Aesthetic Improvement Scale (GAIS), as well as the Satisfaction with Chin and Psychosocial Well-Being modules of the FACE-Q questionnaire, was used for assessment of secondary effectiveness end points. For the GAIS, responder rates for the treatment group (with 95% exact confidence intervals [CIs]) were based on EI and participant assessments. A “responder” was a participant who showed improvement (i.e., improved or much improved) on the overall aesthetic assessment in the chin area at the Month 6 visit. For the Satisfaction with Chin module of the FACE-Q questionnaire, the change from baseline to Month 6 visit in overall scores and a 2-sided paired t-test at the 5% level were used to demonstrate that the mean overall satisfaction score at the Month 6 visit was statistically greater than baseline for the treatment group. Volume change from baseline was measured by a blinded Canfield image analysis technician from three-dimensional (3D) imaging of the participant's facial profile pretreatment and post-treatment for both the treatment and control groups at the 6 Month visit.
Participants
A total of 221 participants were enrolled in the study, with an average of 14 (range 11–21) per investigational site. A total of 192 participants were randomized after 29 participants were screen failures, resulting in 144 in the treatment group and 48 in the control group. One hundred sixty-nine participants (88.0%) completed the Month 6 visit and 167 participants (87.0%) completed the study, with 25 participants (13.0%) discontinuing after randomization. Eighty-eight participants received touch-up treatment and 74 received repeat treatment. For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment. All initial and touch-up treatments occurred between June 28, 2016, and January 25, 2018, and all repeat treatments occurred between July 11, 2017, and August 23, 2018. The treatment and control groups were similar in terms of all demographic and baseline characteristics (See Supplemental Digital Content, Table S2, http://links.lww.com/DSS/A544). Among the 192 enrolled participants, the majority were women (88.5%) and White (81.8%), with a median age at study entry of 52 years (range, 22–80) and mean body mass index of 25.0 kg/m2. Fitzpatrick skin types were I/II (34.9%), III/IV (52.1%), and V/VI (13.0%).
Treatment
Anesthesia was administered to 75.0% (108/144) of participants in the treatment group, with the most common being topical (69.4%, 75/108; median duration 29.0 minutes) while ice was less common (34.3%, 37/108; median duration 15.0 minutes). The primary plane of injection used during the initial treatment was supraperiosteal (99.3%), followed by subcutaneous (63.0%). At touch-up and repeat treatments, the most common injection planes were also supraperiosteal (90.9% and 100.0%, respectively) and subcutaneous (53.4% and 59.5%, respectively). Planes and techniques were similar for the treated control participants. 99.3% of treatment group participants were treated in the pogonion, 77.8% in the menton, and 87.5% in the prejowl sulci. At the touch-up visit, 78.4% of treatment group participants were treated in the pogonion, 52.3% in the menton, and 65.9% in the prejowl sulci. At the repeat treatment visit, 93.2% were treated in the pogonion, 56.8% in the menton, and 66.2% in the prejowl sulci.
Needles were used for 100% of participants, and cannulas were used for 25.0% at initial treatment. There were no cannula/needle malfunctions. Treatment administration was similar for the treated control participants. Treating investigators rated ease of injection and product moldability on an 11-point scale, difficult (0) to easy (10), and stiff (0) to moldable (10), respectively. A total of 66.0% and 21.5% of participants were scored as 10 and 9, respectively, for ease of injection, whereas 62.5% and 20.8% of participants were scored as 10 and 9, respectively, for product moldability.
In the treatment group, 144 participants received initial treatment, 88 received touch-up treatment, and 74 received repeat treatment (Table 1). For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment, with injection volumes similar to the treatment group. The median total initial injection volume was 2.2 mL (range, 0.7–4.0 mL) for the treatment group (initial treatment and touch-up combined) and 2.8 mL (range, 1.3–4.0 mL) for the treated control group (initial treatment and touch-up combined). The median total injection volume for repeat treatment was 1.2 mL (range, 0.2–4.0 mL).
TABLE 1. Injection Volumes (Safety Population)
Total Volume Injected Treatment (N = 144) Control (N = 48)
Initial treatment volume (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 1.9 (0.6) 2.1 (0.6)
Median (range) 2 (0.7–4.0) 2 (1.0–3.8)
Initial/touch-up treatment volume combined (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 2.6 (1.0) 2.7 (0.8)
Median (range) 2.2 (0.7–4.0) 2.8 (1.3–4.0)
Repeat treatment volume (mL)
Received treatment, n (%) 74 (51.4) 0 (0.0)
Mean (SD) 1.4 (0.8) N/A
Median (range) 1.2 (0.2–4.0) N/A
For the control group, data after receiving initial treatment at Month 6 are included.
Results
Effectiveness
The primary efficacy end point was met with 56.3% ACRS responders (photograph assessment) at Month 6, which was greater than 50% and significantly greater than the responder rate for the untreated control group (27.5%, p = .0019) (Table 2). In addition, the ACRS responder rate in the treatment group was 70.1% at Month 1, 57.6% at Month 12, and 73.9% at Month 1 after repeat treatment (See Supplemental Digital Content, Figure S1, http://links.lww.com/DSS/A539). The median ACRS scores improved by a median of 1 point from a baseline score of 3 in the treatment group, whereas the control group remained at a score of 2.5. Notably, the Month 6 responder rate from the EI live assessment was markedly higher than results from the photograph assessment with 91.8% for the treatment group and 23.3% for the control group, a difference of 68.42% (p < .0001).
TABLE 2. Allergan Chin Retrusion Scale Results at Month 6 (Modified Intent-to-Treat Population)
Treatment (N = 144) Control (N = 48)
Month 6
Total participants, n* 126 40
Responder, n (%) 71 (56.3) 11 (27.5)
Nonresponder, n (%) 55 (43.7) 29 (72.5)
95% CI (%)† (47.23–65.16) (14.60–43.89)
Versus control
Responder rate difference, % 28.85
95% CI (%)‡ 11.16–45.60
p-value§ 0.0019
For the untreated control group, data before receiving initial treatment at Month 6 are included.
* Participants with analysis values at baseline and the specified visit.
† 95% CI is based on the exact binomial distribution.
‡ 95% exact CI for the responder rate difference is presented.
§ p-value is based on 2-sided Fisher's exact test comparing the responder rate between treated and untreated control.
On the GAIS, EIs rated 91.2% (114/125) as “improved” or “much improved” in the treatment group and 19.5% (8/41) in the untreated control group at Month 6 (See Supplemental Digital Content, Figure S2, http://links.lww.com/DSS/A540). The treatment group responder rate remained high from Month 1 (94.0%) through Month 12 (91.2%) along with an increase at Month 1 after repeat treatment (98.6%; 70/71). The percentage of responders rated as “much improved” in the treatment group was notably high, with 61.6% at Month 6, 41.6% at Month 12, and 77.5% at Month 1 after repeat treatment. The participant self-evaluation on the GAIS was consistent with the EI assessments with most participants in the treatment group (87.3%; 110/126) rating as “improved” or “much improved” at Month 6. The treatment group responder rate remained high from Month 1 (95.5%) through Month 12 (82.4%) and was 97.1% at Month 1 after repeat treatment, similar to EI assessments. In addition, the mean change in chin volume assessed by 3D digital imaging showed a similar trend with (+)2.6 mL at Month 1, 2.4 mL Month 6, 2.2 cc at Month 12, and 3.9 cc at Month 1 after repeat treatment in the treatment group and 0.1 cc in the untreated control group.
The FACE-Q Satisfaction with Chin overall mean score for the treatment group was 34.9 at baseline and improved by a mean of 35.6 to a score of 71.3 at Month 6 (p < .001), whereas the mean score worsened by a mean of 3.3 from a baseline score of 35.1 for the untreated control group (See Supplemental Digital Content, Figure S3, http://links.lww.com/DSS/A541). The mean scores remained high from Month 1 (74.8) to Month 12 (66.4) and at Month 1 after repeat treatment (77.5).
The FACE-Q Psychological Well-Being overall mean score was 69.9 at baseline and improved by a mean of 15.4 at Month 6 for the treatment group, whereas the mean score worsened by a mean of −5.3 from 72.3 at Month 6 in the untreated control group (See Supplemental Digital Content, Figure S4, http://links.lww.com/DSS/A542). Most treatment group participants reported that they definitely/somewhat agree with each of the 10 individual FACE-Q Psychological Well-Being items at all timepoints, indicating positive well-being.
Safety
For initial/touch-up treatment, 14 treated participants (7.7%) had 20 treatment-related AEs (Table 3) while 3 (4.1%) had 7 treatment-related AEs after repeat treatment (See Supplemental Digital Content, Table S3, http://links.lww.com/DSS/A545). During the repeat treatment period, an injection site mass occurred in 2 participants (2.7%). The most common treatment-related AEs for the initial/touch-up treatment period were injection site erythema (1.6%, 3/182 participants) and injection site pain (1.6%, 3/182 participants). There were no deaths or unanticipated adverse effects. Facial sensation assessments found that treatment did not reduce chin area sensitivity at any timepoint throughout the study.
TABLE 3. Common Treatment-Related Adverse Events (AEs) After Initial/Touch-Up Treatment
Event, n Onset (d) Duration (d) Severity Resolution
Injection site abscess 6 9 Moderate Resolved w/o sequelae
Gingival pain 1 2 Moderate Resolved w/o sequelae
Acne cystic 6 134 Mild Resolved w/o sequelae
Injection site cellulitis 7 36 Severe Resolved w/o sequelae
Injection site inflammation 7 153 Severe Resolved w/o sequelae
w/o, without.
The type and frequency of injection site responses (ISRs) were similar in treatment group participants and treated control participants and are considered to be commonly reported events after treatment with HA soft tissue fillers (See Supplemental Digital Content, Table S4, http://links.lww.com/DSS/A546). Overall, 167 treated participants (92.3%) reported at least 1 ISR after initial treatment, 86 (82.7%) after touch-up treatment, and 55 (75.3%) after repeat treatment. The most frequently reported ISRs after initial treatment included tenderness to touch (81.8%), firmness (75.1%), and swelling (68.5%). Similar results were seen after repeat treatment, where the most common ISRs were also tenderness to touch (71.2%), firmness (69.9%), and swelling (58.9%). Most ISRs were mild or moderate in severity after initial, touch-up, and repeat treatment and resolved within 1 week based on total days from first to last occurrence according to the diaries. Participants assessed procedural pain (pain during injection) immediately after completion of each treatment on an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) and reported minimal pain, with a mean score of 2.3 for the treatment group at each treatment (initial, touch-up, and repeat).
Most treatment-related AEs were mild or moderate in severity (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 2.7% (5/182) of participants had mild treatment-related AEs and 4.4% (8/182) had moderate AEs. For repeat treatment, 4.1% (3/74) of participants had mild and 1.4% (1/74) moderate AEs. Two participants (1.1%) had 3 severe treatment-related AEs, including injection site inflammation and cellulitis in one participant and injection site induration in another participant.
Most treatment-related AEs resolved within 1 week (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 3 participants (1.6%) had 4 treatment-related AEs that lasted longer than 30 days. The first participant had injection site inflammation that lasted 153 days and injection site cellulitis that lasted 36 days. Treatment consisted of antibiotics, anti-inflammatories, and hyaluronidase. These 2 events were considered to be serious AEs. A second participant had injection site erythema that lasted 264 days. A third participant had an acne cyst that lasted 134 days. For repeat treatment, 1 participant (1.4%) had an injection site mass that lasted 42 days. Most treatment-related AEs began within 7 days of treatment. There were no treatment-related AEs that began >30 days after repeat treatment. All treatment-related AEs resolved without sequelae during the study period.
A lower incidence of ISRs was observed for injections with a cannula than without a cannula after initial touch-up and repeat treatments (See Supplemental Digital Content, Table S6, http://links.lww.com/DSS/A548). For initial/touch-up treatment with a cannula, 2 treated participants (4.5%) had 2 treatment-related AEs; without a cannula, 12 treated participants (8.7%) had 18 treatment-related AEs. For repeat treatment with a cannula, there were no treatment-related AEs; without a cannula, 3 treated participants (5.6%) had 7 treatment-related AEs.
Discussion
Although the primary end point was met, the ACRS responder rate of 56.3% was lower than expected. Comparatively, the midface study met its primary end point at Month 6, with 85.6% of treated participants having a clinically meaningful improvement.5 A possible reason for this discrepancy is the markedly higher injection volumes used in the midface study. This study used lower volumes, more closely representative of volumes used in real-world clinical practice. Another potential reason for this discrepancy is the different methods of evaluation. The midface study relied on live assessments, taking into account overall improvement. This study's assessment was limited to 2-dimensional cropped photographs, possibly obscuring a treatment effect because it relates to the whole face. This hypothesis is supported by the notably higher responder rate of 91.8% observed from the EI live assessments, which are more in line with the high responses observed with the GAIS and FACE-Q measures. Another supportive observation is the control responder rate at Month 6, which was observably lower in this study compared with the midface study, 27.5% versus 38.9%, respectively, indicating a lower false-positive rate.5 Although photograph assessments, rather than live assessments, were intended to help raters more consistently assess the relationship between landmarks, the use of cropped photographs as a primary measure may represent a study limitation. Other study limitations may have included the single-blind design, which left participants and injectors unblinded, and that control data were only available through month 6, although data could still be compared with baseline beyond Month 6.
VYC-20L was well tolerated, with most treatment-related AEs being ISRs of mild to moderate severity. Notably, there was an overall decrease in the number of AEs with repeat treatment compared with initial/touch-up treatment. One possibility is the lower volume injected during repeat treatment. Lower AE rates are commonly observed after repeat treatment. In addition, a lower number of AEs were associated with the use of cannulas versus needle injection, which is likely due to the ability of cannulas to assist injectors in avoiding sharp trauma and bruising,4,17,18 although there may be confounding factors as patients were not randomized to a needle or cannula. In a retrospective study of 50 patients treated with VYC 20L administered by a cannula, 8% of patients experienced procedure-related ecchymosis, which was self-limiting and nonserious.19 In a study that compared needle versus cannula in the treatment of nasolabial folds found the use of a cannula had significantly fewer AEs (pain, edema, redness, and hematoma) while maintaining similar efficacy to needle injection.17
One patient experienced 2 serious AEs related to the treatment, injection site cellulitis and injection site inflammation, which resolved without sequelae. The patient experienced severe inflammation beginning 7 days after touch-up treatment. She was admitted to the hospital for treatment with intravenous antibiotics and drainage of the abscess. Cultures of the abscess were negative for gram-positive and gram-negative bacteria. This type of event has been previously reported, although they are not typically observed in prospective clinical studies, in part due to their relatively low incidence.20 The etiology of late-onset inflammation and nodules after soft tissue filler treatment is not well understood and has been attributed to hypersensitivity, foreign body reaction, injection placement, infection, and biofilm development.21
Several soft tissue fillers have been previously reported in the literature for use in chin augmentation19,22–25; VYC-25L (Juvéderm Volux; Allergan plc) being the first HA soft tissue filler designed for chin augmentation and systematically investigated in a randomized controlled clinical trial for safety and effectiveness.25 Similar to VYC-20L, objective and subjective measures for VYC-25L showed sustained clinically meaningful benefits through Month 12, with comparable safety profiles where the incidence of ISRs and AEs were consistent for HA soft tissue fillers. The mean change from baseline to Month 12 in the glabella-subnasale-pogonion angle was 1.28°, and investigator and participant assessments on the GAIS at Month 12 were 83.5% and 77.2%, respectively. FACE-Q Satisfaction with Chin module and Psychological Well-Being module mean scores showed continued improvement over baseline (41.4 and 65.3, respectively) at Month 12 (61.6 and 74.4).
Conclusions
VYC-20L treatment is safe and effective when injected in the chin and prejowl sulci to treat chin retrusion, with results lasting through 1 year.
Acknowledgments
The authors sincerely thank the patients who participated in this study and acknowledge the additional investigators and staff who contributed to the study conduct, including Jeffrey Dover, MD; Todd Schlesinger, MD; Leslie Baumann, MD; Mitchel Goldman, MD; Dee Anna Glaser, MD; Jeanine Downie, MD; Valerie Callender, MD; Edwin Williams, MD; and William P. Werschler, MD.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.dermatologicsurgery.org).
This study was sponsored by Allergan plc, Dublin, Ireland. Medical writing assistance was provided to the authors by W. Kim of Allergan plc, Irvine, CA. All authors met the ICMJE authorship criteria. Neither honoraria nor any other form of compensation was provided for authorship. K. Beer, J. Kaufman-Janette, D. Bank, and S. Dayan have received funding as an investigator, consultant, and trainer for Allergan. B. Biesman has received consulting fees and research funding from Allergan. W. Kim, S. Chawla, and A. Schumacher are employees of Allergan plc and may own stock in the company. | VYC?20L (HYALURONIC ACID SOFT TISSUE FILLER WITH LIDOCAINE) | DrugDosageText | CC BY-NC-ND | 33347003 | 18,840,355 | 2021-01-01 |
What was the outcome of reaction 'Cellulitis'? | Safe and Effective Chin Augmentation With the Hyaluronic Acid Injectable Filler, VYC-20L.
VYC-20L is a hyaluronic acid soft tissue filler with lidocaine designed to restore facial volume.
Evaluate the safety and effectiveness of VYC-20L in patients with chin retrusion.
Adults with chin retrusion were randomized (3:1) to receive VYC-20L in the chin at study onset (treatment group) or 6 months later (control group). The primary effectiveness end point was ≥1-point improvement on the Allergan Chin Retrusion Scale (ACRS) from baseline at Month 6. Safety assessments included injection site responses (ISRs) and adverse events (AEs).
VYC-20L was administered to 192 participants (treatment group, n = 144; control group, n = 48). At Month 6, significantly more participants had an ACRS response in the treatment versus control group (56.3% vs 27.5%; p = .0019). Effectiveness was also demonstrated by the proportion of participants with improved/much improved Global Aesthetic Improvement Scale scores and responses on the FACE-Q Satisfaction with Chin questionnaire and FACE-Q Psychological Wellbeing module. Treatment benefit remained evident at Month 12. Most common ISRs were tenderness (81.1%) and firmness (75.1%). One participant (0.5%) discontinued the study due to 2 treatment-related serious AEs of facial cellulitis and injection site inflammation, both resolved without sequelae.
VYC-20L significantly improved an ACRS response and was generally safe and well tolerated.
Hyaluronic acid (HA) injectable gels are a proven treatment for facial rejuvenation with an established record of safety and effectiveness.1 In 2018, more than 2.1 million HA injectable filler procedures were performed in the United States—a 48% increase over the past decade.2,3 The FDA has approved a range of dermal and subcutaneous indications for HA injectable fillers, including facial wrinkles, folds, lip augmentation, and cheeks.4 One such product, VYC-20L (Juvéderm Voluma XC; Allergan plc, Dublin, Ireland), which is a 20-mg/mL HA gel with lidocaine, was specifically designed for volumizing and has demonstrated effectiveness in restoring age-related volume deficit to the midface.5 Compared with HA gels designed for correction of wrinkles and folds, VYC-20L improved qualities of lift and projection to the midface.
In addition to the midface, the chin area is another facial region where lift and projection are important aspects of volumizing. The chin is defined by the labiomental crease (superiorly), the oral commissures (laterally), and the submental cervical crease (inferiorly). The shape and projection of the chin contribute to a “well-balanced and harmonious” face.6 For both men and women, good chin projection and a youthful jawline are considered the standards of beauty7 and can influence an individual's psychosocial well-being.8 Although congenital elements are the predominant factor in chin aesthetics, aging can result in bony resorption and produce sagging9 as well as laxity and droop in the chin area.10 In addition, aging can result in lumps, bulges, and depressions in the prejowl sulci.11
VYC-20L is a temporary HA soft tissue filler developed to provide a safe, minimally invasive method to restore facial volume, which is also reversible by hyaluronidase in case of adverse events (AEs) requiring treatment.5,12 It is currently indicated in the United States for injection into the subcutaneous and/or supraperiosteal space of the midface to add volume in the cheek area and is approved in other countries for facial volumizing, including the chin and prejowl sulci.5,12–16 As the chin and prejowl sulci are high-mobility areas, VYC-20L represents an ideal option for its volumizing and lifting capabilities. This study was designed to collect effectiveness and safety data for VYC-20L in participants seeking to correct volume deficit and retrusion in the chin and prejowl sulci.
Methods
Study Design
This multicenter, randomized, evaluator-blinded, delayed treatment-controlled study was designed to evaluate the safety and effectiveness of VYC-20L injectable gel for correction of chin volume deficit. A no-treatment control was used because there were no FDA-approved soft tissue fillers for chin augmentation at the time of the study. Participants were randomized in a 3:1 ratio either to have treatment with VYC-20L (treatment group) or a 6-month control period, followed by optional treatment (control group). At the Month 12 visit, participants in the treatment group had the option of receiving repeat treatment, with routine follow-up visits for safety and effectiveness through 1 month after repeat treatment. Treated control group participants were only followed for safety, and no effectiveness measures were performed. Participants underwent a touch-up treatment 30 days after initial treatment to achieve optimal correction if needed. The study was conducted at 14 sites in the United States, each of which had a treating investigator (TI) and at least one blinded evaluating investigator (EI).
The TIs performed the treatments and monitored participant safety throughout the study. Blinded EIs performed all effectiveness assessments. For treatment, the TI used 27 G 1/2 -inch needles for supraperiosteal and/or subcutaneous injections into the pogonion, menton, and prejowl sulci; 25 G 1½-inch cannulas were permitted for supraperiosteal and/or subcutaneous injections in the menton and prejowl sulci. An appropriate injection volume for the chin and chin area was determined by the TI but was not to exceed a maximum total volume of 4.0 mL for initial and touch-up treatments combined and 4.0 mL for repeat treatment. After each treatment, participants completed a daily safety diary for up to 30 days. Visits for both effectiveness and safety occurred at months 1, 3, 6, 9, and 12 after the last treatment.
Participants were required to be aged 22 or older and desire chin augmentation to correct moderate or severe chin retrusion (Grades 2 or 3 on the validated 5-point photonumeric Allergan Chin Retrusion Scale [ACRS]) as determined by a live assessment by both the EI and TI. Participants were ineligible if they had undergone cosmetic facial plastic surgery, tissue grafting, or tissue augmentation with silicone, fat, or permanent dermal fillers; had clinically significant malocclusion (severe overbite); had dentures; any device covering the palate; tattoos; piercings; facial hair; or scars that would interfere with visual assessment of the chin area. Mandatory facial treatment washout periods before study entry were 36 months for semipermanent dermal fillers, 24 months for dermal fillers in the chin or jaw area, 12 months for dermal fillers in the lips or perioral area, and 6 months for mesotherapy, botulinum toxin below the subnasale, or cosmetic treatment (laser, photomodulation, intense pulsed light, radiofrequency, dermabrasion, chemical peel, liposuction, lipolysis, or other ablative procedures). Applicable institutional review boards approved the study protocol, and all participants provided written informed consent before study enrolment (www.clinicaltrials.gov, identifier NCT02833077).
Response Measures and Statistics
The primary end point was based on the EI's blinded assessment of overall chin retrusion using ACRS grades defined as none (0), minimal (1), moderate (2), severe (3), and extreme (4) (See Supplemental Digital Content, Table S1, http://links.lww.com/DSS/A543). The primary effectiveness measure used a profile-view image cropped to include only the participant's lower face for ACRS assessment, which is based on the relationship between facial anatomical landmarks. Photograph assessments, rather than live assessments, facilitated consistent head positioning and were intended to help raters assess the relationship between landmarks. A participant showing ≥1-point improvement (decrease) in an ACRS score compared with baseline was considered a responder. The primary evaluation timepoint for efficacy was Month 6 after last treatment for participants in the treatment group and Month 6 after randomization for participants in the control group (untreated). The primary effectiveness end point was met if the treatment group responder rate was statistically greater (>50%) than the control group at Month 6 based on a 2-sided Fisher's exact test with a 5% significance level.
The Global Aesthetic Improvement Scale (GAIS), as well as the Satisfaction with Chin and Psychosocial Well-Being modules of the FACE-Q questionnaire, was used for assessment of secondary effectiveness end points. For the GAIS, responder rates for the treatment group (with 95% exact confidence intervals [CIs]) were based on EI and participant assessments. A “responder” was a participant who showed improvement (i.e., improved or much improved) on the overall aesthetic assessment in the chin area at the Month 6 visit. For the Satisfaction with Chin module of the FACE-Q questionnaire, the change from baseline to Month 6 visit in overall scores and a 2-sided paired t-test at the 5% level were used to demonstrate that the mean overall satisfaction score at the Month 6 visit was statistically greater than baseline for the treatment group. Volume change from baseline was measured by a blinded Canfield image analysis technician from three-dimensional (3D) imaging of the participant's facial profile pretreatment and post-treatment for both the treatment and control groups at the 6 Month visit.
Participants
A total of 221 participants were enrolled in the study, with an average of 14 (range 11–21) per investigational site. A total of 192 participants were randomized after 29 participants were screen failures, resulting in 144 in the treatment group and 48 in the control group. One hundred sixty-nine participants (88.0%) completed the Month 6 visit and 167 participants (87.0%) completed the study, with 25 participants (13.0%) discontinuing after randomization. Eighty-eight participants received touch-up treatment and 74 received repeat treatment. For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment. All initial and touch-up treatments occurred between June 28, 2016, and January 25, 2018, and all repeat treatments occurred between July 11, 2017, and August 23, 2018. The treatment and control groups were similar in terms of all demographic and baseline characteristics (See Supplemental Digital Content, Table S2, http://links.lww.com/DSS/A544). Among the 192 enrolled participants, the majority were women (88.5%) and White (81.8%), with a median age at study entry of 52 years (range, 22–80) and mean body mass index of 25.0 kg/m2. Fitzpatrick skin types were I/II (34.9%), III/IV (52.1%), and V/VI (13.0%).
Treatment
Anesthesia was administered to 75.0% (108/144) of participants in the treatment group, with the most common being topical (69.4%, 75/108; median duration 29.0 minutes) while ice was less common (34.3%, 37/108; median duration 15.0 minutes). The primary plane of injection used during the initial treatment was supraperiosteal (99.3%), followed by subcutaneous (63.0%). At touch-up and repeat treatments, the most common injection planes were also supraperiosteal (90.9% and 100.0%, respectively) and subcutaneous (53.4% and 59.5%, respectively). Planes and techniques were similar for the treated control participants. 99.3% of treatment group participants were treated in the pogonion, 77.8% in the menton, and 87.5% in the prejowl sulci. At the touch-up visit, 78.4% of treatment group participants were treated in the pogonion, 52.3% in the menton, and 65.9% in the prejowl sulci. At the repeat treatment visit, 93.2% were treated in the pogonion, 56.8% in the menton, and 66.2% in the prejowl sulci.
Needles were used for 100% of participants, and cannulas were used for 25.0% at initial treatment. There were no cannula/needle malfunctions. Treatment administration was similar for the treated control participants. Treating investigators rated ease of injection and product moldability on an 11-point scale, difficult (0) to easy (10), and stiff (0) to moldable (10), respectively. A total of 66.0% and 21.5% of participants were scored as 10 and 9, respectively, for ease of injection, whereas 62.5% and 20.8% of participants were scored as 10 and 9, respectively, for product moldability.
In the treatment group, 144 participants received initial treatment, 88 received touch-up treatment, and 74 received repeat treatment (Table 1). For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment, with injection volumes similar to the treatment group. The median total initial injection volume was 2.2 mL (range, 0.7–4.0 mL) for the treatment group (initial treatment and touch-up combined) and 2.8 mL (range, 1.3–4.0 mL) for the treated control group (initial treatment and touch-up combined). The median total injection volume for repeat treatment was 1.2 mL (range, 0.2–4.0 mL).
TABLE 1. Injection Volumes (Safety Population)
Total Volume Injected Treatment (N = 144) Control (N = 48)
Initial treatment volume (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 1.9 (0.6) 2.1 (0.6)
Median (range) 2 (0.7–4.0) 2 (1.0–3.8)
Initial/touch-up treatment volume combined (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 2.6 (1.0) 2.7 (0.8)
Median (range) 2.2 (0.7–4.0) 2.8 (1.3–4.0)
Repeat treatment volume (mL)
Received treatment, n (%) 74 (51.4) 0 (0.0)
Mean (SD) 1.4 (0.8) N/A
Median (range) 1.2 (0.2–4.0) N/A
For the control group, data after receiving initial treatment at Month 6 are included.
Results
Effectiveness
The primary efficacy end point was met with 56.3% ACRS responders (photograph assessment) at Month 6, which was greater than 50% and significantly greater than the responder rate for the untreated control group (27.5%, p = .0019) (Table 2). In addition, the ACRS responder rate in the treatment group was 70.1% at Month 1, 57.6% at Month 12, and 73.9% at Month 1 after repeat treatment (See Supplemental Digital Content, Figure S1, http://links.lww.com/DSS/A539). The median ACRS scores improved by a median of 1 point from a baseline score of 3 in the treatment group, whereas the control group remained at a score of 2.5. Notably, the Month 6 responder rate from the EI live assessment was markedly higher than results from the photograph assessment with 91.8% for the treatment group and 23.3% for the control group, a difference of 68.42% (p < .0001).
TABLE 2. Allergan Chin Retrusion Scale Results at Month 6 (Modified Intent-to-Treat Population)
Treatment (N = 144) Control (N = 48)
Month 6
Total participants, n* 126 40
Responder, n (%) 71 (56.3) 11 (27.5)
Nonresponder, n (%) 55 (43.7) 29 (72.5)
95% CI (%)† (47.23–65.16) (14.60–43.89)
Versus control
Responder rate difference, % 28.85
95% CI (%)‡ 11.16–45.60
p-value§ 0.0019
For the untreated control group, data before receiving initial treatment at Month 6 are included.
* Participants with analysis values at baseline and the specified visit.
† 95% CI is based on the exact binomial distribution.
‡ 95% exact CI for the responder rate difference is presented.
§ p-value is based on 2-sided Fisher's exact test comparing the responder rate between treated and untreated control.
On the GAIS, EIs rated 91.2% (114/125) as “improved” or “much improved” in the treatment group and 19.5% (8/41) in the untreated control group at Month 6 (See Supplemental Digital Content, Figure S2, http://links.lww.com/DSS/A540). The treatment group responder rate remained high from Month 1 (94.0%) through Month 12 (91.2%) along with an increase at Month 1 after repeat treatment (98.6%; 70/71). The percentage of responders rated as “much improved” in the treatment group was notably high, with 61.6% at Month 6, 41.6% at Month 12, and 77.5% at Month 1 after repeat treatment. The participant self-evaluation on the GAIS was consistent with the EI assessments with most participants in the treatment group (87.3%; 110/126) rating as “improved” or “much improved” at Month 6. The treatment group responder rate remained high from Month 1 (95.5%) through Month 12 (82.4%) and was 97.1% at Month 1 after repeat treatment, similar to EI assessments. In addition, the mean change in chin volume assessed by 3D digital imaging showed a similar trend with (+)2.6 mL at Month 1, 2.4 mL Month 6, 2.2 cc at Month 12, and 3.9 cc at Month 1 after repeat treatment in the treatment group and 0.1 cc in the untreated control group.
The FACE-Q Satisfaction with Chin overall mean score for the treatment group was 34.9 at baseline and improved by a mean of 35.6 to a score of 71.3 at Month 6 (p < .001), whereas the mean score worsened by a mean of 3.3 from a baseline score of 35.1 for the untreated control group (See Supplemental Digital Content, Figure S3, http://links.lww.com/DSS/A541). The mean scores remained high from Month 1 (74.8) to Month 12 (66.4) and at Month 1 after repeat treatment (77.5).
The FACE-Q Psychological Well-Being overall mean score was 69.9 at baseline and improved by a mean of 15.4 at Month 6 for the treatment group, whereas the mean score worsened by a mean of −5.3 from 72.3 at Month 6 in the untreated control group (See Supplemental Digital Content, Figure S4, http://links.lww.com/DSS/A542). Most treatment group participants reported that they definitely/somewhat agree with each of the 10 individual FACE-Q Psychological Well-Being items at all timepoints, indicating positive well-being.
Safety
For initial/touch-up treatment, 14 treated participants (7.7%) had 20 treatment-related AEs (Table 3) while 3 (4.1%) had 7 treatment-related AEs after repeat treatment (See Supplemental Digital Content, Table S3, http://links.lww.com/DSS/A545). During the repeat treatment period, an injection site mass occurred in 2 participants (2.7%). The most common treatment-related AEs for the initial/touch-up treatment period were injection site erythema (1.6%, 3/182 participants) and injection site pain (1.6%, 3/182 participants). There were no deaths or unanticipated adverse effects. Facial sensation assessments found that treatment did not reduce chin area sensitivity at any timepoint throughout the study.
TABLE 3. Common Treatment-Related Adverse Events (AEs) After Initial/Touch-Up Treatment
Event, n Onset (d) Duration (d) Severity Resolution
Injection site abscess 6 9 Moderate Resolved w/o sequelae
Gingival pain 1 2 Moderate Resolved w/o sequelae
Acne cystic 6 134 Mild Resolved w/o sequelae
Injection site cellulitis 7 36 Severe Resolved w/o sequelae
Injection site inflammation 7 153 Severe Resolved w/o sequelae
w/o, without.
The type and frequency of injection site responses (ISRs) were similar in treatment group participants and treated control participants and are considered to be commonly reported events after treatment with HA soft tissue fillers (See Supplemental Digital Content, Table S4, http://links.lww.com/DSS/A546). Overall, 167 treated participants (92.3%) reported at least 1 ISR after initial treatment, 86 (82.7%) after touch-up treatment, and 55 (75.3%) after repeat treatment. The most frequently reported ISRs after initial treatment included tenderness to touch (81.8%), firmness (75.1%), and swelling (68.5%). Similar results were seen after repeat treatment, where the most common ISRs were also tenderness to touch (71.2%), firmness (69.9%), and swelling (58.9%). Most ISRs were mild or moderate in severity after initial, touch-up, and repeat treatment and resolved within 1 week based on total days from first to last occurrence according to the diaries. Participants assessed procedural pain (pain during injection) immediately after completion of each treatment on an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) and reported minimal pain, with a mean score of 2.3 for the treatment group at each treatment (initial, touch-up, and repeat).
Most treatment-related AEs were mild or moderate in severity (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 2.7% (5/182) of participants had mild treatment-related AEs and 4.4% (8/182) had moderate AEs. For repeat treatment, 4.1% (3/74) of participants had mild and 1.4% (1/74) moderate AEs. Two participants (1.1%) had 3 severe treatment-related AEs, including injection site inflammation and cellulitis in one participant and injection site induration in another participant.
Most treatment-related AEs resolved within 1 week (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 3 participants (1.6%) had 4 treatment-related AEs that lasted longer than 30 days. The first participant had injection site inflammation that lasted 153 days and injection site cellulitis that lasted 36 days. Treatment consisted of antibiotics, anti-inflammatories, and hyaluronidase. These 2 events were considered to be serious AEs. A second participant had injection site erythema that lasted 264 days. A third participant had an acne cyst that lasted 134 days. For repeat treatment, 1 participant (1.4%) had an injection site mass that lasted 42 days. Most treatment-related AEs began within 7 days of treatment. There were no treatment-related AEs that began >30 days after repeat treatment. All treatment-related AEs resolved without sequelae during the study period.
A lower incidence of ISRs was observed for injections with a cannula than without a cannula after initial touch-up and repeat treatments (See Supplemental Digital Content, Table S6, http://links.lww.com/DSS/A548). For initial/touch-up treatment with a cannula, 2 treated participants (4.5%) had 2 treatment-related AEs; without a cannula, 12 treated participants (8.7%) had 18 treatment-related AEs. For repeat treatment with a cannula, there were no treatment-related AEs; without a cannula, 3 treated participants (5.6%) had 7 treatment-related AEs.
Discussion
Although the primary end point was met, the ACRS responder rate of 56.3% was lower than expected. Comparatively, the midface study met its primary end point at Month 6, with 85.6% of treated participants having a clinically meaningful improvement.5 A possible reason for this discrepancy is the markedly higher injection volumes used in the midface study. This study used lower volumes, more closely representative of volumes used in real-world clinical practice. Another potential reason for this discrepancy is the different methods of evaluation. The midface study relied on live assessments, taking into account overall improvement. This study's assessment was limited to 2-dimensional cropped photographs, possibly obscuring a treatment effect because it relates to the whole face. This hypothesis is supported by the notably higher responder rate of 91.8% observed from the EI live assessments, which are more in line with the high responses observed with the GAIS and FACE-Q measures. Another supportive observation is the control responder rate at Month 6, which was observably lower in this study compared with the midface study, 27.5% versus 38.9%, respectively, indicating a lower false-positive rate.5 Although photograph assessments, rather than live assessments, were intended to help raters more consistently assess the relationship between landmarks, the use of cropped photographs as a primary measure may represent a study limitation. Other study limitations may have included the single-blind design, which left participants and injectors unblinded, and that control data were only available through month 6, although data could still be compared with baseline beyond Month 6.
VYC-20L was well tolerated, with most treatment-related AEs being ISRs of mild to moderate severity. Notably, there was an overall decrease in the number of AEs with repeat treatment compared with initial/touch-up treatment. One possibility is the lower volume injected during repeat treatment. Lower AE rates are commonly observed after repeat treatment. In addition, a lower number of AEs were associated with the use of cannulas versus needle injection, which is likely due to the ability of cannulas to assist injectors in avoiding sharp trauma and bruising,4,17,18 although there may be confounding factors as patients were not randomized to a needle or cannula. In a retrospective study of 50 patients treated with VYC 20L administered by a cannula, 8% of patients experienced procedure-related ecchymosis, which was self-limiting and nonserious.19 In a study that compared needle versus cannula in the treatment of nasolabial folds found the use of a cannula had significantly fewer AEs (pain, edema, redness, and hematoma) while maintaining similar efficacy to needle injection.17
One patient experienced 2 serious AEs related to the treatment, injection site cellulitis and injection site inflammation, which resolved without sequelae. The patient experienced severe inflammation beginning 7 days after touch-up treatment. She was admitted to the hospital for treatment with intravenous antibiotics and drainage of the abscess. Cultures of the abscess were negative for gram-positive and gram-negative bacteria. This type of event has been previously reported, although they are not typically observed in prospective clinical studies, in part due to their relatively low incidence.20 The etiology of late-onset inflammation and nodules after soft tissue filler treatment is not well understood and has been attributed to hypersensitivity, foreign body reaction, injection placement, infection, and biofilm development.21
Several soft tissue fillers have been previously reported in the literature for use in chin augmentation19,22–25; VYC-25L (Juvéderm Volux; Allergan plc) being the first HA soft tissue filler designed for chin augmentation and systematically investigated in a randomized controlled clinical trial for safety and effectiveness.25 Similar to VYC-20L, objective and subjective measures for VYC-25L showed sustained clinically meaningful benefits through Month 12, with comparable safety profiles where the incidence of ISRs and AEs were consistent for HA soft tissue fillers. The mean change from baseline to Month 12 in the glabella-subnasale-pogonion angle was 1.28°, and investigator and participant assessments on the GAIS at Month 12 were 83.5% and 77.2%, respectively. FACE-Q Satisfaction with Chin module and Psychological Well-Being module mean scores showed continued improvement over baseline (41.4 and 65.3, respectively) at Month 12 (61.6 and 74.4).
Conclusions
VYC-20L treatment is safe and effective when injected in the chin and prejowl sulci to treat chin retrusion, with results lasting through 1 year.
Acknowledgments
The authors sincerely thank the patients who participated in this study and acknowledge the additional investigators and staff who contributed to the study conduct, including Jeffrey Dover, MD; Todd Schlesinger, MD; Leslie Baumann, MD; Mitchel Goldman, MD; Dee Anna Glaser, MD; Jeanine Downie, MD; Valerie Callender, MD; Edwin Williams, MD; and William P. Werschler, MD.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.dermatologicsurgery.org).
This study was sponsored by Allergan plc, Dublin, Ireland. Medical writing assistance was provided to the authors by W. Kim of Allergan plc, Irvine, CA. All authors met the ICMJE authorship criteria. Neither honoraria nor any other form of compensation was provided for authorship. K. Beer, J. Kaufman-Janette, D. Bank, and S. Dayan have received funding as an investigator, consultant, and trainer for Allergan. B. Biesman has received consulting fees and research funding from Allergan. W. Kim, S. Chawla, and A. Schumacher are employees of Allergan plc and may own stock in the company. | Recovered | ReactionOutcome | CC BY-NC-ND | 33347003 | 18,840,355 | 2021-01-01 |
What was the outcome of reaction 'Injection site inflammation'? | Safe and Effective Chin Augmentation With the Hyaluronic Acid Injectable Filler, VYC-20L.
VYC-20L is a hyaluronic acid soft tissue filler with lidocaine designed to restore facial volume.
Evaluate the safety and effectiveness of VYC-20L in patients with chin retrusion.
Adults with chin retrusion were randomized (3:1) to receive VYC-20L in the chin at study onset (treatment group) or 6 months later (control group). The primary effectiveness end point was ≥1-point improvement on the Allergan Chin Retrusion Scale (ACRS) from baseline at Month 6. Safety assessments included injection site responses (ISRs) and adverse events (AEs).
VYC-20L was administered to 192 participants (treatment group, n = 144; control group, n = 48). At Month 6, significantly more participants had an ACRS response in the treatment versus control group (56.3% vs 27.5%; p = .0019). Effectiveness was also demonstrated by the proportion of participants with improved/much improved Global Aesthetic Improvement Scale scores and responses on the FACE-Q Satisfaction with Chin questionnaire and FACE-Q Psychological Wellbeing module. Treatment benefit remained evident at Month 12. Most common ISRs were tenderness (81.1%) and firmness (75.1%). One participant (0.5%) discontinued the study due to 2 treatment-related serious AEs of facial cellulitis and injection site inflammation, both resolved without sequelae.
VYC-20L significantly improved an ACRS response and was generally safe and well tolerated.
Hyaluronic acid (HA) injectable gels are a proven treatment for facial rejuvenation with an established record of safety and effectiveness.1 In 2018, more than 2.1 million HA injectable filler procedures were performed in the United States—a 48% increase over the past decade.2,3 The FDA has approved a range of dermal and subcutaneous indications for HA injectable fillers, including facial wrinkles, folds, lip augmentation, and cheeks.4 One such product, VYC-20L (Juvéderm Voluma XC; Allergan plc, Dublin, Ireland), which is a 20-mg/mL HA gel with lidocaine, was specifically designed for volumizing and has demonstrated effectiveness in restoring age-related volume deficit to the midface.5 Compared with HA gels designed for correction of wrinkles and folds, VYC-20L improved qualities of lift and projection to the midface.
In addition to the midface, the chin area is another facial region where lift and projection are important aspects of volumizing. The chin is defined by the labiomental crease (superiorly), the oral commissures (laterally), and the submental cervical crease (inferiorly). The shape and projection of the chin contribute to a “well-balanced and harmonious” face.6 For both men and women, good chin projection and a youthful jawline are considered the standards of beauty7 and can influence an individual's psychosocial well-being.8 Although congenital elements are the predominant factor in chin aesthetics, aging can result in bony resorption and produce sagging9 as well as laxity and droop in the chin area.10 In addition, aging can result in lumps, bulges, and depressions in the prejowl sulci.11
VYC-20L is a temporary HA soft tissue filler developed to provide a safe, minimally invasive method to restore facial volume, which is also reversible by hyaluronidase in case of adverse events (AEs) requiring treatment.5,12 It is currently indicated in the United States for injection into the subcutaneous and/or supraperiosteal space of the midface to add volume in the cheek area and is approved in other countries for facial volumizing, including the chin and prejowl sulci.5,12–16 As the chin and prejowl sulci are high-mobility areas, VYC-20L represents an ideal option for its volumizing and lifting capabilities. This study was designed to collect effectiveness and safety data for VYC-20L in participants seeking to correct volume deficit and retrusion in the chin and prejowl sulci.
Methods
Study Design
This multicenter, randomized, evaluator-blinded, delayed treatment-controlled study was designed to evaluate the safety and effectiveness of VYC-20L injectable gel for correction of chin volume deficit. A no-treatment control was used because there were no FDA-approved soft tissue fillers for chin augmentation at the time of the study. Participants were randomized in a 3:1 ratio either to have treatment with VYC-20L (treatment group) or a 6-month control period, followed by optional treatment (control group). At the Month 12 visit, participants in the treatment group had the option of receiving repeat treatment, with routine follow-up visits for safety and effectiveness through 1 month after repeat treatment. Treated control group participants were only followed for safety, and no effectiveness measures were performed. Participants underwent a touch-up treatment 30 days after initial treatment to achieve optimal correction if needed. The study was conducted at 14 sites in the United States, each of which had a treating investigator (TI) and at least one blinded evaluating investigator (EI).
The TIs performed the treatments and monitored participant safety throughout the study. Blinded EIs performed all effectiveness assessments. For treatment, the TI used 27 G 1/2 -inch needles for supraperiosteal and/or subcutaneous injections into the pogonion, menton, and prejowl sulci; 25 G 1½-inch cannulas were permitted for supraperiosteal and/or subcutaneous injections in the menton and prejowl sulci. An appropriate injection volume for the chin and chin area was determined by the TI but was not to exceed a maximum total volume of 4.0 mL for initial and touch-up treatments combined and 4.0 mL for repeat treatment. After each treatment, participants completed a daily safety diary for up to 30 days. Visits for both effectiveness and safety occurred at months 1, 3, 6, 9, and 12 after the last treatment.
Participants were required to be aged 22 or older and desire chin augmentation to correct moderate or severe chin retrusion (Grades 2 or 3 on the validated 5-point photonumeric Allergan Chin Retrusion Scale [ACRS]) as determined by a live assessment by both the EI and TI. Participants were ineligible if they had undergone cosmetic facial plastic surgery, tissue grafting, or tissue augmentation with silicone, fat, or permanent dermal fillers; had clinically significant malocclusion (severe overbite); had dentures; any device covering the palate; tattoos; piercings; facial hair; or scars that would interfere with visual assessment of the chin area. Mandatory facial treatment washout periods before study entry were 36 months for semipermanent dermal fillers, 24 months for dermal fillers in the chin or jaw area, 12 months for dermal fillers in the lips or perioral area, and 6 months for mesotherapy, botulinum toxin below the subnasale, or cosmetic treatment (laser, photomodulation, intense pulsed light, radiofrequency, dermabrasion, chemical peel, liposuction, lipolysis, or other ablative procedures). Applicable institutional review boards approved the study protocol, and all participants provided written informed consent before study enrolment (www.clinicaltrials.gov, identifier NCT02833077).
Response Measures and Statistics
The primary end point was based on the EI's blinded assessment of overall chin retrusion using ACRS grades defined as none (0), minimal (1), moderate (2), severe (3), and extreme (4) (See Supplemental Digital Content, Table S1, http://links.lww.com/DSS/A543). The primary effectiveness measure used a profile-view image cropped to include only the participant's lower face for ACRS assessment, which is based on the relationship between facial anatomical landmarks. Photograph assessments, rather than live assessments, facilitated consistent head positioning and were intended to help raters assess the relationship between landmarks. A participant showing ≥1-point improvement (decrease) in an ACRS score compared with baseline was considered a responder. The primary evaluation timepoint for efficacy was Month 6 after last treatment for participants in the treatment group and Month 6 after randomization for participants in the control group (untreated). The primary effectiveness end point was met if the treatment group responder rate was statistically greater (>50%) than the control group at Month 6 based on a 2-sided Fisher's exact test with a 5% significance level.
The Global Aesthetic Improvement Scale (GAIS), as well as the Satisfaction with Chin and Psychosocial Well-Being modules of the FACE-Q questionnaire, was used for assessment of secondary effectiveness end points. For the GAIS, responder rates for the treatment group (with 95% exact confidence intervals [CIs]) were based on EI and participant assessments. A “responder” was a participant who showed improvement (i.e., improved or much improved) on the overall aesthetic assessment in the chin area at the Month 6 visit. For the Satisfaction with Chin module of the FACE-Q questionnaire, the change from baseline to Month 6 visit in overall scores and a 2-sided paired t-test at the 5% level were used to demonstrate that the mean overall satisfaction score at the Month 6 visit was statistically greater than baseline for the treatment group. Volume change from baseline was measured by a blinded Canfield image analysis technician from three-dimensional (3D) imaging of the participant's facial profile pretreatment and post-treatment for both the treatment and control groups at the 6 Month visit.
Participants
A total of 221 participants were enrolled in the study, with an average of 14 (range 11–21) per investigational site. A total of 192 participants were randomized after 29 participants were screen failures, resulting in 144 in the treatment group and 48 in the control group. One hundred sixty-nine participants (88.0%) completed the Month 6 visit and 167 participants (87.0%) completed the study, with 25 participants (13.0%) discontinuing after randomization. Eighty-eight participants received touch-up treatment and 74 received repeat treatment. For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment. All initial and touch-up treatments occurred between June 28, 2016, and January 25, 2018, and all repeat treatments occurred between July 11, 2017, and August 23, 2018. The treatment and control groups were similar in terms of all demographic and baseline characteristics (See Supplemental Digital Content, Table S2, http://links.lww.com/DSS/A544). Among the 192 enrolled participants, the majority were women (88.5%) and White (81.8%), with a median age at study entry of 52 years (range, 22–80) and mean body mass index of 25.0 kg/m2. Fitzpatrick skin types were I/II (34.9%), III/IV (52.1%), and V/VI (13.0%).
Treatment
Anesthesia was administered to 75.0% (108/144) of participants in the treatment group, with the most common being topical (69.4%, 75/108; median duration 29.0 minutes) while ice was less common (34.3%, 37/108; median duration 15.0 minutes). The primary plane of injection used during the initial treatment was supraperiosteal (99.3%), followed by subcutaneous (63.0%). At touch-up and repeat treatments, the most common injection planes were also supraperiosteal (90.9% and 100.0%, respectively) and subcutaneous (53.4% and 59.5%, respectively). Planes and techniques were similar for the treated control participants. 99.3% of treatment group participants were treated in the pogonion, 77.8% in the menton, and 87.5% in the prejowl sulci. At the touch-up visit, 78.4% of treatment group participants were treated in the pogonion, 52.3% in the menton, and 65.9% in the prejowl sulci. At the repeat treatment visit, 93.2% were treated in the pogonion, 56.8% in the menton, and 66.2% in the prejowl sulci.
Needles were used for 100% of participants, and cannulas were used for 25.0% at initial treatment. There were no cannula/needle malfunctions. Treatment administration was similar for the treated control participants. Treating investigators rated ease of injection and product moldability on an 11-point scale, difficult (0) to easy (10), and stiff (0) to moldable (10), respectively. A total of 66.0% and 21.5% of participants were scored as 10 and 9, respectively, for ease of injection, whereas 62.5% and 20.8% of participants were scored as 10 and 9, respectively, for product moldability.
In the treatment group, 144 participants received initial treatment, 88 received touch-up treatment, and 74 received repeat treatment (Table 1). For the treated control participants, 38 participants received initial treatment and 22 received touch-up treatment, with injection volumes similar to the treatment group. The median total initial injection volume was 2.2 mL (range, 0.7–4.0 mL) for the treatment group (initial treatment and touch-up combined) and 2.8 mL (range, 1.3–4.0 mL) for the treated control group (initial treatment and touch-up combined). The median total injection volume for repeat treatment was 1.2 mL (range, 0.2–4.0 mL).
TABLE 1. Injection Volumes (Safety Population)
Total Volume Injected Treatment (N = 144) Control (N = 48)
Initial treatment volume (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 1.9 (0.6) 2.1 (0.6)
Median (range) 2 (0.7–4.0) 2 (1.0–3.8)
Initial/touch-up treatment volume combined (mL)
Received treatment, n (%) 144 (100.0) 38 (100.0)
Mean (SD) 2.6 (1.0) 2.7 (0.8)
Median (range) 2.2 (0.7–4.0) 2.8 (1.3–4.0)
Repeat treatment volume (mL)
Received treatment, n (%) 74 (51.4) 0 (0.0)
Mean (SD) 1.4 (0.8) N/A
Median (range) 1.2 (0.2–4.0) N/A
For the control group, data after receiving initial treatment at Month 6 are included.
Results
Effectiveness
The primary efficacy end point was met with 56.3% ACRS responders (photograph assessment) at Month 6, which was greater than 50% and significantly greater than the responder rate for the untreated control group (27.5%, p = .0019) (Table 2). In addition, the ACRS responder rate in the treatment group was 70.1% at Month 1, 57.6% at Month 12, and 73.9% at Month 1 after repeat treatment (See Supplemental Digital Content, Figure S1, http://links.lww.com/DSS/A539). The median ACRS scores improved by a median of 1 point from a baseline score of 3 in the treatment group, whereas the control group remained at a score of 2.5. Notably, the Month 6 responder rate from the EI live assessment was markedly higher than results from the photograph assessment with 91.8% for the treatment group and 23.3% for the control group, a difference of 68.42% (p < .0001).
TABLE 2. Allergan Chin Retrusion Scale Results at Month 6 (Modified Intent-to-Treat Population)
Treatment (N = 144) Control (N = 48)
Month 6
Total participants, n* 126 40
Responder, n (%) 71 (56.3) 11 (27.5)
Nonresponder, n (%) 55 (43.7) 29 (72.5)
95% CI (%)† (47.23–65.16) (14.60–43.89)
Versus control
Responder rate difference, % 28.85
95% CI (%)‡ 11.16–45.60
p-value§ 0.0019
For the untreated control group, data before receiving initial treatment at Month 6 are included.
* Participants with analysis values at baseline and the specified visit.
† 95% CI is based on the exact binomial distribution.
‡ 95% exact CI for the responder rate difference is presented.
§ p-value is based on 2-sided Fisher's exact test comparing the responder rate between treated and untreated control.
On the GAIS, EIs rated 91.2% (114/125) as “improved” or “much improved” in the treatment group and 19.5% (8/41) in the untreated control group at Month 6 (See Supplemental Digital Content, Figure S2, http://links.lww.com/DSS/A540). The treatment group responder rate remained high from Month 1 (94.0%) through Month 12 (91.2%) along with an increase at Month 1 after repeat treatment (98.6%; 70/71). The percentage of responders rated as “much improved” in the treatment group was notably high, with 61.6% at Month 6, 41.6% at Month 12, and 77.5% at Month 1 after repeat treatment. The participant self-evaluation on the GAIS was consistent with the EI assessments with most participants in the treatment group (87.3%; 110/126) rating as “improved” or “much improved” at Month 6. The treatment group responder rate remained high from Month 1 (95.5%) through Month 12 (82.4%) and was 97.1% at Month 1 after repeat treatment, similar to EI assessments. In addition, the mean change in chin volume assessed by 3D digital imaging showed a similar trend with (+)2.6 mL at Month 1, 2.4 mL Month 6, 2.2 cc at Month 12, and 3.9 cc at Month 1 after repeat treatment in the treatment group and 0.1 cc in the untreated control group.
The FACE-Q Satisfaction with Chin overall mean score for the treatment group was 34.9 at baseline and improved by a mean of 35.6 to a score of 71.3 at Month 6 (p < .001), whereas the mean score worsened by a mean of 3.3 from a baseline score of 35.1 for the untreated control group (See Supplemental Digital Content, Figure S3, http://links.lww.com/DSS/A541). The mean scores remained high from Month 1 (74.8) to Month 12 (66.4) and at Month 1 after repeat treatment (77.5).
The FACE-Q Psychological Well-Being overall mean score was 69.9 at baseline and improved by a mean of 15.4 at Month 6 for the treatment group, whereas the mean score worsened by a mean of −5.3 from 72.3 at Month 6 in the untreated control group (See Supplemental Digital Content, Figure S4, http://links.lww.com/DSS/A542). Most treatment group participants reported that they definitely/somewhat agree with each of the 10 individual FACE-Q Psychological Well-Being items at all timepoints, indicating positive well-being.
Safety
For initial/touch-up treatment, 14 treated participants (7.7%) had 20 treatment-related AEs (Table 3) while 3 (4.1%) had 7 treatment-related AEs after repeat treatment (See Supplemental Digital Content, Table S3, http://links.lww.com/DSS/A545). During the repeat treatment period, an injection site mass occurred in 2 participants (2.7%). The most common treatment-related AEs for the initial/touch-up treatment period were injection site erythema (1.6%, 3/182 participants) and injection site pain (1.6%, 3/182 participants). There were no deaths or unanticipated adverse effects. Facial sensation assessments found that treatment did not reduce chin area sensitivity at any timepoint throughout the study.
TABLE 3. Common Treatment-Related Adverse Events (AEs) After Initial/Touch-Up Treatment
Event, n Onset (d) Duration (d) Severity Resolution
Injection site abscess 6 9 Moderate Resolved w/o sequelae
Gingival pain 1 2 Moderate Resolved w/o sequelae
Acne cystic 6 134 Mild Resolved w/o sequelae
Injection site cellulitis 7 36 Severe Resolved w/o sequelae
Injection site inflammation 7 153 Severe Resolved w/o sequelae
w/o, without.
The type and frequency of injection site responses (ISRs) were similar in treatment group participants and treated control participants and are considered to be commonly reported events after treatment with HA soft tissue fillers (See Supplemental Digital Content, Table S4, http://links.lww.com/DSS/A546). Overall, 167 treated participants (92.3%) reported at least 1 ISR after initial treatment, 86 (82.7%) after touch-up treatment, and 55 (75.3%) after repeat treatment. The most frequently reported ISRs after initial treatment included tenderness to touch (81.8%), firmness (75.1%), and swelling (68.5%). Similar results were seen after repeat treatment, where the most common ISRs were also tenderness to touch (71.2%), firmness (69.9%), and swelling (58.9%). Most ISRs were mild or moderate in severity after initial, touch-up, and repeat treatment and resolved within 1 week based on total days from first to last occurrence according to the diaries. Participants assessed procedural pain (pain during injection) immediately after completion of each treatment on an 11-point scale ranging from 0 (no pain) to 10 (worst pain imaginable) and reported minimal pain, with a mean score of 2.3 for the treatment group at each treatment (initial, touch-up, and repeat).
Most treatment-related AEs were mild or moderate in severity (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 2.7% (5/182) of participants had mild treatment-related AEs and 4.4% (8/182) had moderate AEs. For repeat treatment, 4.1% (3/74) of participants had mild and 1.4% (1/74) moderate AEs. Two participants (1.1%) had 3 severe treatment-related AEs, including injection site inflammation and cellulitis in one participant and injection site induration in another participant.
Most treatment-related AEs resolved within 1 week (See Supplemental Digital Content, Table S5, http://links.lww.com/DSS/A547). For initial/touch-up treatment, 3 participants (1.6%) had 4 treatment-related AEs that lasted longer than 30 days. The first participant had injection site inflammation that lasted 153 days and injection site cellulitis that lasted 36 days. Treatment consisted of antibiotics, anti-inflammatories, and hyaluronidase. These 2 events were considered to be serious AEs. A second participant had injection site erythema that lasted 264 days. A third participant had an acne cyst that lasted 134 days. For repeat treatment, 1 participant (1.4%) had an injection site mass that lasted 42 days. Most treatment-related AEs began within 7 days of treatment. There were no treatment-related AEs that began >30 days after repeat treatment. All treatment-related AEs resolved without sequelae during the study period.
A lower incidence of ISRs was observed for injections with a cannula than without a cannula after initial touch-up and repeat treatments (See Supplemental Digital Content, Table S6, http://links.lww.com/DSS/A548). For initial/touch-up treatment with a cannula, 2 treated participants (4.5%) had 2 treatment-related AEs; without a cannula, 12 treated participants (8.7%) had 18 treatment-related AEs. For repeat treatment with a cannula, there were no treatment-related AEs; without a cannula, 3 treated participants (5.6%) had 7 treatment-related AEs.
Discussion
Although the primary end point was met, the ACRS responder rate of 56.3% was lower than expected. Comparatively, the midface study met its primary end point at Month 6, with 85.6% of treated participants having a clinically meaningful improvement.5 A possible reason for this discrepancy is the markedly higher injection volumes used in the midface study. This study used lower volumes, more closely representative of volumes used in real-world clinical practice. Another potential reason for this discrepancy is the different methods of evaluation. The midface study relied on live assessments, taking into account overall improvement. This study's assessment was limited to 2-dimensional cropped photographs, possibly obscuring a treatment effect because it relates to the whole face. This hypothesis is supported by the notably higher responder rate of 91.8% observed from the EI live assessments, which are more in line with the high responses observed with the GAIS and FACE-Q measures. Another supportive observation is the control responder rate at Month 6, which was observably lower in this study compared with the midface study, 27.5% versus 38.9%, respectively, indicating a lower false-positive rate.5 Although photograph assessments, rather than live assessments, were intended to help raters more consistently assess the relationship between landmarks, the use of cropped photographs as a primary measure may represent a study limitation. Other study limitations may have included the single-blind design, which left participants and injectors unblinded, and that control data were only available through month 6, although data could still be compared with baseline beyond Month 6.
VYC-20L was well tolerated, with most treatment-related AEs being ISRs of mild to moderate severity. Notably, there was an overall decrease in the number of AEs with repeat treatment compared with initial/touch-up treatment. One possibility is the lower volume injected during repeat treatment. Lower AE rates are commonly observed after repeat treatment. In addition, a lower number of AEs were associated with the use of cannulas versus needle injection, which is likely due to the ability of cannulas to assist injectors in avoiding sharp trauma and bruising,4,17,18 although there may be confounding factors as patients were not randomized to a needle or cannula. In a retrospective study of 50 patients treated with VYC 20L administered by a cannula, 8% of patients experienced procedure-related ecchymosis, which was self-limiting and nonserious.19 In a study that compared needle versus cannula in the treatment of nasolabial folds found the use of a cannula had significantly fewer AEs (pain, edema, redness, and hematoma) while maintaining similar efficacy to needle injection.17
One patient experienced 2 serious AEs related to the treatment, injection site cellulitis and injection site inflammation, which resolved without sequelae. The patient experienced severe inflammation beginning 7 days after touch-up treatment. She was admitted to the hospital for treatment with intravenous antibiotics and drainage of the abscess. Cultures of the abscess were negative for gram-positive and gram-negative bacteria. This type of event has been previously reported, although they are not typically observed in prospective clinical studies, in part due to their relatively low incidence.20 The etiology of late-onset inflammation and nodules after soft tissue filler treatment is not well understood and has been attributed to hypersensitivity, foreign body reaction, injection placement, infection, and biofilm development.21
Several soft tissue fillers have been previously reported in the literature for use in chin augmentation19,22–25; VYC-25L (Juvéderm Volux; Allergan plc) being the first HA soft tissue filler designed for chin augmentation and systematically investigated in a randomized controlled clinical trial for safety and effectiveness.25 Similar to VYC-20L, objective and subjective measures for VYC-25L showed sustained clinically meaningful benefits through Month 12, with comparable safety profiles where the incidence of ISRs and AEs were consistent for HA soft tissue fillers. The mean change from baseline to Month 12 in the glabella-subnasale-pogonion angle was 1.28°, and investigator and participant assessments on the GAIS at Month 12 were 83.5% and 77.2%, respectively. FACE-Q Satisfaction with Chin module and Psychological Well-Being module mean scores showed continued improvement over baseline (41.4 and 65.3, respectively) at Month 12 (61.6 and 74.4).
Conclusions
VYC-20L treatment is safe and effective when injected in the chin and prejowl sulci to treat chin retrusion, with results lasting through 1 year.
Acknowledgments
The authors sincerely thank the patients who participated in this study and acknowledge the additional investigators and staff who contributed to the study conduct, including Jeffrey Dover, MD; Todd Schlesinger, MD; Leslie Baumann, MD; Mitchel Goldman, MD; Dee Anna Glaser, MD; Jeanine Downie, MD; Valerie Callender, MD; Edwin Williams, MD; and William P. Werschler, MD.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.dermatologicsurgery.org).
This study was sponsored by Allergan plc, Dublin, Ireland. Medical writing assistance was provided to the authors by W. Kim of Allergan plc, Irvine, CA. All authors met the ICMJE authorship criteria. Neither honoraria nor any other form of compensation was provided for authorship. K. Beer, J. Kaufman-Janette, D. Bank, and S. Dayan have received funding as an investigator, consultant, and trainer for Allergan. B. Biesman has received consulting fees and research funding from Allergan. W. Kim, S. Chawla, and A. Schumacher are employees of Allergan plc and may own stock in the company. | Recovered | ReactionOutcome | CC BY-NC-ND | 33347003 | 18,840,355 | 2021-01-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bacteraemia'. | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | CEFAZOLIN, METRONIDAZOLE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peritonitis'. | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | CEFAZOLIN, METRONIDAZOLE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia klebsiella'. | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | CEFAZOLIN, METRONIDAZOLE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pseudomembranous colitis'. | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | CEFAZOLIN, METRONIDAZOLE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | CEFAZOLIN, METRONIDAZOLE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Septic shock'. | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | CEFAZOLIN, METRONIDAZOLE, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the administration route of drug 'METRONIDAZOLE'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the administration route of drug 'NOREPINEPHRINE'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33352444 | 18,700,665 | 2021-01 |
What was the administration route of drug 'VANCOMYCIN'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the outcome of reaction 'Bacteraemia'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the outcome of reaction 'Klebsiella infection'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33352444 | 18,700,665 | 2021-01 |
What was the outcome of reaction 'Peritonitis'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the outcome of reaction 'Pneumonia klebsiella'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the outcome of reaction 'Pseudomembranous colitis'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the outcome of reaction 'Sepsis'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
What was the outcome of reaction 'Septic shock'? | Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report.
BACKGROUND
Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome.
METHODS
A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died.
CONCLUSIONS
In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae.
CONCLUSIONS
Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
1 Introduction
Clostridium difficile infection (CDI) is one of the most common healthcare-associated infections, with high morbidity and mortality rates. Clostridium difficile is a spore-forming, anaerobic, Gram-positive bacterium. Clostridium difficile toxins can cause severe complications, including non-stopping diarrhoea, pseudomembranous colitis (PMC), toxic megacolon, perforations of the colon and sepsis [[1], [2], [3], [4]].
A sudden increase in white blood cell (WBC) count coinciding in asymptomatic patients who receive antibacterial therapy after septic surgery may be a predictor of Clostridium difficile-associated diarrhoea, while extremely high leucocytosis may be a predictor of a poor outcome [5].
Meta-analyses suggest that exposure to several antibiotic categories, including clindamycin, fluoroquinolones, cephalosporins, penicillins, macrolides and sulphonamides/trimethoprim, is associated with an increased risk of CDI in adults [5].
Severe CDIs are often complicated by the development of nosocomial bloodstream infections (BSIs) that significantly worsen the prognosis of the disease. Candida or enteric bacteria for the most part cause BSIs, and the mortality rate associated with this infection is very high – up to 50 % [[6], [7], [8], [9], [10]].
The aim of this paper is to report a fatal case of orthopaedic surgery complicated by Clostridium difficile infection and bloodstream Klebsiella pneumoniae infection.
The case report was written according to SCARE guidelines [11,12].
2 Presentation of case
A 77 years old male with a medical history of hypertension, atherosclerosis, ischaemic attacks and chronic kidney disease was admitted at the ICU because of an altered mental state and cardiovascular collapse. The patient was afebrile and stuporous, with a pulse rate of 110 bpm and white blood cell count of 100,440/mm3. The level of haemoglobin was 73 g/L and of C-reactive protein – 251 mg/L. Urinalysis was unremarkable.
The patient was hospitalised six days earlier due to left tibia chronic osteomyelitis that had developed after osteosynthesis with a locked intramedullary nail seven years ago. The patient presented with stable infected pseudarthrosis, bone resorption around the nail and locking screws, abscess in soft tissue and a healed fibula fracture. The patient has not had any surgical treatment due to infection before, except abscess incision. He had not been taking any prescription antimicrobial agents at home. Two days after admission the patient was operated. Under general anaesthesia in supine position, using a tourniquet on the thigh, the following steps were performed: wound revision, implant removal, bone channel reaming, rinsing and antibiotic-loaded cement nail and spacer implantation. Surgery was performed by a trauma surgeon specialising in bone and joint infections. Analyses from the bone infection site revealed Methicillin-sensitive Staphylococcus aureus. The patient received antibacterial therapy with Cefazolin 1 g every six hours for three days after the surgery and then suddenly developed an elevated WBC count of up to 54,000/mm3 without any concomitant symptoms.
The course of the disease was fulminant, with a rapid increase in the WBC count up to 133,420/mm3 and a septic shock. Oro-tracheal intubation and fluid resuscitation were performed, followed by intravenous norepinephrine and cardiovascular and ventilatory support. Flow cytometry was done for the purpose of differential diagnosis, to exclude a malignant haematological disease. Blood culture was negative. Promisingly, a positive Clostridium difficile A and B toxin test was obtained from stool. The patient was started on intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (500 mg every six hours).
Following five days of treatment the patient’s condition gradually improved. Then, suddenly, a hyperthermia above 39 degrees Celsius, shivering, hypotension and painful abdominal bloating developed. The WBC count peaked to 186,230/mm3 (Table 1). The rapidly developing, unstable haemodynamics required increasing doses of vasopressors. An urgent CT scan was performed, and neither open air, nor fluid were found in the abdomen. The consulting abdominal surgeon refused surgical intervention. The patient died 20 h after the beginning of the episode concerned. The microbiological blood cultures collected before death showed Klebsiella pneumoniae resistant to some antibacterial drugs, such as cephalosporins.Table 1 Laboratory investigations in the course of the disease.
Table 1Day WBC
/mm3 CRP
mg/L Microbiology Lactate
level
mmol/L Albumin level
g/L Serum
creatinine
mkmol/L GFR
mL/min/1.73 m2 SOFA
Score
points
0 54,840 154 173 35
1
(admitted at
ICU) 100,440
132,420 251 Cl. Diff. A and B toxins positive
Blood culture negative 1.2 22.6 251
259 23
22 15
2 116,580 223.9 1.5 274 20
3 83,870 125.4 2.3 21.8 219 27
4 59,260 150.7 Low 162 38
5 55,290 131.5 1.2 21.8 132 48
6 70,560 69.4 118 55
7 63,890 28.4 23.4 86 79
8 186,230 80.3 Kl. pneumoniae 3.0 131 48 12
A post-mortem was done, and the findings were as follows: Clostridium difficile pseudomembranous colitis, local purulent-fibrinous peritonitis, septicaemia with local foci (in the heart, spleen, lungs, kidneys) (Fig. 1, Fig. 2, Fig. 3, Fig. 4).Fig. 1 Representative image of the colon descendens surface obtained during the post-mortem examination.
Fig. 1Fig. 2 Representative photomicrographs demonstrate extensive neutrophil infiltration in the lung tissue and blood vessels. The haematoxylin-eosin staining method, magnification ×100 (A), magnification ×200 (B).
Fig. 2Fig. 3 Representative photomicrographs demonstrate: (A) the myocardial tissue with extensive neutrophil infiltration among cardiomyocytes and in blood vessels; (B) extensive neutrophil infiltration in the kidney tissue, mostly among the tubules and in small blood vessels. The haematoxylin-eosin staining method, magnification x 100.
Fig. 3Fig. 4 Representative photomicrographs demonstrate: (A) extensive neutrophil infiltration in the liver tissue, magnification ×100; (B) extensive neutrophil infiltration in the pulmonary artery lumen, magnification x 200. The haematoxylin-eosin staining method.
Fig. 4
3 Discussion
A prior antibiotic treatment is the most important risk factor for the development of CDI. The antibiotic treatment disrupts the normal colonic microbiota, making individuals susceptible to CDI [13].
Data on the antibiotic therapy within the previous 30 days as well as other risk factors for the multidrug-resistant organisms were gathered from the discharge letter and summary from the previous hospitalisation in other facilities. These data were negative [[1], [2], [3],14].
We can assume that this patient was an asymptomatic carrier since the previous hospitalisation episodes, despite the fact that the last episode was five years ago [14,15].
Typically at our surgical wards we start treatment with oral Metronidazole if a patient has unexplained diarrhoea, leucocytosis and subfebrile temperature, and we start empirical treatment with intravenous Metronidazole (500 mg IV every eight hours) and oral Vancomycin (125–500 mg every six hours) at the Intensive Care Unit when the symptoms worsen [5].
The more rapidly the life-threatening symptoms occur, the more motivated clinicians become to initiate early and intensive empirical treatment [16].
The recommended treatment for first recognised episodes is stratified based on the severity (mild to moderate or severe) of CDI assessed by WBC count (above or below 15,000 cells/mm3), serum creatinine level (1.5 times the pre-morbid level), hypotension or shock, ileus and megacolon, which are characteristic of a severe, complicated (a.k.a. fulminant) CDI [17].
We followed the recommendation for an initial fulminant episode with hypotension and shock: Vancomycin 500 mg four times a day via nasogastric tube and Metronidazole 500 mg every eight hours intravenously. Gastric bypassing was applied [5].
Neutrophils are the first cells recruited to the colon in response to a CDI, and the neutrophil response is believed to be a determinant of the severity of the disease. Autopsy showed extremely dense leukocyte infiltration in tissues.
The production of neutrophil growth factor in the inflamed tissue facilitates the initial migration of neutrophils from the bone marrow into peripheral circulation and the recruitment of neutrophils to the CDI site. Neutrophil-mediated inflammation and neutrophil activity itself can lead to immune-mediated damage of host tissues [18].
The following parameters had the most evidence to support their use as markers of risk for mortality in CDI when assessed at or near the time of diagnosis: age, most likely with a cut-off between >65 and 75 years; WBC, with a cut-off of >20,000/mm3; serum creatinine, possibly with a cut-off of >200 mmol/L; and serum albumin, most likely with a cut-off of <25 to 35 g/L [17].
The impact of healthcare-associated bloodstream infections (BSIs) in complicating CDIs is huge [10]. The alterations occurring in the intestinal flora, which represents a microbiome, can promote the translocation of pathogens into the blood stream and the development of nosocomial BSIs. The most common aetiology is the Candida species (47.3 %), followed by enterobacteria (19.4 %), mixed infections, including Klebsiella pneumoniae (19.4 %), and enterococci (13.9 %) [[6], [7], [8], [9], [10]].
In the case presented here the administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae in the gastrointestinal tract.
4 Conclusions
We can assume that extremely high leucocytosis was a factor for unfavourable prognosis. The gut inflammatory injury caused by the severe CDI may be considered as the “second hit,” allowing the bacterial translocation and BSI. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.
Declaration of Competing Interest
The authors report no declarations of interest.
Funding
No funding received for this article.
Ethical approval
The case report was approved by the Ethical Board of the Hospital of Traumatology and Orthopaedics, Riga, Latvia, Statement of 20 November 2020.
Consent
Informed consent could not be obtained as the patient died in the course of the disease.
Written informed consent was obtained from the Chief Physician of the Hospital of Traumatology and Orthopaedics for publication of this case report and accompanying images. A copy of the written consent may be provided to the Editor-in-Chief of this journal on request.
Author contribution
Dr. med. Iveta Golubovska conceptualization, project administration, writing the case report, literature analysis; Dr. Martins Malzubris operating surgeon-data collection; Dr. Luize Raga, operating surgeon – data collection; Dr. Dace Vigante – infectologist, data analysis, text corrections; Ass. Prof. Sergejs Isajevs – visual design and microphotography, Ass. Prof. Aleksejs Miscuks-discussion and project administration.
Iveta Golubovska, Aleksejs Miscuks: anaesthesiologists and intensive care specialists.
Martins Malzubris, Luize Raga: surgeons.
Dace Vigante: infectious diseases specialist.
Sergejs Isajevs: pathologist.
Registration of research studies
Not applicable.
Guarantor
Prof. Ass. Iveta Golubovska, MD, PhD.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgments
The authors would like to thank the staff of the Hospital of Traumatology and Orthopaedics for support in writing this article. | Fatal | ReactionOutcome | CC BY-NC-ND | 33352444 | 18,764,487 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'. | Kidney re-transplantation in a child across the barrier of persisting angiotensin II type I receptor antibodies.
Approximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT1R-Ab). While the role of AT1R-Ab for ABMR and graft failure is increasingly recognized, there is little information available on the management of these patients for re-transplantation over the barrier of persisting AT1R-Ab.
We report on a male patient with kidney failure in infancy due to obstructive uropathy who had lost his first kidney transplant due to AT1R-Ab-mediated chronic ABMR. Because this antibody persisted during 4 years of hemodialysis, for the 2nd kidney transplantation (living-related transplantation from his mother), he underwent a desensitization regimen consisting of 15 plasmapheresis sessions, infusions of intravenous immunoglobulin G and thymoglobulin, as well as pharmacological blockade of the Angiotensin II (AT II) pathway by candesartan. This intense desensitization regimen transiently decreased elevated AT1R-Ab titers, resulting in stable short-term kidney allograft function. The subsequent clinical course, however, was complicated by acute cellular rejection and chronic ABMR due to persistent AT1R-Ab and de novo HLA-DSA, which shortened allograft survival to a period of only 4 years.
This case highlights the difficulty of persistently decreasing elevated AT1R-Ab titers by a desensitization regimen for re-transplantation and the detrimental effect of the interplay between AT1R-Ab and HLA-DSA on kidney transplant survival.
Introduction
Antibody-mediated rejection (ABMR) plays a significant role in graft loss in both adult [1–3] and pediatric kidney transplant recipients [2, 4]. The majority of these rejections are caused by pre-formed and/or de novo donor-specific antibodies against human leucocyte antigens (HLA-DSA). However, there is a significant subset of patients with histological features of ABMR in the graft biopsy, in whom HLA-DSA cannot be detected in the circulation [5, 6]. In recent years, therefore, there have been increasing efforts directed towards the detection and biological characterization of antibodies against other endothelial targets beside HLA. In the year 2005, the discovery of antibodies against the angiotensin type 1 receptor (AT1R) in patients undergoing ABMR without detectable HLA-DSA by Dragun et al. significantly increased our understanding of the role of non-HLA antibodies in the pathophysiology of ABMR [7]. Approximately 20% of ABMR episodes in the absence of HLA-DSA in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, AT1R antibodies (AT1R-Ab) [8, 9].
AT1R-Ab are a group of receptor-activating antibodies (agonists) inducing downstream events such as vasoconstriction, remodeling of the extracellular matrix, and induction of proinflammatory cascades [10]. It has been hypothesized that ischaemia-reperfusion injury increases the expression of donor AT1R on vascular smooth-muscle and endothelial cells, predisposing the graft to injury by pre-existing AT1R-Ab [11]. Furthermore, AT1R-Ab upregulate HLA class II antigens on endothelial cells, thereby potentially enhancing the detrimental effects of HLA-DSA [6]. A few case reports have highlighted the broad spectrum of different clinical phenotypes of AT1R-Ab-mediated tissue injury [12–15].
While the role of AT1R-Ab for ABMR and graft failure is increasingly recognized, there is little information available on the management of these patients for re-transplantation over the barrier of persisting AT1R-Ab. We therefore report here the desensitization for re-transplantation and long-term follow-up of a pediatric patient, who had lost his first kidney allograft due to AT1R-Ab-mediated ABMR.
Case report
We report on a male patient with chronic kidney disease stage 5 in infancy due to obstructive uropathy. He received a first kidney transplant at the age of 3.2 years from a deceased female donor (42 years of age, one HLA-A and one HLA-DR mismatch) in the year 2000.
The initial immunosuppressive therapy consisted of cyclosporin A microemulsion (CsA), mycophenolate mofetil (MMF), and methylprednisolone. On day 7 post-transplant, during a period of inadequate CsA exposure, he experienced acute T cell–mediated rejection with mild to moderate intimal arteritis (BANFF ‘97 Grade IIa), which was treated with methylprednisolone pulses, OKT3, and switch of CsA to tacrolimus. Thereafter, graft function was stable for 6 years post-transplant with a serum creatinine concentration of approximately 1.4 mg/dL. He then experienced a progressive decline of graft function (increase of serum creatinine to 2.5 mg/dL) accompanied by severe arterial hypertension. Kidney allograft biopsy revealed chronic transplant glomerulopathy with partial glomerular sclerosis, interstitial fibrosis and tubular atrophy (IFTA), mild tubulitis, and arterial intimal fibrosis of new onset; C4d staining by immunohistochemistry was negative. These histopathological lesions were at the time categorized as acute vascular and interstitial rejection (BANFF IIb). With today’s histopathological classification, these lesions were consistent with chronic active ABMR. There was no serological evidence of HLA-DSA measured by the LABScreen Single Antigen assays (OneLambda, Thermofischer Scientific Canoga Park, CA), but the serum concentration of AT1R-Ab was markedly elevated (112 U/L, reference range <10 U/L). AT1R-Ab were initially measured with a bioassay [7], subsequently with a cell-based enzyme-linked immunosorbent assay (ELISA) (CellTrend GmbH, Luckenwalde, Germany, now OneLambda, Thermofischer Scientific Canoga Park, CA). The categories of binding reported in the ELISA test usually indicate negative binding at < 10 U/mL and lower, intermediate binding at 10–17 U/mL, and strong binding at > 17 U/mL [16]. Endothelin type A receptor antibodies (ETAR-Ab) were also measured with a sandwich ELISA (CellTrend GmbH, Luckenwalde, Germany, now OneLambda, Thermofischer Scientific Canoga Park, CA). As the potential role of AT1R-Ab in refractory vascular rejection had only been published 1 year before the patient’s episode of rapid loss of graft function and onset of arterial hypertension [7], no baseline measurement of non-HLA-antibodies had been performed prior to transplantation.
Despite antirejection therapy with methylprednisolone pulses, increased tacrolimus exposure (target trough level of 10–12 μg/L), and pharmacological blockade of the angiotensin (AT) II pathway by candesartan (0.1 mg/kg body weight per day), graft function rapidly declined. Candesartan has the highest affinity for the AT1R and was therefore used [17]. Five therapeutic plasma exchange sessions transiently decreased the AT1R-Ab titer from 110 to 25 U/mL, followed by a rapid secondary increase. Transplant function did not recover, and after 6.5 years with a functioning graft, the patient required kidney replacement therapy with hemodialysis. Transplant nephrectomy was performed because of recurrent pyelonephritis and nearly complete loss of transplant function. Histology of the explanted graft showed severe transplant glomerulopathy and severe IFTA. AT1R-Ab concentration peaked at 276 U/mL 16 months after transplantectomy, then slowly decreased to 55 U/mL over 2 years but remained persistently elevated (serum concentration around 20 U/mL) in the following years. While being on chronic hemodialysis therapy for 4 years, he experienced recurrent thromboembolic events in his central venous (jugular) catheter and arterio-venous fistula without any other known thrombophilic risk factors except high serum AT1R-Ab. Elevated AT1R-Ab might have contributed to these recurrent shunt thromboses, as they stimulate coagulation by inducing tissue factor expression and inhibiting fibrinolysis [13]. Antihypertensive medication was slowly weaned; candesartan was stopped after 3 years.
At the age of 13 years, he received a 2nd kidney allograft as a living-related transplantation from his mother (one HLA-A, -B, and –DR mismatch each, pre-transplant HLA class I and class II DSA-negative). Because of the persistently elevated AT1R-Ab prior to transplantation, he underwent a desensitization regimen consisting of 15 plasmapheresis sessions (three sessions per week over 5 weeks, each time 150% exchange of plasma volume with human albumin 5%), followed by three infusions of intravenous immunoglobulin G (IVIG). The desensitization regimen was based on our local desensitization protocol for kidney transplantation across the HLA and ABO barriers (for adults and children) and the protocol for treatment of rejection episodes due to AT1R-Ab in adult patients [7, 18–20], because no published protocol was available for desensitization across the barrier of persisting AT1R-Ab. This regimen decreased the AT1R-Ab titer from 19.8 to 9.5 U/mL and the ETAR antibody titer from 56 to 9.5 U/mL (Fig. 1). For immunosuppressive induction therapy, the patient received 3-times thymoglobulin i.v. (cumulative dose of 4.5 mg/kg body weight) and three sessions of plasmapheresis in the first 10 days post-transplant. Immunosuppressive maintenance therapy consisted of tacrolimus (initial dose 0.3 mg/kg per day), MMF (1200 mg/m2 per day), and methylprednisolone. Pharmacological blockade of the AT II pathway by candesartan (0.15 mg/kg body weight per day) was resumed on day 10 post-transplant, and therapy with iloprost (0.5 ng/kg/min infused over 6 hours) for 7 days was initiated to improve renal microcirculation, as iloprost attenuates AT II–mediated vasoconstriction [21]. Initial graft function was excellent. A surveillance allograft biopsy on day 17 post-transplant revealed interstitial borderline rejection without signs of vascular rejection; therefore, tacrolimus exposure was increased (target trough level 10–12 μg/L).Fig. 1 Course of antibodies against the angiotensin type 1 receptor (AT1R-Ab), the endothelin type A receptor (ETAR-Ab), and graft function (serum creatinine) pre-transplant and during the first 10 months after the second kidney transplantation
On day 87 post-transplant, he experienced a rapid decline in transplant function, accompanied by an increase in AT1R-Ab and ETAR-Ab (Fig. 1); in addition, a de novo DSA against the donor mismatch HLA-DQ7 (MFI value > 9000 by the Luminex single antigen assay) was detected. The histopathological evaluation showed acute interstitial rejection (BANFF 1A) with pronounced IFTA. Antirejection therapy consisted of methylprednisolone pulse therapy, six sessions of plasmapheresis, and one dose of rituximab (375 mg/m2). Furthermore, the patient again received vasodilatory therapy with iloprost (initially once weekly and thereafter every second week). For-cause kidney allograft biopsies on day 123 and day 168 post-transplant were performed due to decreasing kidney function and rising AT1R-Ab and ETAR-Ab titers; but there were no histopathological signs of acute rejection or accelerated IFTA. In order to reduce antibody titers, three additional sessions of plasmapheresis were conducted, and anti-humoral therapy with high-dose IVIG (four weekly doses, 1 g/kg body weight per dose) was administered.
In the following 2 years, serum creatinine slowly increased from 2.0 to 2.8 mg/dL. Besides the DSA against donor mismatch HLA-DQ7 (DQB1*03:01), he also developed a DSA against HLA-DQA1 (DQA1*03:03) and transiently against HLA-DR11 (DRB1*11:01) despite adequate immunosuppressive triple therapy with tacrolimus, MMF and steroids, and good treatment adherence. AT1R-Ab and ETAR-Ab concentrations remained high with a saturation binding at > 40 U/mL at most times. His clinical course was further complicated by recurrent episodes of pyelonephritis and pneumonia, which as inflammatory events might have stimulated HLA-DSA and non-HLA antibody formation. Serum creatinine steadily increased; another allograft biopsy at 4 years post-transplant showed chronic ABMR with mononuclear interstitial infiltration, mild tubulitis, C4d positivity in 25% of the peritubular capillaries, and pronounced IFTA. After 4 years with a functioning graft, he had to resume chronic hemodialysis therapy.
Discussion
This is the first case report of re-transplantation in a patient who had lost his first graft due to AT1R-Ab-mediated chronic ABMR. Our data show that an intense desensitization regimen consisting of plasmapheresis and IVIG (to remove circulating AT1R-Ab) and thymoglobulin (to prevent new antibody production) can transiently decrease elevated AT1R-Ab titers, resulting in stable short-term kidney allograft function. However, the subsequent clinical course was complicated by acute cellular rejection and chronic ABMR, which shortened allograft survival to a period of only 4 years. It is difficult to assess to what extent the persistently elevated AT1R-Ab and ETAR-Ab titers contributed to allograft injury of his second graft, because he also developed two de novo HLA-DSA, but the unfavorable course of his first graft in the absence of any HLA-DSA render a pathogenic role of elevated AT1R-Ab and ETAR-Ab quite likely. It is currently not known whether elevated ETAR-Ab have a pathogenic role for graft rejection independent of elevated AT1R-Ab. AT1R-Ab appear to stimulate the development of de novo HLA-DSA [10], and the negative effect of the interplay between AT1R-Ab and HLA-DSA on kidney and liver transplant survival has well been demonstrated [8, 16, 22]. Other case series on patients with only AT1R-Ab-mediated graft injury without HLA-DSA report a more favorable outcome with good long-term graft survival and absence of major complications after adequate anti-humoral therapy [7, 15]. Whether the sole presence of pre-transplant AT1R-Ab positivity justifies a prophylactic desensitization regimen is still a matter of debate. Carroll et al. investigated in a retrospective single-center study in adult kidney transplant recipients the effect of peri-operative plasma exchange and candesartan in patients with high pre-transplant AT1R-Ab positivity and observed that this perioperative regimen may alter the risk of rejection compared to a historical control group [23], but further studies are needed.
An elevated AT1R-Ab and ETAR-Ab titer may induce severe arterial hypertension. These antibodies lead to a sustained activation of the AT1R and ETAR, which stimulates vasoconstriction via G-protein coupling [7] and upregulation of the respective receptor expression at the target cell membrane [10]. While we previously observed an association of AT1R-Ab positivity and higher systolic blood pressure in pediatric kidney transplanted patients [8], this association was not observed in the study of Pearl et al. [24]. The pathophysiological relevance of these antibodies for arterial hypertension remains therefore to be elucidated. The variable clinical phenotype of high AT1R-Ab positivity may be explained by inter-individually different (genotypic) receptor expression at the target cell membrane, different autoantibody epitopes with variable agonistic function, or a desensitization of the post-receptor pathway in endothelial cells due to persisting activation of the AT1R [10].
This case also highlights the medical need to develop more effective therapies against elevated AT1R-Ab and ETAR-Ab. Our conventional multimodal therapeutic approach, which was used in analogy to barrier transplantations in patients highly immunized against HLA antigens, led only to a partial and transient reduction of AT1R-Ab and ETAR-Ab titers with an overall unsatisfactory clinical course. It remains to be seen whether newer induction regimens with other anti-B cell biologicals such as daratumumab, perhaps in conjunction with the dual AT1R and ETAR blocker sparsentan, allow a more favorable outcome in these difficult-to-treat patients.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest. | CANDESARTAN, CYCLOSPORINE, ILOPROST, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33355703 | 19,773,230 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Kidney re-transplantation in a child across the barrier of persisting angiotensin II type I receptor antibodies.
Approximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT1R-Ab). While the role of AT1R-Ab for ABMR and graft failure is increasingly recognized, there is little information available on the management of these patients for re-transplantation over the barrier of persisting AT1R-Ab.
We report on a male patient with kidney failure in infancy due to obstructive uropathy who had lost his first kidney transplant due to AT1R-Ab-mediated chronic ABMR. Because this antibody persisted during 4 years of hemodialysis, for the 2nd kidney transplantation (living-related transplantation from his mother), he underwent a desensitization regimen consisting of 15 plasmapheresis sessions, infusions of intravenous immunoglobulin G and thymoglobulin, as well as pharmacological blockade of the Angiotensin II (AT II) pathway by candesartan. This intense desensitization regimen transiently decreased elevated AT1R-Ab titers, resulting in stable short-term kidney allograft function. The subsequent clinical course, however, was complicated by acute cellular rejection and chronic ABMR due to persistent AT1R-Ab and de novo HLA-DSA, which shortened allograft survival to a period of only 4 years.
This case highlights the difficulty of persistently decreasing elevated AT1R-Ab titers by a desensitization regimen for re-transplantation and the detrimental effect of the interplay between AT1R-Ab and HLA-DSA on kidney transplant survival.
Introduction
Antibody-mediated rejection (ABMR) plays a significant role in graft loss in both adult [1–3] and pediatric kidney transplant recipients [2, 4]. The majority of these rejections are caused by pre-formed and/or de novo donor-specific antibodies against human leucocyte antigens (HLA-DSA). However, there is a significant subset of patients with histological features of ABMR in the graft biopsy, in whom HLA-DSA cannot be detected in the circulation [5, 6]. In recent years, therefore, there have been increasing efforts directed towards the detection and biological characterization of antibodies against other endothelial targets beside HLA. In the year 2005, the discovery of antibodies against the angiotensin type 1 receptor (AT1R) in patients undergoing ABMR without detectable HLA-DSA by Dragun et al. significantly increased our understanding of the role of non-HLA antibodies in the pathophysiology of ABMR [7]. Approximately 20% of ABMR episodes in the absence of HLA-DSA in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, AT1R antibodies (AT1R-Ab) [8, 9].
AT1R-Ab are a group of receptor-activating antibodies (agonists) inducing downstream events such as vasoconstriction, remodeling of the extracellular matrix, and induction of proinflammatory cascades [10]. It has been hypothesized that ischaemia-reperfusion injury increases the expression of donor AT1R on vascular smooth-muscle and endothelial cells, predisposing the graft to injury by pre-existing AT1R-Ab [11]. Furthermore, AT1R-Ab upregulate HLA class II antigens on endothelial cells, thereby potentially enhancing the detrimental effects of HLA-DSA [6]. A few case reports have highlighted the broad spectrum of different clinical phenotypes of AT1R-Ab-mediated tissue injury [12–15].
While the role of AT1R-Ab for ABMR and graft failure is increasingly recognized, there is little information available on the management of these patients for re-transplantation over the barrier of persisting AT1R-Ab. We therefore report here the desensitization for re-transplantation and long-term follow-up of a pediatric patient, who had lost his first kidney allograft due to AT1R-Ab-mediated ABMR.
Case report
We report on a male patient with chronic kidney disease stage 5 in infancy due to obstructive uropathy. He received a first kidney transplant at the age of 3.2 years from a deceased female donor (42 years of age, one HLA-A and one HLA-DR mismatch) in the year 2000.
The initial immunosuppressive therapy consisted of cyclosporin A microemulsion (CsA), mycophenolate mofetil (MMF), and methylprednisolone. On day 7 post-transplant, during a period of inadequate CsA exposure, he experienced acute T cell–mediated rejection with mild to moderate intimal arteritis (BANFF ‘97 Grade IIa), which was treated with methylprednisolone pulses, OKT3, and switch of CsA to tacrolimus. Thereafter, graft function was stable for 6 years post-transplant with a serum creatinine concentration of approximately 1.4 mg/dL. He then experienced a progressive decline of graft function (increase of serum creatinine to 2.5 mg/dL) accompanied by severe arterial hypertension. Kidney allograft biopsy revealed chronic transplant glomerulopathy with partial glomerular sclerosis, interstitial fibrosis and tubular atrophy (IFTA), mild tubulitis, and arterial intimal fibrosis of new onset; C4d staining by immunohistochemistry was negative. These histopathological lesions were at the time categorized as acute vascular and interstitial rejection (BANFF IIb). With today’s histopathological classification, these lesions were consistent with chronic active ABMR. There was no serological evidence of HLA-DSA measured by the LABScreen Single Antigen assays (OneLambda, Thermofischer Scientific Canoga Park, CA), but the serum concentration of AT1R-Ab was markedly elevated (112 U/L, reference range <10 U/L). AT1R-Ab were initially measured with a bioassay [7], subsequently with a cell-based enzyme-linked immunosorbent assay (ELISA) (CellTrend GmbH, Luckenwalde, Germany, now OneLambda, Thermofischer Scientific Canoga Park, CA). The categories of binding reported in the ELISA test usually indicate negative binding at < 10 U/mL and lower, intermediate binding at 10–17 U/mL, and strong binding at > 17 U/mL [16]. Endothelin type A receptor antibodies (ETAR-Ab) were also measured with a sandwich ELISA (CellTrend GmbH, Luckenwalde, Germany, now OneLambda, Thermofischer Scientific Canoga Park, CA). As the potential role of AT1R-Ab in refractory vascular rejection had only been published 1 year before the patient’s episode of rapid loss of graft function and onset of arterial hypertension [7], no baseline measurement of non-HLA-antibodies had been performed prior to transplantation.
Despite antirejection therapy with methylprednisolone pulses, increased tacrolimus exposure (target trough level of 10–12 μg/L), and pharmacological blockade of the angiotensin (AT) II pathway by candesartan (0.1 mg/kg body weight per day), graft function rapidly declined. Candesartan has the highest affinity for the AT1R and was therefore used [17]. Five therapeutic plasma exchange sessions transiently decreased the AT1R-Ab titer from 110 to 25 U/mL, followed by a rapid secondary increase. Transplant function did not recover, and after 6.5 years with a functioning graft, the patient required kidney replacement therapy with hemodialysis. Transplant nephrectomy was performed because of recurrent pyelonephritis and nearly complete loss of transplant function. Histology of the explanted graft showed severe transplant glomerulopathy and severe IFTA. AT1R-Ab concentration peaked at 276 U/mL 16 months after transplantectomy, then slowly decreased to 55 U/mL over 2 years but remained persistently elevated (serum concentration around 20 U/mL) in the following years. While being on chronic hemodialysis therapy for 4 years, he experienced recurrent thromboembolic events in his central venous (jugular) catheter and arterio-venous fistula without any other known thrombophilic risk factors except high serum AT1R-Ab. Elevated AT1R-Ab might have contributed to these recurrent shunt thromboses, as they stimulate coagulation by inducing tissue factor expression and inhibiting fibrinolysis [13]. Antihypertensive medication was slowly weaned; candesartan was stopped after 3 years.
At the age of 13 years, he received a 2nd kidney allograft as a living-related transplantation from his mother (one HLA-A, -B, and –DR mismatch each, pre-transplant HLA class I and class II DSA-negative). Because of the persistently elevated AT1R-Ab prior to transplantation, he underwent a desensitization regimen consisting of 15 plasmapheresis sessions (three sessions per week over 5 weeks, each time 150% exchange of plasma volume with human albumin 5%), followed by three infusions of intravenous immunoglobulin G (IVIG). The desensitization regimen was based on our local desensitization protocol for kidney transplantation across the HLA and ABO barriers (for adults and children) and the protocol for treatment of rejection episodes due to AT1R-Ab in adult patients [7, 18–20], because no published protocol was available for desensitization across the barrier of persisting AT1R-Ab. This regimen decreased the AT1R-Ab titer from 19.8 to 9.5 U/mL and the ETAR antibody titer from 56 to 9.5 U/mL (Fig. 1). For immunosuppressive induction therapy, the patient received 3-times thymoglobulin i.v. (cumulative dose of 4.5 mg/kg body weight) and three sessions of plasmapheresis in the first 10 days post-transplant. Immunosuppressive maintenance therapy consisted of tacrolimus (initial dose 0.3 mg/kg per day), MMF (1200 mg/m2 per day), and methylprednisolone. Pharmacological blockade of the AT II pathway by candesartan (0.15 mg/kg body weight per day) was resumed on day 10 post-transplant, and therapy with iloprost (0.5 ng/kg/min infused over 6 hours) for 7 days was initiated to improve renal microcirculation, as iloprost attenuates AT II–mediated vasoconstriction [21]. Initial graft function was excellent. A surveillance allograft biopsy on day 17 post-transplant revealed interstitial borderline rejection without signs of vascular rejection; therefore, tacrolimus exposure was increased (target trough level 10–12 μg/L).Fig. 1 Course of antibodies against the angiotensin type 1 receptor (AT1R-Ab), the endothelin type A receptor (ETAR-Ab), and graft function (serum creatinine) pre-transplant and during the first 10 months after the second kidney transplantation
On day 87 post-transplant, he experienced a rapid decline in transplant function, accompanied by an increase in AT1R-Ab and ETAR-Ab (Fig. 1); in addition, a de novo DSA against the donor mismatch HLA-DQ7 (MFI value > 9000 by the Luminex single antigen assay) was detected. The histopathological evaluation showed acute interstitial rejection (BANFF 1A) with pronounced IFTA. Antirejection therapy consisted of methylprednisolone pulse therapy, six sessions of plasmapheresis, and one dose of rituximab (375 mg/m2). Furthermore, the patient again received vasodilatory therapy with iloprost (initially once weekly and thereafter every second week). For-cause kidney allograft biopsies on day 123 and day 168 post-transplant were performed due to decreasing kidney function and rising AT1R-Ab and ETAR-Ab titers; but there were no histopathological signs of acute rejection or accelerated IFTA. In order to reduce antibody titers, three additional sessions of plasmapheresis were conducted, and anti-humoral therapy with high-dose IVIG (four weekly doses, 1 g/kg body weight per dose) was administered.
In the following 2 years, serum creatinine slowly increased from 2.0 to 2.8 mg/dL. Besides the DSA against donor mismatch HLA-DQ7 (DQB1*03:01), he also developed a DSA against HLA-DQA1 (DQA1*03:03) and transiently against HLA-DR11 (DRB1*11:01) despite adequate immunosuppressive triple therapy with tacrolimus, MMF and steroids, and good treatment adherence. AT1R-Ab and ETAR-Ab concentrations remained high with a saturation binding at > 40 U/mL at most times. His clinical course was further complicated by recurrent episodes of pyelonephritis and pneumonia, which as inflammatory events might have stimulated HLA-DSA and non-HLA antibody formation. Serum creatinine steadily increased; another allograft biopsy at 4 years post-transplant showed chronic ABMR with mononuclear interstitial infiltration, mild tubulitis, C4d positivity in 25% of the peritubular capillaries, and pronounced IFTA. After 4 years with a functioning graft, he had to resume chronic hemodialysis therapy.
Discussion
This is the first case report of re-transplantation in a patient who had lost his first graft due to AT1R-Ab-mediated chronic ABMR. Our data show that an intense desensitization regimen consisting of plasmapheresis and IVIG (to remove circulating AT1R-Ab) and thymoglobulin (to prevent new antibody production) can transiently decrease elevated AT1R-Ab titers, resulting in stable short-term kidney allograft function. However, the subsequent clinical course was complicated by acute cellular rejection and chronic ABMR, which shortened allograft survival to a period of only 4 years. It is difficult to assess to what extent the persistently elevated AT1R-Ab and ETAR-Ab titers contributed to allograft injury of his second graft, because he also developed two de novo HLA-DSA, but the unfavorable course of his first graft in the absence of any HLA-DSA render a pathogenic role of elevated AT1R-Ab and ETAR-Ab quite likely. It is currently not known whether elevated ETAR-Ab have a pathogenic role for graft rejection independent of elevated AT1R-Ab. AT1R-Ab appear to stimulate the development of de novo HLA-DSA [10], and the negative effect of the interplay between AT1R-Ab and HLA-DSA on kidney and liver transplant survival has well been demonstrated [8, 16, 22]. Other case series on patients with only AT1R-Ab-mediated graft injury without HLA-DSA report a more favorable outcome with good long-term graft survival and absence of major complications after adequate anti-humoral therapy [7, 15]. Whether the sole presence of pre-transplant AT1R-Ab positivity justifies a prophylactic desensitization regimen is still a matter of debate. Carroll et al. investigated in a retrospective single-center study in adult kidney transplant recipients the effect of peri-operative plasma exchange and candesartan in patients with high pre-transplant AT1R-Ab positivity and observed that this perioperative regimen may alter the risk of rejection compared to a historical control group [23], but further studies are needed.
An elevated AT1R-Ab and ETAR-Ab titer may induce severe arterial hypertension. These antibodies lead to a sustained activation of the AT1R and ETAR, which stimulates vasoconstriction via G-protein coupling [7] and upregulation of the respective receptor expression at the target cell membrane [10]. While we previously observed an association of AT1R-Ab positivity and higher systolic blood pressure in pediatric kidney transplanted patients [8], this association was not observed in the study of Pearl et al. [24]. The pathophysiological relevance of these antibodies for arterial hypertension remains therefore to be elucidated. The variable clinical phenotype of high AT1R-Ab positivity may be explained by inter-individually different (genotypic) receptor expression at the target cell membrane, different autoantibody epitopes with variable agonistic function, or a desensitization of the post-receptor pathway in endothelial cells due to persisting activation of the AT1R [10].
This case also highlights the medical need to develop more effective therapies against elevated AT1R-Ab and ETAR-Ab. Our conventional multimodal therapeutic approach, which was used in analogy to barrier transplantations in patients highly immunized against HLA antigens, led only to a partial and transient reduction of AT1R-Ab and ETAR-Ab titers with an overall unsatisfactory clinical course. It remains to be seen whether newer induction regimens with other anti-B cell biologicals such as daratumumab, perhaps in conjunction with the dual AT1R and ETAR blocker sparsentan, allow a more favorable outcome in these difficult-to-treat patients.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Funding
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The authors declare that they have no conflicts of interest. | CANDESARTAN, CYCLOSPORINE, ILOPROST, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, RITUXIMAB, TACROLIMUS | DrugsGivenReaction | CC BY | 33355703 | 19,773,230 | 2021-03 |
What was the dosage of drug 'ILOPROST TROMETHAMINE'? | Kidney re-transplantation in a child across the barrier of persisting angiotensin II type I receptor antibodies.
Approximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT1R-Ab). While the role of AT1R-Ab for ABMR and graft failure is increasingly recognized, there is little information available on the management of these patients for re-transplantation over the barrier of persisting AT1R-Ab.
We report on a male patient with kidney failure in infancy due to obstructive uropathy who had lost his first kidney transplant due to AT1R-Ab-mediated chronic ABMR. Because this antibody persisted during 4 years of hemodialysis, for the 2nd kidney transplantation (living-related transplantation from his mother), he underwent a desensitization regimen consisting of 15 plasmapheresis sessions, infusions of intravenous immunoglobulin G and thymoglobulin, as well as pharmacological blockade of the Angiotensin II (AT II) pathway by candesartan. This intense desensitization regimen transiently decreased elevated AT1R-Ab titers, resulting in stable short-term kidney allograft function. The subsequent clinical course, however, was complicated by acute cellular rejection and chronic ABMR due to persistent AT1R-Ab and de novo HLA-DSA, which shortened allograft survival to a period of only 4 years.
This case highlights the difficulty of persistently decreasing elevated AT1R-Ab titers by a desensitization regimen for re-transplantation and the detrimental effect of the interplay between AT1R-Ab and HLA-DSA on kidney transplant survival.
Introduction
Antibody-mediated rejection (ABMR) plays a significant role in graft loss in both adult [1–3] and pediatric kidney transplant recipients [2, 4]. The majority of these rejections are caused by pre-formed and/or de novo donor-specific antibodies against human leucocyte antigens (HLA-DSA). However, there is a significant subset of patients with histological features of ABMR in the graft biopsy, in whom HLA-DSA cannot be detected in the circulation [5, 6]. In recent years, therefore, there have been increasing efforts directed towards the detection and biological characterization of antibodies against other endothelial targets beside HLA. In the year 2005, the discovery of antibodies against the angiotensin type 1 receptor (AT1R) in patients undergoing ABMR without detectable HLA-DSA by Dragun et al. significantly increased our understanding of the role of non-HLA antibodies in the pathophysiology of ABMR [7]. Approximately 20% of ABMR episodes in the absence of HLA-DSA in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, AT1R antibodies (AT1R-Ab) [8, 9].
AT1R-Ab are a group of receptor-activating antibodies (agonists) inducing downstream events such as vasoconstriction, remodeling of the extracellular matrix, and induction of proinflammatory cascades [10]. It has been hypothesized that ischaemia-reperfusion injury increases the expression of donor AT1R on vascular smooth-muscle and endothelial cells, predisposing the graft to injury by pre-existing AT1R-Ab [11]. Furthermore, AT1R-Ab upregulate HLA class II antigens on endothelial cells, thereby potentially enhancing the detrimental effects of HLA-DSA [6]. A few case reports have highlighted the broad spectrum of different clinical phenotypes of AT1R-Ab-mediated tissue injury [12–15].
While the role of AT1R-Ab for ABMR and graft failure is increasingly recognized, there is little information available on the management of these patients for re-transplantation over the barrier of persisting AT1R-Ab. We therefore report here the desensitization for re-transplantation and long-term follow-up of a pediatric patient, who had lost his first kidney allograft due to AT1R-Ab-mediated ABMR.
Case report
We report on a male patient with chronic kidney disease stage 5 in infancy due to obstructive uropathy. He received a first kidney transplant at the age of 3.2 years from a deceased female donor (42 years of age, one HLA-A and one HLA-DR mismatch) in the year 2000.
The initial immunosuppressive therapy consisted of cyclosporin A microemulsion (CsA), mycophenolate mofetil (MMF), and methylprednisolone. On day 7 post-transplant, during a period of inadequate CsA exposure, he experienced acute T cell–mediated rejection with mild to moderate intimal arteritis (BANFF ‘97 Grade IIa), which was treated with methylprednisolone pulses, OKT3, and switch of CsA to tacrolimus. Thereafter, graft function was stable for 6 years post-transplant with a serum creatinine concentration of approximately 1.4 mg/dL. He then experienced a progressive decline of graft function (increase of serum creatinine to 2.5 mg/dL) accompanied by severe arterial hypertension. Kidney allograft biopsy revealed chronic transplant glomerulopathy with partial glomerular sclerosis, interstitial fibrosis and tubular atrophy (IFTA), mild tubulitis, and arterial intimal fibrosis of new onset; C4d staining by immunohistochemistry was negative. These histopathological lesions were at the time categorized as acute vascular and interstitial rejection (BANFF IIb). With today’s histopathological classification, these lesions were consistent with chronic active ABMR. There was no serological evidence of HLA-DSA measured by the LABScreen Single Antigen assays (OneLambda, Thermofischer Scientific Canoga Park, CA), but the serum concentration of AT1R-Ab was markedly elevated (112 U/L, reference range <10 U/L). AT1R-Ab were initially measured with a bioassay [7], subsequently with a cell-based enzyme-linked immunosorbent assay (ELISA) (CellTrend GmbH, Luckenwalde, Germany, now OneLambda, Thermofischer Scientific Canoga Park, CA). The categories of binding reported in the ELISA test usually indicate negative binding at < 10 U/mL and lower, intermediate binding at 10–17 U/mL, and strong binding at > 17 U/mL [16]. Endothelin type A receptor antibodies (ETAR-Ab) were also measured with a sandwich ELISA (CellTrend GmbH, Luckenwalde, Germany, now OneLambda, Thermofischer Scientific Canoga Park, CA). As the potential role of AT1R-Ab in refractory vascular rejection had only been published 1 year before the patient’s episode of rapid loss of graft function and onset of arterial hypertension [7], no baseline measurement of non-HLA-antibodies had been performed prior to transplantation.
Despite antirejection therapy with methylprednisolone pulses, increased tacrolimus exposure (target trough level of 10–12 μg/L), and pharmacological blockade of the angiotensin (AT) II pathway by candesartan (0.1 mg/kg body weight per day), graft function rapidly declined. Candesartan has the highest affinity for the AT1R and was therefore used [17]. Five therapeutic plasma exchange sessions transiently decreased the AT1R-Ab titer from 110 to 25 U/mL, followed by a rapid secondary increase. Transplant function did not recover, and after 6.5 years with a functioning graft, the patient required kidney replacement therapy with hemodialysis. Transplant nephrectomy was performed because of recurrent pyelonephritis and nearly complete loss of transplant function. Histology of the explanted graft showed severe transplant glomerulopathy and severe IFTA. AT1R-Ab concentration peaked at 276 U/mL 16 months after transplantectomy, then slowly decreased to 55 U/mL over 2 years but remained persistently elevated (serum concentration around 20 U/mL) in the following years. While being on chronic hemodialysis therapy for 4 years, he experienced recurrent thromboembolic events in his central venous (jugular) catheter and arterio-venous fistula without any other known thrombophilic risk factors except high serum AT1R-Ab. Elevated AT1R-Ab might have contributed to these recurrent shunt thromboses, as they stimulate coagulation by inducing tissue factor expression and inhibiting fibrinolysis [13]. Antihypertensive medication was slowly weaned; candesartan was stopped after 3 years.
At the age of 13 years, he received a 2nd kidney allograft as a living-related transplantation from his mother (one HLA-A, -B, and –DR mismatch each, pre-transplant HLA class I and class II DSA-negative). Because of the persistently elevated AT1R-Ab prior to transplantation, he underwent a desensitization regimen consisting of 15 plasmapheresis sessions (three sessions per week over 5 weeks, each time 150% exchange of plasma volume with human albumin 5%), followed by three infusions of intravenous immunoglobulin G (IVIG). The desensitization regimen was based on our local desensitization protocol for kidney transplantation across the HLA and ABO barriers (for adults and children) and the protocol for treatment of rejection episodes due to AT1R-Ab in adult patients [7, 18–20], because no published protocol was available for desensitization across the barrier of persisting AT1R-Ab. This regimen decreased the AT1R-Ab titer from 19.8 to 9.5 U/mL and the ETAR antibody titer from 56 to 9.5 U/mL (Fig. 1). For immunosuppressive induction therapy, the patient received 3-times thymoglobulin i.v. (cumulative dose of 4.5 mg/kg body weight) and three sessions of plasmapheresis in the first 10 days post-transplant. Immunosuppressive maintenance therapy consisted of tacrolimus (initial dose 0.3 mg/kg per day), MMF (1200 mg/m2 per day), and methylprednisolone. Pharmacological blockade of the AT II pathway by candesartan (0.15 mg/kg body weight per day) was resumed on day 10 post-transplant, and therapy with iloprost (0.5 ng/kg/min infused over 6 hours) for 7 days was initiated to improve renal microcirculation, as iloprost attenuates AT II–mediated vasoconstriction [21]. Initial graft function was excellent. A surveillance allograft biopsy on day 17 post-transplant revealed interstitial borderline rejection without signs of vascular rejection; therefore, tacrolimus exposure was increased (target trough level 10–12 μg/L).Fig. 1 Course of antibodies against the angiotensin type 1 receptor (AT1R-Ab), the endothelin type A receptor (ETAR-Ab), and graft function (serum creatinine) pre-transplant and during the first 10 months after the second kidney transplantation
On day 87 post-transplant, he experienced a rapid decline in transplant function, accompanied by an increase in AT1R-Ab and ETAR-Ab (Fig. 1); in addition, a de novo DSA against the donor mismatch HLA-DQ7 (MFI value > 9000 by the Luminex single antigen assay) was detected. The histopathological evaluation showed acute interstitial rejection (BANFF 1A) with pronounced IFTA. Antirejection therapy consisted of methylprednisolone pulse therapy, six sessions of plasmapheresis, and one dose of rituximab (375 mg/m2). Furthermore, the patient again received vasodilatory therapy with iloprost (initially once weekly and thereafter every second week). For-cause kidney allograft biopsies on day 123 and day 168 post-transplant were performed due to decreasing kidney function and rising AT1R-Ab and ETAR-Ab titers; but there were no histopathological signs of acute rejection or accelerated IFTA. In order to reduce antibody titers, three additional sessions of plasmapheresis were conducted, and anti-humoral therapy with high-dose IVIG (four weekly doses, 1 g/kg body weight per dose) was administered.
In the following 2 years, serum creatinine slowly increased from 2.0 to 2.8 mg/dL. Besides the DSA against donor mismatch HLA-DQ7 (DQB1*03:01), he also developed a DSA against HLA-DQA1 (DQA1*03:03) and transiently against HLA-DR11 (DRB1*11:01) despite adequate immunosuppressive triple therapy with tacrolimus, MMF and steroids, and good treatment adherence. AT1R-Ab and ETAR-Ab concentrations remained high with a saturation binding at > 40 U/mL at most times. His clinical course was further complicated by recurrent episodes of pyelonephritis and pneumonia, which as inflammatory events might have stimulated HLA-DSA and non-HLA antibody formation. Serum creatinine steadily increased; another allograft biopsy at 4 years post-transplant showed chronic ABMR with mononuclear interstitial infiltration, mild tubulitis, C4d positivity in 25% of the peritubular capillaries, and pronounced IFTA. After 4 years with a functioning graft, he had to resume chronic hemodialysis therapy.
Discussion
This is the first case report of re-transplantation in a patient who had lost his first graft due to AT1R-Ab-mediated chronic ABMR. Our data show that an intense desensitization regimen consisting of plasmapheresis and IVIG (to remove circulating AT1R-Ab) and thymoglobulin (to prevent new antibody production) can transiently decrease elevated AT1R-Ab titers, resulting in stable short-term kidney allograft function. However, the subsequent clinical course was complicated by acute cellular rejection and chronic ABMR, which shortened allograft survival to a period of only 4 years. It is difficult to assess to what extent the persistently elevated AT1R-Ab and ETAR-Ab titers contributed to allograft injury of his second graft, because he also developed two de novo HLA-DSA, but the unfavorable course of his first graft in the absence of any HLA-DSA render a pathogenic role of elevated AT1R-Ab and ETAR-Ab quite likely. It is currently not known whether elevated ETAR-Ab have a pathogenic role for graft rejection independent of elevated AT1R-Ab. AT1R-Ab appear to stimulate the development of de novo HLA-DSA [10], and the negative effect of the interplay between AT1R-Ab and HLA-DSA on kidney and liver transplant survival has well been demonstrated [8, 16, 22]. Other case series on patients with only AT1R-Ab-mediated graft injury without HLA-DSA report a more favorable outcome with good long-term graft survival and absence of major complications after adequate anti-humoral therapy [7, 15]. Whether the sole presence of pre-transplant AT1R-Ab positivity justifies a prophylactic desensitization regimen is still a matter of debate. Carroll et al. investigated in a retrospective single-center study in adult kidney transplant recipients the effect of peri-operative plasma exchange and candesartan in patients with high pre-transplant AT1R-Ab positivity and observed that this perioperative regimen may alter the risk of rejection compared to a historical control group [23], but further studies are needed.
An elevated AT1R-Ab and ETAR-Ab titer may induce severe arterial hypertension. These antibodies lead to a sustained activation of the AT1R and ETAR, which stimulates vasoconstriction via G-protein coupling [7] and upregulation of the respective receptor expression at the target cell membrane [10]. While we previously observed an association of AT1R-Ab positivity and higher systolic blood pressure in pediatric kidney transplanted patients [8], this association was not observed in the study of Pearl et al. [24]. The pathophysiological relevance of these antibodies for arterial hypertension remains therefore to be elucidated. The variable clinical phenotype of high AT1R-Ab positivity may be explained by inter-individually different (genotypic) receptor expression at the target cell membrane, different autoantibody epitopes with variable agonistic function, or a desensitization of the post-receptor pathway in endothelial cells due to persisting activation of the AT1R [10].
This case also highlights the medical need to develop more effective therapies against elevated AT1R-Ab and ETAR-Ab. Our conventional multimodal therapeutic approach, which was used in analogy to barrier transplantations in patients highly immunized against HLA antigens, led only to a partial and transient reduction of AT1R-Ab and ETAR-Ab titers with an overall unsatisfactory clinical course. It remains to be seen whether newer induction regimens with other anti-B cell biologicals such as daratumumab, perhaps in conjunction with the dual AT1R and ETAR blocker sparsentan, allow a more favorable outcome in these difficult-to-treat patients.
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The authors declare that they have no conflicts of interest. | 0.5 NG/KG/MIN INFUSED OVER 6 HOURS | DrugDosageText | CC BY | 33355703 | 18,692,004 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | A case report of Vagus nerve stimulation for intractable hiccups.
BACKGROUND
Intractable hiccups frequently result from an underlying pathology and can cause considerable illness in the patients. Initial remedies such as drinking cold water, induction of emesis, carotid sinus massage or Valsalva manoeuvre all seem to work by over stimulating the Vagus nerve. Pharmacotherapy with baclofen, gabapentin and other centrally and peripherally acting agents such as chlorpromazine and metoclopramide are reserved as second line treatment. Medical refractory cases even indulge in unconventional therapies such as hypnosis, massages and acupuncture. Surgical intervention, although undertaken very rarely, predominantly revolves around phrenic nerve crushing, blockade or pacing. A novel surgical strategy is emerging in the form of Vagus nerve stimulator (VNS) placement with three cases cited in literature to date with varying degrees of success. Here the authors report a case of VNS placement for intractable hiccups with partial success, in accordance with SCARE-2018 guidelines.
An 85-year-old gentleman with a 9-year history of intractable hiccups secondary to pneumonia came to our hospital. The hiccups were symptomatic causing anorexia, insomnia, irritability, depression, exhaustion, muscle wasting and weight loss. The patient underwent countless medical evaluations. All examinations and investigations yielded normal results. The patient underwent aggressive pharmacotherapy, home remedies and unconventional therapies for intractable hiccups but to no avail. He also underwent left phrenic nerve blocking and resection without therapeutic success. The patient presented to our hospital and decision for VNS insertion was taken for compassionate reasons considering patient morbidity. The patient demonstrated significant improvement in his symptoms following VNS insertion.
CONCLUSIONS
A temporary hiccup is an occasional happening experienced by everyone. However, intractable hiccups are associated with significant morbidity and often mortality. Several medical, pharmacological, surgical and novel treatment options are available for intractable hiccups.
CONCLUSIONS
VNS insertion is a novel surgical option for the treatment of intractable hiccups.
1 Introduction
Hiccup is a widely experienced and less understood phenomenon. Although much is known about the afferent and efferent limbs of the hiccup reflex pathway, no definitive consensus exists on the hiccup centre generating this reflex. Even the word “hiccup” is an onomatopoeic for the sound the reflex arc produces [1]. The hiccup reflex arc can be categorised as having afferent and efferent limbs and a central connection. The afferent limb is composed of the Vagus and phrenic nerves, and the lower sympathetic (T6-12) segments. The efferent pathway is constituted by the phrenic nerve (C3-5) innervating the diaphragm, plexal branches to the scalene muscles (C5-7), recurrent laryngeal nerve to the glottis and the intercostal nerves (T1-11) innervating the intercostal muscles [2,3]. The hiccup central connection is believed to be spinal cord segments rostral to medulla oblongata (C3-5) in the reticular formation in the middle and dorsolateral segment, connecting to the hiccup rhythm centre in the Pre-Botzinger complex, nucleus ambiguous, lateral reticular nucleus, hypothalamus and mesial temporal lobes [[2], [3], [4], [5]]. Gama-aminobutyric acid (GABA) and dopamine act as neurotransmitters for this reflex. It is speculated that the hiccup centre and the respiratory centre although separate may interact with one another through the various neuronal connections [2,5]. When the hiccup reflex is triggered there is synchronous contraction of the inspiratory thoracic muscles and the diaphragm. This is followed, in 35 milliseconds, by an abrupt glottal closure producing the typical “hicc” [6].
There is no conclusive knowledge on how this reflex is triggered but a safe idea would be that any mechanism which irritates or damages the components of the reflex arc, the central nuclei, the Vagus, phrenic or other nerves of the autonomic system can trigger a hiccup. Of these the Vagus is particularly important. The “wanderer” has such immense distribution throughout the body that the reflex can be triggered by any number of odd reasons such as irritation of the ear drum, rapid change in body temperature, over distension of stomach, irritation of the respiratory tractor stroking of hair [7,8]. As such most initial remedies seem to centre on over stimulating the Vagus nerve [9,10]. In cases of known underlying pathology treatment of the causative factor may help relieve the symptoms [11]. Table 1 enlists the various causes of a hiccup. Gastro-oesophageal reflux disease (GERD) has been shown to be both a cause of as well as a consequence of hiccups [1]. Although GERD can induce hiccups via the irritation of the Vagus nerve, long standing hiccups in themselves can cause reduction in the oesophageal motility as well as lowering of oesophageal-gastric sphincter pressure thus favouring GERD [1,6]. Hiccups are classified as temporary (<48 h), persistent (48 h-1 month) or intractable (>1 month), depending on their duration [3]. Intractable hiccups may cause debilitating problems such as insomnia, anorexia, fatigue, exhaustion, weight loss, depression, opening of surgical wounds, development of hernia and haemorrhoids, inability to undergo imaging such as MRI and even death. In such cases active management is required. Numerous medical and alternative therapies are available for the treatment of hiccups. Rarely surgical interventions are employed [2,8,12]. Table 2 provides an overview of the different treatment modalities for hiccups (Table 3).Table 1 Possible Causes of Hiccups adapted from Steger et al.
Table 1Central/Peripheral Nervous System Gastrointestinal Thoracic Ear, Nose & Throat (ENT) Metabolic Pharmacologic/Toxic Surgical Psychosomatic
Ischemic/haemorrhagic stroke Gastric Distension Cardiac Ischemic Injury Infection Hypo/Hyper-Glycaemia Alcohol Thoracic Surgery Anxiety
Tumours Gastro-oesophageal Reflux Disease Cardiac Infection Inflammation Hypo/Hyper-Natremia Chemotherapy/Radiotherapy Abdominal Surgery Stress
Traumatic Brain Injury Hiatus Hernia Cardiac Inflammation Foreign Body Hypo/Hyper-Kalemia Steroids Ear, nose, throat Surgery Excitement
Infection Gastrointestinal tumours Pulmonary Infection Tumours Hypo/Hyper-Calcemia Inhalational Oxygen Endoscopy Fear
Inflammation Infection Pulmonary Inflammation Hypocapnemia Benzodiazepines Pharyngeal Intubation
Demyelinating diseases Inflammation Thoracic Tumours Hypo/Hyper-Uraemia Dopamine Agonists Placement of Central Venous Catheter
Auto-immune diseases Obstruction Aneurysms Metabolic Diseases Opioids Iatrogenic Injury
Neuro-transmitter abnormalities Haemorrhage Auto-immune diseases Hypo/Hyper-Thermia Barbiturates
Vascular abnormalities Smoking Anti-biotics
Anatomical Abnormalities Anaesthetic Agents
Table 2 Various Treatments of Hiccups adapted from Steger et al.
Table 2Vagal Stimulation Respiratory Manoeuvres Centrally Acting Pharmacological Peripherally Acting Pharmacological Surgical Alternative Treatment
Intra-Nasal application of Vinegar Valsalva Maneuver Chlorpromazine Metoclopramide Phrenic Nerve Blockage or Crushing Hypnosis
Inhalation of Smelling Salts/Strong Odours Breath Holding (Inspiration, Expiration) Phenytoin Domperidone Phrenic Nerve Pacing Acupuncture
Swallowing Ice Water Re-Breathing (Hyper-capnia) Haloperidol Nifedipine Percutaneous Phrenic Nerve Stimulation Massage
Splashing Cold water Or Cold Compress On Face Baclofen Cervical Epidural Block
Induce Vomiting Gabapentin Implantation of Vagal Nerve Stimulator
Induce Fright Pregabalin
Carotid Massage Carbamazepine
Pressure Over Eyeball Sodium Valproate
Digital Rectal Massage Amitriptylline
Induce Orgasm
Table 3 Functional Components of the Vagus Nerve.
Table 320% Efferent 80% Afferent
General Visceral Efferent (Pre-Ganglionic Parasympathetic) Special Visceral Efferent General Somatic Afferent General Visceral Afferent Special Visceral Afferent
Dorsal Motor Nucleus Nucleus Accumbens Motor Innervation Reflexes Sensory Sensory Receptors Reflexes Sensory
Thoracic Organs Cardio-inhibitory Function Soft Palate Gag Reflex Pharynx Abdominal Organs Aortic Arch Baroreceptors Reflex Regulation of Gastrointestinal Tract Epiglottis
Abdominal Organs Pharynx Cough Reflex Larynx Thoracic Organs Carotid Sinus Baroreceptors Reflex Regulation of Cardiovascular System Taste Buds
Larynx Peristaltic Reflex Oesophagus Chemoreceptors Reflex Regulation of Respiratory System
Upper Part of Oesophagus Trachea
Bronchi
External Auditory Meatus
Tympanic Membrane
Concha
2 Case report
An 85-year-old Caucasian gentleman with a 9-year history of intractable hiccups came to National Hospital for Neurology and Neurosurgery, a 244-bed quaternary care hospital, after numerous unsuccessful traditional medical and alternative treatments.
His symptoms started in October 2010 when he suffered from pneumonia which caused severe respiratory compromise and fever. Prompt hospitalization and medical management attained full recovery, however a few days later the patient developed hiccups. Patient had a past medical history of ischaemic heart disease of 10 years, hypertension and hypercholesterolemia, both of which were very well controlled with amlodipine and rosuvastatin and had no symptoms of hiccups prior to the pneumonia in 2010. Patient neither consumed alcohol nor smoked and did not indulge in recreational drugs. Initially the hiccups were for intermittent onset, about 2–3 per day with months of remission between successive episode. Gradually they became more consistent, occurring daily with a frequency of about 50–100 per day. Patient was still able to carry out his daily routine and used home remedies such as drinking cold water, re-breathing in a paper bag, pressure over eyeballs, Valsalva manoeuvre and splashing cold water on face to treat his hiccups.
However, the hiccups progressively worsened in frequency, rate, intensity and magnitude. In 2013 patient developed GERD, possibly as a consequence of the ongoing hiccups and underwent Nissen fundoplication. Fundoplication completely resolved GERD but the hiccups continued to worsen. 3 years ago, they became non-stop occurring every 5 s and continued during sleep. They were symptomatically disabling and scored 9/10 on a 10-point subjective patient scale. They caused severe distress to the patient who became progressively anorexic, irritated, short tempered, fatigued and depressed. He became emaciated over the years and found it hard to talk. Even normal breathing was upset with sensations of choking secondary to glottis spasms. Patient underwent countless medical evaluations; physical and neurological examinations including ENT, chest and abdomen; laboratory investigations including blood urea nitrogen; imagining including magnetic resonance imaging (MRI) of brain and neck, computed tomography (CT) of abdomen and thorax and even upper gastrointestinal endoscopy and bronchoscopy. All examinations and investigations yielded normal results. In the absence of a definitive underlying cause an aggressive pharmaco-medical treatment was started. These medical therapies including prochlorperazine, metoclopramide, levetiracetam, baclofen, chlorpromazine, omeprazole, domperidone, gabapentin, carbamazepine, lansoprazole and Maalox plus remained ineffective. Patient also tried acupuncture, massage and hypnosis but to no avail. In April 2018 the patient underwent left phrenic nerve blocking which provided temporary relief for half a day. Following this, in June 2018 the patient underwent left phrenic nerve resection which cured the hiccups for only 2 days.
Patient became progressively unwell and lost half of his body weight. Furthermore, the disquieting symptoms were temporarily relieved for approximately 30 min. only by the induction of vomiting. Patient induced vomiting about 15 times in a day to experience relief from the hiccups.
In February 2020 the patient was referred to our neurosurgery department for evaluation. All physical and neurological examinations, relevant imaging and blood investigations were normal. No underlying cause was ascertained. VNS is currently not approved for the indication of intractable hiccups but given the fact that the patient had failed multiple lines of treatment and was disconsolate, after meticulous consideration and careful review of literature a decision was made for VNS insertion as a compassionate indication. Patient was positioned supine under general anaesthesia. The procedure was performed by senior consultants Ms Miserocchi and Mr McEvoy. Livanova VNS electrode was wrapped around the left Vagus nerve of the patient and a pulse generator was implanted on the left chest above the pectoralis muscle 2–3 cm below the collar bone. The surgery and post-operative period were uneventful. After 2 weeks of rest, the device was switched on with automatic current settings of amplitude between 1–2 mA, frequency between 10–30 hertz, pulse width between 250–750 microseconds and duration of between 20–60 seconds. Pharmaco-medical treatment for the hiccups was discontinued. There was no hoarseness or change in voice of the patient and no chest pain or any sign of cardiac compromise.
This provided complete remission for few hours after which the hiccups returned but were infrequent with episodes lasting for up to 15 min, with a rate of 1 hiccup per second, every 4–6 hours, thus demonstrating a much-decreased rate and magnitude. Patient and his family noted the intensity to be 5/10 on a subjective scale with marked improvement in speech. Due to the coronavirus (Covid-19) outbreak the patient is currently awaiting a follow up appointment to review prognosis and revise the automatic current settings.
We therefore document partial success with the surgical placement of Vagus nerve stimulator for the treatment of intractable hiccups at our centre with short term results. As seen with epilepsy, VNS tends to continue to improve prognosis up to 1–1.5 years. We will continue to monitor the patient and present a follow up report with long term results.
3 Discussion
Although temporary hiccups are a benign occurrence having no significant impact on the life of a person but intractable hiccups are a serious and debilitating pathology and often lead to dire consequences [[1], [2], [3],7]. The world record of longest hiccups is 69 years with notable people such as Pope Pius XII dying from the ailment [13]. Therefore, symptomatic intractable hiccups warrant medical and surgical treatment [1].
The Vagus nerve forms a significant component of the hiccup reflex arc and can explain several odd triggers as well as the basis for most initial remedies [4,9,10]. In fact hiccups most frequently occur during inspiration when lung inflation impedes vagal afferents known to suppress hiccups [6]. The Vagus nerve, also referred to as the “wandering” nerve or the “vagabond” nerve, greatly innervates multiple organs of the body and forms a part of several bodily reflexes [4,7,10]. Its stimulation has demonstrated varied functional outcomes the exact mechanism of most of which are not clearly understood [7]. VNS is an acknowledged treatment for epilepsy and depression [2].
Medical therapy for intractable hiccups comprises of GABA-derivatives, baclofen, dopaminergic antagonists and anticonvulsants. Non-traditional treatments such as acupuncture, massages and hypnosis are also widely used. Non-pharmacological options such as phrenic nerve blocking, crushing and pacing, percutaneous phrenic nerve stimulation and cervical epidural block have shown limited success due to the occasional presence of an accessory phrenic nerve as well as the bilateral diaphragmatic contraction aetiology of centrally originated hiccups [2,3,7,13].
Recently surgical placement of Vagus nerve stimulators have been undertaken for chronic hiccups with varying degrees of success [2,5,7,10]. We report a case of intractable hiccups secondary to pneumonia, treated with VNS placement at our centre with short term results demonstrating partial success, in accordance with SCARE-2018 guidelines [14]. Since the thorax is of immense anatomical importance in the hiccup reflex, it is reasonable to consider that infections of the chest can lead to hiccups [1]. Seeing as no validated questionnaires have been formulated to document the intensity of hiccups [1], a 10-point patient subjective scale was employed.
Very little research is available on the cure of hiccups and even the pathogenesis of hiccups is less understood. Due to the lack of a physiological relevance in adults and the observation of hiccups in foetuses along with the efficacy of baclofen in arresting gill-ventilation in tadpoles, it is speculated that hiccup is a phylogenetical reflex [2,4,6,13]. Future research will help us better understand this phenomenon and its treatment.
Declaration of Competing Interest
The authors have no conflict of interest. We confirm that where other sources of information have been utilised and cited, it is with the permission of the corresponding authors.
Funding
Not applicable, this is not a research project.
Ethical approval
Not applicable, this is not a research project.
Consent
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Dr Joe M. Das: Writing - Review & Editing.
Ms Sasha Monaghan: Writing - Review & Editing.
Ms Anna Miserocchi: Supervision, Project administration.
Mr Andrew McEvoy: Supervision, Project administration.
Registration of research studies
Not applicable.
Guarantor
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Provenance and peer review
Not commissioned, externally peer-reviewed. | BACLOFEN, CARBAMAZEPINE, CHLORPROMAZINE, DOMPERIDONE, GABAPENTIN, LANSOPRAZOLE, LEVETIRACETAM, METOCLOPRAMIDE, OMEPRAZOLE, PROCHLORPERAZINE | DrugsGivenReaction | CC BY-NC-ND | 33360634 | 18,817,592 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malaise'. | A case report of Vagus nerve stimulation for intractable hiccups.
BACKGROUND
Intractable hiccups frequently result from an underlying pathology and can cause considerable illness in the patients. Initial remedies such as drinking cold water, induction of emesis, carotid sinus massage or Valsalva manoeuvre all seem to work by over stimulating the Vagus nerve. Pharmacotherapy with baclofen, gabapentin and other centrally and peripherally acting agents such as chlorpromazine and metoclopramide are reserved as second line treatment. Medical refractory cases even indulge in unconventional therapies such as hypnosis, massages and acupuncture. Surgical intervention, although undertaken very rarely, predominantly revolves around phrenic nerve crushing, blockade or pacing. A novel surgical strategy is emerging in the form of Vagus nerve stimulator (VNS) placement with three cases cited in literature to date with varying degrees of success. Here the authors report a case of VNS placement for intractable hiccups with partial success, in accordance with SCARE-2018 guidelines.
An 85-year-old gentleman with a 9-year history of intractable hiccups secondary to pneumonia came to our hospital. The hiccups were symptomatic causing anorexia, insomnia, irritability, depression, exhaustion, muscle wasting and weight loss. The patient underwent countless medical evaluations. All examinations and investigations yielded normal results. The patient underwent aggressive pharmacotherapy, home remedies and unconventional therapies for intractable hiccups but to no avail. He also underwent left phrenic nerve blocking and resection without therapeutic success. The patient presented to our hospital and decision for VNS insertion was taken for compassionate reasons considering patient morbidity. The patient demonstrated significant improvement in his symptoms following VNS insertion.
CONCLUSIONS
A temporary hiccup is an occasional happening experienced by everyone. However, intractable hiccups are associated with significant morbidity and often mortality. Several medical, pharmacological, surgical and novel treatment options are available for intractable hiccups.
CONCLUSIONS
VNS insertion is a novel surgical option for the treatment of intractable hiccups.
1 Introduction
Hiccup is a widely experienced and less understood phenomenon. Although much is known about the afferent and efferent limbs of the hiccup reflex pathway, no definitive consensus exists on the hiccup centre generating this reflex. Even the word “hiccup” is an onomatopoeic for the sound the reflex arc produces [1]. The hiccup reflex arc can be categorised as having afferent and efferent limbs and a central connection. The afferent limb is composed of the Vagus and phrenic nerves, and the lower sympathetic (T6-12) segments. The efferent pathway is constituted by the phrenic nerve (C3-5) innervating the diaphragm, plexal branches to the scalene muscles (C5-7), recurrent laryngeal nerve to the glottis and the intercostal nerves (T1-11) innervating the intercostal muscles [2,3]. The hiccup central connection is believed to be spinal cord segments rostral to medulla oblongata (C3-5) in the reticular formation in the middle and dorsolateral segment, connecting to the hiccup rhythm centre in the Pre-Botzinger complex, nucleus ambiguous, lateral reticular nucleus, hypothalamus and mesial temporal lobes [[2], [3], [4], [5]]. Gama-aminobutyric acid (GABA) and dopamine act as neurotransmitters for this reflex. It is speculated that the hiccup centre and the respiratory centre although separate may interact with one another through the various neuronal connections [2,5]. When the hiccup reflex is triggered there is synchronous contraction of the inspiratory thoracic muscles and the diaphragm. This is followed, in 35 milliseconds, by an abrupt glottal closure producing the typical “hicc” [6].
There is no conclusive knowledge on how this reflex is triggered but a safe idea would be that any mechanism which irritates or damages the components of the reflex arc, the central nuclei, the Vagus, phrenic or other nerves of the autonomic system can trigger a hiccup. Of these the Vagus is particularly important. The “wanderer” has such immense distribution throughout the body that the reflex can be triggered by any number of odd reasons such as irritation of the ear drum, rapid change in body temperature, over distension of stomach, irritation of the respiratory tractor stroking of hair [7,8]. As such most initial remedies seem to centre on over stimulating the Vagus nerve [9,10]. In cases of known underlying pathology treatment of the causative factor may help relieve the symptoms [11]. Table 1 enlists the various causes of a hiccup. Gastro-oesophageal reflux disease (GERD) has been shown to be both a cause of as well as a consequence of hiccups [1]. Although GERD can induce hiccups via the irritation of the Vagus nerve, long standing hiccups in themselves can cause reduction in the oesophageal motility as well as lowering of oesophageal-gastric sphincter pressure thus favouring GERD [1,6]. Hiccups are classified as temporary (<48 h), persistent (48 h-1 month) or intractable (>1 month), depending on their duration [3]. Intractable hiccups may cause debilitating problems such as insomnia, anorexia, fatigue, exhaustion, weight loss, depression, opening of surgical wounds, development of hernia and haemorrhoids, inability to undergo imaging such as MRI and even death. In such cases active management is required. Numerous medical and alternative therapies are available for the treatment of hiccups. Rarely surgical interventions are employed [2,8,12]. Table 2 provides an overview of the different treatment modalities for hiccups (Table 3).Table 1 Possible Causes of Hiccups adapted from Steger et al.
Table 1Central/Peripheral Nervous System Gastrointestinal Thoracic Ear, Nose & Throat (ENT) Metabolic Pharmacologic/Toxic Surgical Psychosomatic
Ischemic/haemorrhagic stroke Gastric Distension Cardiac Ischemic Injury Infection Hypo/Hyper-Glycaemia Alcohol Thoracic Surgery Anxiety
Tumours Gastro-oesophageal Reflux Disease Cardiac Infection Inflammation Hypo/Hyper-Natremia Chemotherapy/Radiotherapy Abdominal Surgery Stress
Traumatic Brain Injury Hiatus Hernia Cardiac Inflammation Foreign Body Hypo/Hyper-Kalemia Steroids Ear, nose, throat Surgery Excitement
Infection Gastrointestinal tumours Pulmonary Infection Tumours Hypo/Hyper-Calcemia Inhalational Oxygen Endoscopy Fear
Inflammation Infection Pulmonary Inflammation Hypocapnemia Benzodiazepines Pharyngeal Intubation
Demyelinating diseases Inflammation Thoracic Tumours Hypo/Hyper-Uraemia Dopamine Agonists Placement of Central Venous Catheter
Auto-immune diseases Obstruction Aneurysms Metabolic Diseases Opioids Iatrogenic Injury
Neuro-transmitter abnormalities Haemorrhage Auto-immune diseases Hypo/Hyper-Thermia Barbiturates
Vascular abnormalities Smoking Anti-biotics
Anatomical Abnormalities Anaesthetic Agents
Table 2 Various Treatments of Hiccups adapted from Steger et al.
Table 2Vagal Stimulation Respiratory Manoeuvres Centrally Acting Pharmacological Peripherally Acting Pharmacological Surgical Alternative Treatment
Intra-Nasal application of Vinegar Valsalva Maneuver Chlorpromazine Metoclopramide Phrenic Nerve Blockage or Crushing Hypnosis
Inhalation of Smelling Salts/Strong Odours Breath Holding (Inspiration, Expiration) Phenytoin Domperidone Phrenic Nerve Pacing Acupuncture
Swallowing Ice Water Re-Breathing (Hyper-capnia) Haloperidol Nifedipine Percutaneous Phrenic Nerve Stimulation Massage
Splashing Cold water Or Cold Compress On Face Baclofen Cervical Epidural Block
Induce Vomiting Gabapentin Implantation of Vagal Nerve Stimulator
Induce Fright Pregabalin
Carotid Massage Carbamazepine
Pressure Over Eyeball Sodium Valproate
Digital Rectal Massage Amitriptylline
Induce Orgasm
Table 3 Functional Components of the Vagus Nerve.
Table 320% Efferent 80% Afferent
General Visceral Efferent (Pre-Ganglionic Parasympathetic) Special Visceral Efferent General Somatic Afferent General Visceral Afferent Special Visceral Afferent
Dorsal Motor Nucleus Nucleus Accumbens Motor Innervation Reflexes Sensory Sensory Receptors Reflexes Sensory
Thoracic Organs Cardio-inhibitory Function Soft Palate Gag Reflex Pharynx Abdominal Organs Aortic Arch Baroreceptors Reflex Regulation of Gastrointestinal Tract Epiglottis
Abdominal Organs Pharynx Cough Reflex Larynx Thoracic Organs Carotid Sinus Baroreceptors Reflex Regulation of Cardiovascular System Taste Buds
Larynx Peristaltic Reflex Oesophagus Chemoreceptors Reflex Regulation of Respiratory System
Upper Part of Oesophagus Trachea
Bronchi
External Auditory Meatus
Tympanic Membrane
Concha
2 Case report
An 85-year-old Caucasian gentleman with a 9-year history of intractable hiccups came to National Hospital for Neurology and Neurosurgery, a 244-bed quaternary care hospital, after numerous unsuccessful traditional medical and alternative treatments.
His symptoms started in October 2010 when he suffered from pneumonia which caused severe respiratory compromise and fever. Prompt hospitalization and medical management attained full recovery, however a few days later the patient developed hiccups. Patient had a past medical history of ischaemic heart disease of 10 years, hypertension and hypercholesterolemia, both of which were very well controlled with amlodipine and rosuvastatin and had no symptoms of hiccups prior to the pneumonia in 2010. Patient neither consumed alcohol nor smoked and did not indulge in recreational drugs. Initially the hiccups were for intermittent onset, about 2–3 per day with months of remission between successive episode. Gradually they became more consistent, occurring daily with a frequency of about 50–100 per day. Patient was still able to carry out his daily routine and used home remedies such as drinking cold water, re-breathing in a paper bag, pressure over eyeballs, Valsalva manoeuvre and splashing cold water on face to treat his hiccups.
However, the hiccups progressively worsened in frequency, rate, intensity and magnitude. In 2013 patient developed GERD, possibly as a consequence of the ongoing hiccups and underwent Nissen fundoplication. Fundoplication completely resolved GERD but the hiccups continued to worsen. 3 years ago, they became non-stop occurring every 5 s and continued during sleep. They were symptomatically disabling and scored 9/10 on a 10-point subjective patient scale. They caused severe distress to the patient who became progressively anorexic, irritated, short tempered, fatigued and depressed. He became emaciated over the years and found it hard to talk. Even normal breathing was upset with sensations of choking secondary to glottis spasms. Patient underwent countless medical evaluations; physical and neurological examinations including ENT, chest and abdomen; laboratory investigations including blood urea nitrogen; imagining including magnetic resonance imaging (MRI) of brain and neck, computed tomography (CT) of abdomen and thorax and even upper gastrointestinal endoscopy and bronchoscopy. All examinations and investigations yielded normal results. In the absence of a definitive underlying cause an aggressive pharmaco-medical treatment was started. These medical therapies including prochlorperazine, metoclopramide, levetiracetam, baclofen, chlorpromazine, omeprazole, domperidone, gabapentin, carbamazepine, lansoprazole and Maalox plus remained ineffective. Patient also tried acupuncture, massage and hypnosis but to no avail. In April 2018 the patient underwent left phrenic nerve blocking which provided temporary relief for half a day. Following this, in June 2018 the patient underwent left phrenic nerve resection which cured the hiccups for only 2 days.
Patient became progressively unwell and lost half of his body weight. Furthermore, the disquieting symptoms were temporarily relieved for approximately 30 min. only by the induction of vomiting. Patient induced vomiting about 15 times in a day to experience relief from the hiccups.
In February 2020 the patient was referred to our neurosurgery department for evaluation. All physical and neurological examinations, relevant imaging and blood investigations were normal. No underlying cause was ascertained. VNS is currently not approved for the indication of intractable hiccups but given the fact that the patient had failed multiple lines of treatment and was disconsolate, after meticulous consideration and careful review of literature a decision was made for VNS insertion as a compassionate indication. Patient was positioned supine under general anaesthesia. The procedure was performed by senior consultants Ms Miserocchi and Mr McEvoy. Livanova VNS electrode was wrapped around the left Vagus nerve of the patient and a pulse generator was implanted on the left chest above the pectoralis muscle 2–3 cm below the collar bone. The surgery and post-operative period were uneventful. After 2 weeks of rest, the device was switched on with automatic current settings of amplitude between 1–2 mA, frequency between 10–30 hertz, pulse width between 250–750 microseconds and duration of between 20–60 seconds. Pharmaco-medical treatment for the hiccups was discontinued. There was no hoarseness or change in voice of the patient and no chest pain or any sign of cardiac compromise.
This provided complete remission for few hours after which the hiccups returned but were infrequent with episodes lasting for up to 15 min, with a rate of 1 hiccup per second, every 4–6 hours, thus demonstrating a much-decreased rate and magnitude. Patient and his family noted the intensity to be 5/10 on a subjective scale with marked improvement in speech. Due to the coronavirus (Covid-19) outbreak the patient is currently awaiting a follow up appointment to review prognosis and revise the automatic current settings.
We therefore document partial success with the surgical placement of Vagus nerve stimulator for the treatment of intractable hiccups at our centre with short term results. As seen with epilepsy, VNS tends to continue to improve prognosis up to 1–1.5 years. We will continue to monitor the patient and present a follow up report with long term results.
3 Discussion
Although temporary hiccups are a benign occurrence having no significant impact on the life of a person but intractable hiccups are a serious and debilitating pathology and often lead to dire consequences [[1], [2], [3],7]. The world record of longest hiccups is 69 years with notable people such as Pope Pius XII dying from the ailment [13]. Therefore, symptomatic intractable hiccups warrant medical and surgical treatment [1].
The Vagus nerve forms a significant component of the hiccup reflex arc and can explain several odd triggers as well as the basis for most initial remedies [4,9,10]. In fact hiccups most frequently occur during inspiration when lung inflation impedes vagal afferents known to suppress hiccups [6]. The Vagus nerve, also referred to as the “wandering” nerve or the “vagabond” nerve, greatly innervates multiple organs of the body and forms a part of several bodily reflexes [4,7,10]. Its stimulation has demonstrated varied functional outcomes the exact mechanism of most of which are not clearly understood [7]. VNS is an acknowledged treatment for epilepsy and depression [2].
Medical therapy for intractable hiccups comprises of GABA-derivatives, baclofen, dopaminergic antagonists and anticonvulsants. Non-traditional treatments such as acupuncture, massages and hypnosis are also widely used. Non-pharmacological options such as phrenic nerve blocking, crushing and pacing, percutaneous phrenic nerve stimulation and cervical epidural block have shown limited success due to the occasional presence of an accessory phrenic nerve as well as the bilateral diaphragmatic contraction aetiology of centrally originated hiccups [2,3,7,13].
Recently surgical placement of Vagus nerve stimulators have been undertaken for chronic hiccups with varying degrees of success [2,5,7,10]. We report a case of intractable hiccups secondary to pneumonia, treated with VNS placement at our centre with short term results demonstrating partial success, in accordance with SCARE-2018 guidelines [14]. Since the thorax is of immense anatomical importance in the hiccup reflex, it is reasonable to consider that infections of the chest can lead to hiccups [1]. Seeing as no validated questionnaires have been formulated to document the intensity of hiccups [1], a 10-point patient subjective scale was employed.
Very little research is available on the cure of hiccups and even the pathogenesis of hiccups is less understood. Due to the lack of a physiological relevance in adults and the observation of hiccups in foetuses along with the efficacy of baclofen in arresting gill-ventilation in tadpoles, it is speculated that hiccup is a phylogenetical reflex [2,4,6,13]. Future research will help us better understand this phenomenon and its treatment.
Declaration of Competing Interest
The authors have no conflict of interest. We confirm that where other sources of information have been utilised and cited, it is with the permission of the corresponding authors.
Funding
Not applicable, this is not a research project.
Ethical approval
Not applicable, this is not a research project.
Consent
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Dr Joe M. Das: Writing - Review & Editing.
Ms Sasha Monaghan: Writing - Review & Editing.
Ms Anna Miserocchi: Supervision, Project administration.
Mr Andrew McEvoy: Supervision, Project administration.
Registration of research studies
Not applicable.
Guarantor
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Provenance and peer review
Not commissioned, externally peer-reviewed. | BACLOFEN, CARBAMAZEPINE, CHLORPROMAZINE, DOMPERIDONE, GABAPENTIN, LANSOPRAZOLE, LEVETIRACETAM, METOCLOPRAMIDE, OMEPRAZOLE, PROCHLORPERAZINE | DrugsGivenReaction | CC BY-NC-ND | 33360634 | 18,817,592 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | A case report of Vagus nerve stimulation for intractable hiccups.
BACKGROUND
Intractable hiccups frequently result from an underlying pathology and can cause considerable illness in the patients. Initial remedies such as drinking cold water, induction of emesis, carotid sinus massage or Valsalva manoeuvre all seem to work by over stimulating the Vagus nerve. Pharmacotherapy with baclofen, gabapentin and other centrally and peripherally acting agents such as chlorpromazine and metoclopramide are reserved as second line treatment. Medical refractory cases even indulge in unconventional therapies such as hypnosis, massages and acupuncture. Surgical intervention, although undertaken very rarely, predominantly revolves around phrenic nerve crushing, blockade or pacing. A novel surgical strategy is emerging in the form of Vagus nerve stimulator (VNS) placement with three cases cited in literature to date with varying degrees of success. Here the authors report a case of VNS placement for intractable hiccups with partial success, in accordance with SCARE-2018 guidelines.
An 85-year-old gentleman with a 9-year history of intractable hiccups secondary to pneumonia came to our hospital. The hiccups were symptomatic causing anorexia, insomnia, irritability, depression, exhaustion, muscle wasting and weight loss. The patient underwent countless medical evaluations. All examinations and investigations yielded normal results. The patient underwent aggressive pharmacotherapy, home remedies and unconventional therapies for intractable hiccups but to no avail. He also underwent left phrenic nerve blocking and resection without therapeutic success. The patient presented to our hospital and decision for VNS insertion was taken for compassionate reasons considering patient morbidity. The patient demonstrated significant improvement in his symptoms following VNS insertion.
CONCLUSIONS
A temporary hiccup is an occasional happening experienced by everyone. However, intractable hiccups are associated with significant morbidity and often mortality. Several medical, pharmacological, surgical and novel treatment options are available for intractable hiccups.
CONCLUSIONS
VNS insertion is a novel surgical option for the treatment of intractable hiccups.
1 Introduction
Hiccup is a widely experienced and less understood phenomenon. Although much is known about the afferent and efferent limbs of the hiccup reflex pathway, no definitive consensus exists on the hiccup centre generating this reflex. Even the word “hiccup” is an onomatopoeic for the sound the reflex arc produces [1]. The hiccup reflex arc can be categorised as having afferent and efferent limbs and a central connection. The afferent limb is composed of the Vagus and phrenic nerves, and the lower sympathetic (T6-12) segments. The efferent pathway is constituted by the phrenic nerve (C3-5) innervating the diaphragm, plexal branches to the scalene muscles (C5-7), recurrent laryngeal nerve to the glottis and the intercostal nerves (T1-11) innervating the intercostal muscles [2,3]. The hiccup central connection is believed to be spinal cord segments rostral to medulla oblongata (C3-5) in the reticular formation in the middle and dorsolateral segment, connecting to the hiccup rhythm centre in the Pre-Botzinger complex, nucleus ambiguous, lateral reticular nucleus, hypothalamus and mesial temporal lobes [[2], [3], [4], [5]]. Gama-aminobutyric acid (GABA) and dopamine act as neurotransmitters for this reflex. It is speculated that the hiccup centre and the respiratory centre although separate may interact with one another through the various neuronal connections [2,5]. When the hiccup reflex is triggered there is synchronous contraction of the inspiratory thoracic muscles and the diaphragm. This is followed, in 35 milliseconds, by an abrupt glottal closure producing the typical “hicc” [6].
There is no conclusive knowledge on how this reflex is triggered but a safe idea would be that any mechanism which irritates or damages the components of the reflex arc, the central nuclei, the Vagus, phrenic or other nerves of the autonomic system can trigger a hiccup. Of these the Vagus is particularly important. The “wanderer” has such immense distribution throughout the body that the reflex can be triggered by any number of odd reasons such as irritation of the ear drum, rapid change in body temperature, over distension of stomach, irritation of the respiratory tractor stroking of hair [7,8]. As such most initial remedies seem to centre on over stimulating the Vagus nerve [9,10]. In cases of known underlying pathology treatment of the causative factor may help relieve the symptoms [11]. Table 1 enlists the various causes of a hiccup. Gastro-oesophageal reflux disease (GERD) has been shown to be both a cause of as well as a consequence of hiccups [1]. Although GERD can induce hiccups via the irritation of the Vagus nerve, long standing hiccups in themselves can cause reduction in the oesophageal motility as well as lowering of oesophageal-gastric sphincter pressure thus favouring GERD [1,6]. Hiccups are classified as temporary (<48 h), persistent (48 h-1 month) or intractable (>1 month), depending on their duration [3]. Intractable hiccups may cause debilitating problems such as insomnia, anorexia, fatigue, exhaustion, weight loss, depression, opening of surgical wounds, development of hernia and haemorrhoids, inability to undergo imaging such as MRI and even death. In such cases active management is required. Numerous medical and alternative therapies are available for the treatment of hiccups. Rarely surgical interventions are employed [2,8,12]. Table 2 provides an overview of the different treatment modalities for hiccups (Table 3).Table 1 Possible Causes of Hiccups adapted from Steger et al.
Table 1Central/Peripheral Nervous System Gastrointestinal Thoracic Ear, Nose & Throat (ENT) Metabolic Pharmacologic/Toxic Surgical Psychosomatic
Ischemic/haemorrhagic stroke Gastric Distension Cardiac Ischemic Injury Infection Hypo/Hyper-Glycaemia Alcohol Thoracic Surgery Anxiety
Tumours Gastro-oesophageal Reflux Disease Cardiac Infection Inflammation Hypo/Hyper-Natremia Chemotherapy/Radiotherapy Abdominal Surgery Stress
Traumatic Brain Injury Hiatus Hernia Cardiac Inflammation Foreign Body Hypo/Hyper-Kalemia Steroids Ear, nose, throat Surgery Excitement
Infection Gastrointestinal tumours Pulmonary Infection Tumours Hypo/Hyper-Calcemia Inhalational Oxygen Endoscopy Fear
Inflammation Infection Pulmonary Inflammation Hypocapnemia Benzodiazepines Pharyngeal Intubation
Demyelinating diseases Inflammation Thoracic Tumours Hypo/Hyper-Uraemia Dopamine Agonists Placement of Central Venous Catheter
Auto-immune diseases Obstruction Aneurysms Metabolic Diseases Opioids Iatrogenic Injury
Neuro-transmitter abnormalities Haemorrhage Auto-immune diseases Hypo/Hyper-Thermia Barbiturates
Vascular abnormalities Smoking Anti-biotics
Anatomical Abnormalities Anaesthetic Agents
Table 2 Various Treatments of Hiccups adapted from Steger et al.
Table 2Vagal Stimulation Respiratory Manoeuvres Centrally Acting Pharmacological Peripherally Acting Pharmacological Surgical Alternative Treatment
Intra-Nasal application of Vinegar Valsalva Maneuver Chlorpromazine Metoclopramide Phrenic Nerve Blockage or Crushing Hypnosis
Inhalation of Smelling Salts/Strong Odours Breath Holding (Inspiration, Expiration) Phenytoin Domperidone Phrenic Nerve Pacing Acupuncture
Swallowing Ice Water Re-Breathing (Hyper-capnia) Haloperidol Nifedipine Percutaneous Phrenic Nerve Stimulation Massage
Splashing Cold water Or Cold Compress On Face Baclofen Cervical Epidural Block
Induce Vomiting Gabapentin Implantation of Vagal Nerve Stimulator
Induce Fright Pregabalin
Carotid Massage Carbamazepine
Pressure Over Eyeball Sodium Valproate
Digital Rectal Massage Amitriptylline
Induce Orgasm
Table 3 Functional Components of the Vagus Nerve.
Table 320% Efferent 80% Afferent
General Visceral Efferent (Pre-Ganglionic Parasympathetic) Special Visceral Efferent General Somatic Afferent General Visceral Afferent Special Visceral Afferent
Dorsal Motor Nucleus Nucleus Accumbens Motor Innervation Reflexes Sensory Sensory Receptors Reflexes Sensory
Thoracic Organs Cardio-inhibitory Function Soft Palate Gag Reflex Pharynx Abdominal Organs Aortic Arch Baroreceptors Reflex Regulation of Gastrointestinal Tract Epiglottis
Abdominal Organs Pharynx Cough Reflex Larynx Thoracic Organs Carotid Sinus Baroreceptors Reflex Regulation of Cardiovascular System Taste Buds
Larynx Peristaltic Reflex Oesophagus Chemoreceptors Reflex Regulation of Respiratory System
Upper Part of Oesophagus Trachea
Bronchi
External Auditory Meatus
Tympanic Membrane
Concha
2 Case report
An 85-year-old Caucasian gentleman with a 9-year history of intractable hiccups came to National Hospital for Neurology and Neurosurgery, a 244-bed quaternary care hospital, after numerous unsuccessful traditional medical and alternative treatments.
His symptoms started in October 2010 when he suffered from pneumonia which caused severe respiratory compromise and fever. Prompt hospitalization and medical management attained full recovery, however a few days later the patient developed hiccups. Patient had a past medical history of ischaemic heart disease of 10 years, hypertension and hypercholesterolemia, both of which were very well controlled with amlodipine and rosuvastatin and had no symptoms of hiccups prior to the pneumonia in 2010. Patient neither consumed alcohol nor smoked and did not indulge in recreational drugs. Initially the hiccups were for intermittent onset, about 2–3 per day with months of remission between successive episode. Gradually they became more consistent, occurring daily with a frequency of about 50–100 per day. Patient was still able to carry out his daily routine and used home remedies such as drinking cold water, re-breathing in a paper bag, pressure over eyeballs, Valsalva manoeuvre and splashing cold water on face to treat his hiccups.
However, the hiccups progressively worsened in frequency, rate, intensity and magnitude. In 2013 patient developed GERD, possibly as a consequence of the ongoing hiccups and underwent Nissen fundoplication. Fundoplication completely resolved GERD but the hiccups continued to worsen. 3 years ago, they became non-stop occurring every 5 s and continued during sleep. They were symptomatically disabling and scored 9/10 on a 10-point subjective patient scale. They caused severe distress to the patient who became progressively anorexic, irritated, short tempered, fatigued and depressed. He became emaciated over the years and found it hard to talk. Even normal breathing was upset with sensations of choking secondary to glottis spasms. Patient underwent countless medical evaluations; physical and neurological examinations including ENT, chest and abdomen; laboratory investigations including blood urea nitrogen; imagining including magnetic resonance imaging (MRI) of brain and neck, computed tomography (CT) of abdomen and thorax and even upper gastrointestinal endoscopy and bronchoscopy. All examinations and investigations yielded normal results. In the absence of a definitive underlying cause an aggressive pharmaco-medical treatment was started. These medical therapies including prochlorperazine, metoclopramide, levetiracetam, baclofen, chlorpromazine, omeprazole, domperidone, gabapentin, carbamazepine, lansoprazole and Maalox plus remained ineffective. Patient also tried acupuncture, massage and hypnosis but to no avail. In April 2018 the patient underwent left phrenic nerve blocking which provided temporary relief for half a day. Following this, in June 2018 the patient underwent left phrenic nerve resection which cured the hiccups for only 2 days.
Patient became progressively unwell and lost half of his body weight. Furthermore, the disquieting symptoms were temporarily relieved for approximately 30 min. only by the induction of vomiting. Patient induced vomiting about 15 times in a day to experience relief from the hiccups.
In February 2020 the patient was referred to our neurosurgery department for evaluation. All physical and neurological examinations, relevant imaging and blood investigations were normal. No underlying cause was ascertained. VNS is currently not approved for the indication of intractable hiccups but given the fact that the patient had failed multiple lines of treatment and was disconsolate, after meticulous consideration and careful review of literature a decision was made for VNS insertion as a compassionate indication. Patient was positioned supine under general anaesthesia. The procedure was performed by senior consultants Ms Miserocchi and Mr McEvoy. Livanova VNS electrode was wrapped around the left Vagus nerve of the patient and a pulse generator was implanted on the left chest above the pectoralis muscle 2–3 cm below the collar bone. The surgery and post-operative period were uneventful. After 2 weeks of rest, the device was switched on with automatic current settings of amplitude between 1–2 mA, frequency between 10–30 hertz, pulse width between 250–750 microseconds and duration of between 20–60 seconds. Pharmaco-medical treatment for the hiccups was discontinued. There was no hoarseness or change in voice of the patient and no chest pain or any sign of cardiac compromise.
This provided complete remission for few hours after which the hiccups returned but were infrequent with episodes lasting for up to 15 min, with a rate of 1 hiccup per second, every 4–6 hours, thus demonstrating a much-decreased rate and magnitude. Patient and his family noted the intensity to be 5/10 on a subjective scale with marked improvement in speech. Due to the coronavirus (Covid-19) outbreak the patient is currently awaiting a follow up appointment to review prognosis and revise the automatic current settings.
We therefore document partial success with the surgical placement of Vagus nerve stimulator for the treatment of intractable hiccups at our centre with short term results. As seen with epilepsy, VNS tends to continue to improve prognosis up to 1–1.5 years. We will continue to monitor the patient and present a follow up report with long term results.
3 Discussion
Although temporary hiccups are a benign occurrence having no significant impact on the life of a person but intractable hiccups are a serious and debilitating pathology and often lead to dire consequences [[1], [2], [3],7]. The world record of longest hiccups is 69 years with notable people such as Pope Pius XII dying from the ailment [13]. Therefore, symptomatic intractable hiccups warrant medical and surgical treatment [1].
The Vagus nerve forms a significant component of the hiccup reflex arc and can explain several odd triggers as well as the basis for most initial remedies [4,9,10]. In fact hiccups most frequently occur during inspiration when lung inflation impedes vagal afferents known to suppress hiccups [6]. The Vagus nerve, also referred to as the “wandering” nerve or the “vagabond” nerve, greatly innervates multiple organs of the body and forms a part of several bodily reflexes [4,7,10]. Its stimulation has demonstrated varied functional outcomes the exact mechanism of most of which are not clearly understood [7]. VNS is an acknowledged treatment for epilepsy and depression [2].
Medical therapy for intractable hiccups comprises of GABA-derivatives, baclofen, dopaminergic antagonists and anticonvulsants. Non-traditional treatments such as acupuncture, massages and hypnosis are also widely used. Non-pharmacological options such as phrenic nerve blocking, crushing and pacing, percutaneous phrenic nerve stimulation and cervical epidural block have shown limited success due to the occasional presence of an accessory phrenic nerve as well as the bilateral diaphragmatic contraction aetiology of centrally originated hiccups [2,3,7,13].
Recently surgical placement of Vagus nerve stimulators have been undertaken for chronic hiccups with varying degrees of success [2,5,7,10]. We report a case of intractable hiccups secondary to pneumonia, treated with VNS placement at our centre with short term results demonstrating partial success, in accordance with SCARE-2018 guidelines [14]. Since the thorax is of immense anatomical importance in the hiccup reflex, it is reasonable to consider that infections of the chest can lead to hiccups [1]. Seeing as no validated questionnaires have been formulated to document the intensity of hiccups [1], a 10-point patient subjective scale was employed.
Very little research is available on the cure of hiccups and even the pathogenesis of hiccups is less understood. Due to the lack of a physiological relevance in adults and the observation of hiccups in foetuses along with the efficacy of baclofen in arresting gill-ventilation in tadpoles, it is speculated that hiccup is a phylogenetical reflex [2,4,6,13]. Future research will help us better understand this phenomenon and its treatment.
Declaration of Competing Interest
The authors have no conflict of interest. We confirm that where other sources of information have been utilised and cited, it is with the permission of the corresponding authors.
Funding
Not applicable, this is not a research project.
Ethical approval
Not applicable, this is not a research project.
Consent
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Dr Joe M. Das: Writing - Review & Editing.
Ms Sasha Monaghan: Writing - Review & Editing.
Ms Anna Miserocchi: Supervision, Project administration.
Mr Andrew McEvoy: Supervision, Project administration.
Registration of research studies
Not applicable.
Guarantor
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Provenance and peer review
Not commissioned, externally peer-reviewed. | BACLOFEN, CARBAMAZEPINE, CHLORPROMAZINE, DOMPERIDONE, GABAPENTIN, LANSOPRAZOLE, LEVETIRACETAM, METOCLOPRAMIDE, OMEPRAZOLE, PROCHLORPERAZINE | DrugsGivenReaction | CC BY-NC-ND | 33360634 | 18,817,592 | 2021-01 |
What was the dosage of drug 'LEVETIRACETAM'? | A case report of Vagus nerve stimulation for intractable hiccups.
BACKGROUND
Intractable hiccups frequently result from an underlying pathology and can cause considerable illness in the patients. Initial remedies such as drinking cold water, induction of emesis, carotid sinus massage or Valsalva manoeuvre all seem to work by over stimulating the Vagus nerve. Pharmacotherapy with baclofen, gabapentin and other centrally and peripherally acting agents such as chlorpromazine and metoclopramide are reserved as second line treatment. Medical refractory cases even indulge in unconventional therapies such as hypnosis, massages and acupuncture. Surgical intervention, although undertaken very rarely, predominantly revolves around phrenic nerve crushing, blockade or pacing. A novel surgical strategy is emerging in the form of Vagus nerve stimulator (VNS) placement with three cases cited in literature to date with varying degrees of success. Here the authors report a case of VNS placement for intractable hiccups with partial success, in accordance with SCARE-2018 guidelines.
An 85-year-old gentleman with a 9-year history of intractable hiccups secondary to pneumonia came to our hospital. The hiccups were symptomatic causing anorexia, insomnia, irritability, depression, exhaustion, muscle wasting and weight loss. The patient underwent countless medical evaluations. All examinations and investigations yielded normal results. The patient underwent aggressive pharmacotherapy, home remedies and unconventional therapies for intractable hiccups but to no avail. He also underwent left phrenic nerve blocking and resection without therapeutic success. The patient presented to our hospital and decision for VNS insertion was taken for compassionate reasons considering patient morbidity. The patient demonstrated significant improvement in his symptoms following VNS insertion.
CONCLUSIONS
A temporary hiccup is an occasional happening experienced by everyone. However, intractable hiccups are associated with significant morbidity and often mortality. Several medical, pharmacological, surgical and novel treatment options are available for intractable hiccups.
CONCLUSIONS
VNS insertion is a novel surgical option for the treatment of intractable hiccups.
1 Introduction
Hiccup is a widely experienced and less understood phenomenon. Although much is known about the afferent and efferent limbs of the hiccup reflex pathway, no definitive consensus exists on the hiccup centre generating this reflex. Even the word “hiccup” is an onomatopoeic for the sound the reflex arc produces [1]. The hiccup reflex arc can be categorised as having afferent and efferent limbs and a central connection. The afferent limb is composed of the Vagus and phrenic nerves, and the lower sympathetic (T6-12) segments. The efferent pathway is constituted by the phrenic nerve (C3-5) innervating the diaphragm, plexal branches to the scalene muscles (C5-7), recurrent laryngeal nerve to the glottis and the intercostal nerves (T1-11) innervating the intercostal muscles [2,3]. The hiccup central connection is believed to be spinal cord segments rostral to medulla oblongata (C3-5) in the reticular formation in the middle and dorsolateral segment, connecting to the hiccup rhythm centre in the Pre-Botzinger complex, nucleus ambiguous, lateral reticular nucleus, hypothalamus and mesial temporal lobes [[2], [3], [4], [5]]. Gama-aminobutyric acid (GABA) and dopamine act as neurotransmitters for this reflex. It is speculated that the hiccup centre and the respiratory centre although separate may interact with one another through the various neuronal connections [2,5]. When the hiccup reflex is triggered there is synchronous contraction of the inspiratory thoracic muscles and the diaphragm. This is followed, in 35 milliseconds, by an abrupt glottal closure producing the typical “hicc” [6].
There is no conclusive knowledge on how this reflex is triggered but a safe idea would be that any mechanism which irritates or damages the components of the reflex arc, the central nuclei, the Vagus, phrenic or other nerves of the autonomic system can trigger a hiccup. Of these the Vagus is particularly important. The “wanderer” has such immense distribution throughout the body that the reflex can be triggered by any number of odd reasons such as irritation of the ear drum, rapid change in body temperature, over distension of stomach, irritation of the respiratory tractor stroking of hair [7,8]. As such most initial remedies seem to centre on over stimulating the Vagus nerve [9,10]. In cases of known underlying pathology treatment of the causative factor may help relieve the symptoms [11]. Table 1 enlists the various causes of a hiccup. Gastro-oesophageal reflux disease (GERD) has been shown to be both a cause of as well as a consequence of hiccups [1]. Although GERD can induce hiccups via the irritation of the Vagus nerve, long standing hiccups in themselves can cause reduction in the oesophageal motility as well as lowering of oesophageal-gastric sphincter pressure thus favouring GERD [1,6]. Hiccups are classified as temporary (<48 h), persistent (48 h-1 month) or intractable (>1 month), depending on their duration [3]. Intractable hiccups may cause debilitating problems such as insomnia, anorexia, fatigue, exhaustion, weight loss, depression, opening of surgical wounds, development of hernia and haemorrhoids, inability to undergo imaging such as MRI and even death. In such cases active management is required. Numerous medical and alternative therapies are available for the treatment of hiccups. Rarely surgical interventions are employed [2,8,12]. Table 2 provides an overview of the different treatment modalities for hiccups (Table 3).Table 1 Possible Causes of Hiccups adapted from Steger et al.
Table 1Central/Peripheral Nervous System Gastrointestinal Thoracic Ear, Nose & Throat (ENT) Metabolic Pharmacologic/Toxic Surgical Psychosomatic
Ischemic/haemorrhagic stroke Gastric Distension Cardiac Ischemic Injury Infection Hypo/Hyper-Glycaemia Alcohol Thoracic Surgery Anxiety
Tumours Gastro-oesophageal Reflux Disease Cardiac Infection Inflammation Hypo/Hyper-Natremia Chemotherapy/Radiotherapy Abdominal Surgery Stress
Traumatic Brain Injury Hiatus Hernia Cardiac Inflammation Foreign Body Hypo/Hyper-Kalemia Steroids Ear, nose, throat Surgery Excitement
Infection Gastrointestinal tumours Pulmonary Infection Tumours Hypo/Hyper-Calcemia Inhalational Oxygen Endoscopy Fear
Inflammation Infection Pulmonary Inflammation Hypocapnemia Benzodiazepines Pharyngeal Intubation
Demyelinating diseases Inflammation Thoracic Tumours Hypo/Hyper-Uraemia Dopamine Agonists Placement of Central Venous Catheter
Auto-immune diseases Obstruction Aneurysms Metabolic Diseases Opioids Iatrogenic Injury
Neuro-transmitter abnormalities Haemorrhage Auto-immune diseases Hypo/Hyper-Thermia Barbiturates
Vascular abnormalities Smoking Anti-biotics
Anatomical Abnormalities Anaesthetic Agents
Table 2 Various Treatments of Hiccups adapted from Steger et al.
Table 2Vagal Stimulation Respiratory Manoeuvres Centrally Acting Pharmacological Peripherally Acting Pharmacological Surgical Alternative Treatment
Intra-Nasal application of Vinegar Valsalva Maneuver Chlorpromazine Metoclopramide Phrenic Nerve Blockage or Crushing Hypnosis
Inhalation of Smelling Salts/Strong Odours Breath Holding (Inspiration, Expiration) Phenytoin Domperidone Phrenic Nerve Pacing Acupuncture
Swallowing Ice Water Re-Breathing (Hyper-capnia) Haloperidol Nifedipine Percutaneous Phrenic Nerve Stimulation Massage
Splashing Cold water Or Cold Compress On Face Baclofen Cervical Epidural Block
Induce Vomiting Gabapentin Implantation of Vagal Nerve Stimulator
Induce Fright Pregabalin
Carotid Massage Carbamazepine
Pressure Over Eyeball Sodium Valproate
Digital Rectal Massage Amitriptylline
Induce Orgasm
Table 3 Functional Components of the Vagus Nerve.
Table 320% Efferent 80% Afferent
General Visceral Efferent (Pre-Ganglionic Parasympathetic) Special Visceral Efferent General Somatic Afferent General Visceral Afferent Special Visceral Afferent
Dorsal Motor Nucleus Nucleus Accumbens Motor Innervation Reflexes Sensory Sensory Receptors Reflexes Sensory
Thoracic Organs Cardio-inhibitory Function Soft Palate Gag Reflex Pharynx Abdominal Organs Aortic Arch Baroreceptors Reflex Regulation of Gastrointestinal Tract Epiglottis
Abdominal Organs Pharynx Cough Reflex Larynx Thoracic Organs Carotid Sinus Baroreceptors Reflex Regulation of Cardiovascular System Taste Buds
Larynx Peristaltic Reflex Oesophagus Chemoreceptors Reflex Regulation of Respiratory System
Upper Part of Oesophagus Trachea
Bronchi
External Auditory Meatus
Tympanic Membrane
Concha
2 Case report
An 85-year-old Caucasian gentleman with a 9-year history of intractable hiccups came to National Hospital for Neurology and Neurosurgery, a 244-bed quaternary care hospital, after numerous unsuccessful traditional medical and alternative treatments.
His symptoms started in October 2010 when he suffered from pneumonia which caused severe respiratory compromise and fever. Prompt hospitalization and medical management attained full recovery, however a few days later the patient developed hiccups. Patient had a past medical history of ischaemic heart disease of 10 years, hypertension and hypercholesterolemia, both of which were very well controlled with amlodipine and rosuvastatin and had no symptoms of hiccups prior to the pneumonia in 2010. Patient neither consumed alcohol nor smoked and did not indulge in recreational drugs. Initially the hiccups were for intermittent onset, about 2–3 per day with months of remission between successive episode. Gradually they became more consistent, occurring daily with a frequency of about 50–100 per day. Patient was still able to carry out his daily routine and used home remedies such as drinking cold water, re-breathing in a paper bag, pressure over eyeballs, Valsalva manoeuvre and splashing cold water on face to treat his hiccups.
However, the hiccups progressively worsened in frequency, rate, intensity and magnitude. In 2013 patient developed GERD, possibly as a consequence of the ongoing hiccups and underwent Nissen fundoplication. Fundoplication completely resolved GERD but the hiccups continued to worsen. 3 years ago, they became non-stop occurring every 5 s and continued during sleep. They were symptomatically disabling and scored 9/10 on a 10-point subjective patient scale. They caused severe distress to the patient who became progressively anorexic, irritated, short tempered, fatigued and depressed. He became emaciated over the years and found it hard to talk. Even normal breathing was upset with sensations of choking secondary to glottis spasms. Patient underwent countless medical evaluations; physical and neurological examinations including ENT, chest and abdomen; laboratory investigations including blood urea nitrogen; imagining including magnetic resonance imaging (MRI) of brain and neck, computed tomography (CT) of abdomen and thorax and even upper gastrointestinal endoscopy and bronchoscopy. All examinations and investigations yielded normal results. In the absence of a definitive underlying cause an aggressive pharmaco-medical treatment was started. These medical therapies including prochlorperazine, metoclopramide, levetiracetam, baclofen, chlorpromazine, omeprazole, domperidone, gabapentin, carbamazepine, lansoprazole and Maalox plus remained ineffective. Patient also tried acupuncture, massage and hypnosis but to no avail. In April 2018 the patient underwent left phrenic nerve blocking which provided temporary relief for half a day. Following this, in June 2018 the patient underwent left phrenic nerve resection which cured the hiccups for only 2 days.
Patient became progressively unwell and lost half of his body weight. Furthermore, the disquieting symptoms were temporarily relieved for approximately 30 min. only by the induction of vomiting. Patient induced vomiting about 15 times in a day to experience relief from the hiccups.
In February 2020 the patient was referred to our neurosurgery department for evaluation. All physical and neurological examinations, relevant imaging and blood investigations were normal. No underlying cause was ascertained. VNS is currently not approved for the indication of intractable hiccups but given the fact that the patient had failed multiple lines of treatment and was disconsolate, after meticulous consideration and careful review of literature a decision was made for VNS insertion as a compassionate indication. Patient was positioned supine under general anaesthesia. The procedure was performed by senior consultants Ms Miserocchi and Mr McEvoy. Livanova VNS electrode was wrapped around the left Vagus nerve of the patient and a pulse generator was implanted on the left chest above the pectoralis muscle 2–3 cm below the collar bone. The surgery and post-operative period were uneventful. After 2 weeks of rest, the device was switched on with automatic current settings of amplitude between 1–2 mA, frequency between 10–30 hertz, pulse width between 250–750 microseconds and duration of between 20–60 seconds. Pharmaco-medical treatment for the hiccups was discontinued. There was no hoarseness or change in voice of the patient and no chest pain or any sign of cardiac compromise.
This provided complete remission for few hours after which the hiccups returned but were infrequent with episodes lasting for up to 15 min, with a rate of 1 hiccup per second, every 4–6 hours, thus demonstrating a much-decreased rate and magnitude. Patient and his family noted the intensity to be 5/10 on a subjective scale with marked improvement in speech. Due to the coronavirus (Covid-19) outbreak the patient is currently awaiting a follow up appointment to review prognosis and revise the automatic current settings.
We therefore document partial success with the surgical placement of Vagus nerve stimulator for the treatment of intractable hiccups at our centre with short term results. As seen with epilepsy, VNS tends to continue to improve prognosis up to 1–1.5 years. We will continue to monitor the patient and present a follow up report with long term results.
3 Discussion
Although temporary hiccups are a benign occurrence having no significant impact on the life of a person but intractable hiccups are a serious and debilitating pathology and often lead to dire consequences [[1], [2], [3],7]. The world record of longest hiccups is 69 years with notable people such as Pope Pius XII dying from the ailment [13]. Therefore, symptomatic intractable hiccups warrant medical and surgical treatment [1].
The Vagus nerve forms a significant component of the hiccup reflex arc and can explain several odd triggers as well as the basis for most initial remedies [4,9,10]. In fact hiccups most frequently occur during inspiration when lung inflation impedes vagal afferents known to suppress hiccups [6]. The Vagus nerve, also referred to as the “wandering” nerve or the “vagabond” nerve, greatly innervates multiple organs of the body and forms a part of several bodily reflexes [4,7,10]. Its stimulation has demonstrated varied functional outcomes the exact mechanism of most of which are not clearly understood [7]. VNS is an acknowledged treatment for epilepsy and depression [2].
Medical therapy for intractable hiccups comprises of GABA-derivatives, baclofen, dopaminergic antagonists and anticonvulsants. Non-traditional treatments such as acupuncture, massages and hypnosis are also widely used. Non-pharmacological options such as phrenic nerve blocking, crushing and pacing, percutaneous phrenic nerve stimulation and cervical epidural block have shown limited success due to the occasional presence of an accessory phrenic nerve as well as the bilateral diaphragmatic contraction aetiology of centrally originated hiccups [2,3,7,13].
Recently surgical placement of Vagus nerve stimulators have been undertaken for chronic hiccups with varying degrees of success [2,5,7,10]. We report a case of intractable hiccups secondary to pneumonia, treated with VNS placement at our centre with short term results demonstrating partial success, in accordance with SCARE-2018 guidelines [14]. Since the thorax is of immense anatomical importance in the hiccup reflex, it is reasonable to consider that infections of the chest can lead to hiccups [1]. Seeing as no validated questionnaires have been formulated to document the intensity of hiccups [1], a 10-point patient subjective scale was employed.
Very little research is available on the cure of hiccups and even the pathogenesis of hiccups is less understood. Due to the lack of a physiological relevance in adults and the observation of hiccups in foetuses along with the efficacy of baclofen in arresting gill-ventilation in tadpoles, it is speculated that hiccup is a phylogenetical reflex [2,4,6,13]. Future research will help us better understand this phenomenon and its treatment.
Declaration of Competing Interest
The authors have no conflict of interest. We confirm that where other sources of information have been utilised and cited, it is with the permission of the corresponding authors.
Funding
Not applicable, this is not a research project.
Ethical approval
Not applicable, this is not a research project.
Consent
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Dr Joe M. Das: Writing - Review & Editing.
Ms Sasha Monaghan: Writing - Review & Editing.
Ms Anna Miserocchi: Supervision, Project administration.
Mr Andrew McEvoy: Supervision, Project administration.
Registration of research studies
Not applicable.
Guarantor
Dr Kanza Tariq: Writing - Original Draft, Writing - Review & Editing, Visualization.
Provenance and peer review
Not commissioned, externally peer-reviewed. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33360634 | 18,817,592 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paraesthesia'. | Aquaporin-4-antibody-positive Neuromyelitis Optica Spectrum Disorder in a Patient with Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy, and its involvement in the central nervous system (CNS) is very rare. We herein report a 51-year-old woman with CMT1A who suffered from recurrent optic neuritis and myelopathy. Under the diagnosis of anti-aquaporin-4 (anti-AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD), we treated her successfully with corticosteroids. This is the first report of CMT1A complicated with anti-AQP4-positive NMOSD. Although the coexistence of the two disorders may simply be a coincidence, we speculated that immune cross-reaction between overexpressed peripheral myelin protein 22 and CNS myelin may have caused concomitant CMT1A and NMOSD.
Introduction
Charcot-Marie-Tooth disease (CMT) is a group of inherited motor sensory neuropathies. Demyelination in the central nervous system (CNS) is a rare complication of CMT, except for in its X-linked subtype (CMTX), in which CNS involvement has occasionally been reported (1).
We herein report a patient with CMT type 1A (CMT1A) who suffered from recurrent optic neuritis and myelopathy. We discuss the immune mechanisms underlying the concomitant involvement of the peripheral nervous system and the CNS.
Case Report
A 51-year-old Japanese woman was admitted to our hospital because of left ophthalmic pain and progressive blindness during the previous 9 days. One year before this presentation, she had experienced repeated numbness and pain in the lower extremities, which spontaneously remitted after a couple of weeks. One month before the admission, she had experienced blurred vision and discomfort of the right eye, which improved spontaneously after several days. She had experienced gait disturbance since childhood and had developed atrophy and paresthesia of the distal lower extremities during adolescence. She had a family history of peripheral neuropathy with the autosomal dominant form of inheritance (Fig. 1). The disease onset was in adolescence in all affected members, except for in a sister of the patient, whose onset was at elementary school age.
Figure 1. Pedigree tree of the family. Filled symbols indicate individuals with peripheral neuropathy and pes cavus. The father of the patient (I-1) had had difficulty running since he was a teenager. The older sister of the patient (II-1) had suffered from neuropathy since elementary school. Two siblings (II-3, 4), two nephews (III-2, 4), and one niece (III-5) of the patient had developed neuropathy in their teenage years. No family members had disorders involving the central nervous system, including optic neuritis. The arrow indicates the proband. Squares and circles indicate men and women, respectively.
On admission, her left eye was blind with a dilated pupil and an absent light reflex. A fundoscopic examination revealed redness of the left optic nerve papilla. The right eye had visual acuity of 0.80 (Snellen fraction of 20/25) with a normal light reflex and a normal fundoscopic appearance. The critical flicker fusion threshold (CFF) was unmeasurable in the left eye and 34 Hz in the right eye. Distal extremities exhibited wasting and weakness, especially the lower extremities. There was sensory loss of all modalities in the distal lower limbs. All deep tendon reflexes were absent, and pathological reflexes were not elicited. Pes cavus and hammer toe were noticed. She could walk without support but exhibited high steppage due to foot drop. Magnetic resonance imaging (MRI) revealed T2 elongation in the left optic nerve, and multiple high-intensity T2-weighted lesions were present in the cerebral deep white matter. Long spinal cord lesions were also observed on MRI (Fig. 2). Gadolinium-enhanced images were not obtained.
Figure 2. MRI of the brain and spinal cord. (A) A coronal T2-weighted image shows high-intensity signals in the left optic nerve (arrowhead; TE=21.6 ms/TR=7,300 ms). (B) An axial FLAIR image of the brain shows multiple high-intensity spots in the white matter (TE=105.3 ms/TR=8,000 ms). (C) A midsagittal image of the spinal cord with axial sections at the levels indicated by the white lines (Th4, Th6, Th9, and Th10 from top to bottom). Longitudinal hyperintense lesions are evident in the spinal cord (TE=103.0 ms/TR=3,000 ms).
Nerve conduction studies indicated systemic demyelinating neuropathy (Table 1). Visual evoked potentials (VEPs) were not detectable on left eye stimulation, and the latency was mildly prolonged in the right eye. Blood test results were unremarkable except for serum positivity for aquaporin-4 antibody (anti-AQP4). Serum myelin oligodendrocyte glycoprotein antibody (anti-MOG) was negative. Autoantibodies, including antinuclear antibody, SS-A, SS-B, and Sm, were negative. Thyroid hormones were normal. Cerebrospinal fluid (CSF) showed a normal protein level (18 mg/dL) without pleocytosis or oligoclonal bands (OCB). The IgG index was mildly elevated (0.84; normal limit 0.65). A genetic analysis revealed duplication of the peripheral myelin protein 22 (PMP22) gene.
Table 1. Electrophysiological Findings.
Nerve Amp (mV, μV) DL (ms) CV (m/s)
MCSs Median 7.8* 11.4* 24*
Ulnar 4.2* 8.4* 24*
Tibial 0.05* 13.2* 18*
SCSs Median 1.0* 7.04* 18*
Ulnar 0.6* 5.66* 20*
Sural 0.5* 8.52* 18*
Side P100 latency (ms)
VEPs Right 121.2*
Left Not evoked*
Nerve conduction studies were performed on the right median, ulnar, tibial, and sural nerves. Asterisks indicate significant results with reference to the standard values in our institute. Unit for amplitude is mv for MCSs and μV for SCSs. Amp: amplitude, CV: conduction velocity, DL: distal latency, MCSs: motor nerve conduction studies, SCSs: sensory nerve conduction studies, VEPs: visual evoked potentials
We diagnosed the patient with anti-AQP4-positive neuromyelitis optica spectrum disorder (NMOSD) plus underlying CMT1A. We treated her with three courses of methylprednisolone pulse therapy and seven plasma exchanges. The visual acuity of the left eye recovered to 0.03 (Snellen fraction of 20/630), and the CFF became measurable (20 Hz).
During maintenance therapy with 30 mg oral prednisolone, the patient experienced worsening of paresthesia of the extremities, hand tremor, and gastric ulcer. These symptoms subsided after reducing oral prednisolone and adding azathioprine.
Discussion
We encountered a case of recurrent optic neuritis and myelitis with long-standing sensorimotor polyneuropathy. The clinical picture of the chronic neuropathy in this patient was typical of CMT1A, and the diagnosis was confirmed genetically. Patients with CMT1A typically do not present with visual symptoms. However, subclinical prolongation of VEP is reported in 10-16% of CMT1A patients, which may be associated with asymptomatic optic neuropathy (2). Apart from the above-mentioned degenerative optic neuropathy, acute inflammatory processes in the CNS are an extremely rare complication of CMT1A.
To our knowledge, only eight cases of acute CNS inflammatory lesions have been reported in association with CMT1A (3-8). Of these, four cases of CMT1A with optic neuritis are summarized in Table 2. In one case, antibodies to the proteolipid protein (PLP) and MOG were positive, but anti-APQ4 was not reported in these previous cases. A CSF analysis was positive for OCB in three cases, and protein-cell dissociation was present in two cases. Neither OCB nor protein-cell dissociation was present in our patient. The IgG index was often elevated including our patient, suggesting inflammation in the CNS. These reports raise the possibility that the abnormal expression of PMP22 in peripheral nerve and demyelination of the CNS are causally related. One hypothesis is that PMP22 shares homology with other CNS myelin proteins, such as the PLP, and that the PMP22 overexpression in CMT1A induces an autoimmune response in the CNS (1,6). PLP has been studied extensively as a relevant primary antigen in multiple sclerosis (MS), and the T-cell response to PLP epitope induces experimental autoimmune encephalomyelitis (9,10). Wakerley et al. (6) observed increased immunity against PLP and MOG epitopes in their patient, supporting the immune cross-reactivity hypothesis. There are clinical conditions that suggest a pathophysiological link between peripheral and central myelin; (i) Pelizeus-Merzbacher disease is a leukodystrophy caused by the overexpression of PLP protein gene and is known to be associated with CMT-like neuropathy (11), (ii) hereditary neuropathy with liability to pressure palsy is caused by a deletion or mutation in PMP22 and known to manifest CNS white matter lesions (12).
Table 2. Previously Reported Cases of Optic Neuritis with CMT1A.
Reference Age
(years)/
Sex Diagnosis OCB IgG
index CSF
cell CSF
protein
(mg/dL) Demyelination on MRI VEPs
3 38/F MS + 0.89 ND ND ND Prolonged
3 30/F MS + 0.98 ND ND Cerebral white matter and spinal cord Prolonged
6 57/M Optic neuritis
(anti-MOG) + ND Normal 1,290 Only optic nerve Prolonged
1 31/M MS – 0.65 Normal 52 Cerebral white matter and spinal cord ND
Present case 51/F NMOSD
(anti-AQP4) – 0.84 Normal 18 Optic nerve, cerebral white matter and spinal cord Prolonged
F: female, M: male, anti-MOG: anti-myelin oligodendrocyte glycoprotein antibody, MS: multiple sclerosis, ND: not described, OCB: oligoclonal band, CSF: cerebrospinal fluid, VEPs: visual evoked potentials, anti-AQP4: anti-aquaporin-4 antibody, NMOSD: neuromyelitis optica spectrum disorder
NMOSD was previously considered a variant of MS but is now recognized as a distinct clinical entity. In MS, T cells are thought to target PLP expressed in oligodendrocytes. In contrast, NMOSD is primarily mediated by B-cell autoimmunity to AQP4, with AQP4-IgG antibodies binding to AQP4 expressed on astrocytes and activating the complement pathway (13). However, T-cell immunity in NMOSD is receiving increasing attention. For example, Matsuya et al. reported that PLP induced a significant T-cell response in NMOSD, suggesting that immunity to myelin proteins plays a pathological role (14). Michalski et al. reported that small amounts of PLP were expressed in astrocytes in mice (15). To our knowledge, the present report is the first of CMT1A complicated with anti-AQP4-positive NMOSD. Thus, the coexistence may simply be coincidental. However, an immune cross-reaction remains a potential explanation, and further research is needed.
Our patient experienced exacerbation of paresthesia in the lower extremities after corticosteroid maintenance therapy was initiated, which we attributed to peripheral neuropathy based on the sensory distribution. It is unclear why corticosteroid therapy elicited sensory neuropathy in this CMT1A patient. We speculated that methylprednisolone up-regulated the already-overexpressed PMP22 via its effect as a progesterone receptor agonist and consequently worsened the CMT1A symptoms. Progesterone is known to regulate the expression of PMP22; for example, a progesterone antagonist reduced PMP22 overexpression in a mouse model of CMT1A and improved the severity of the symptoms (16).
There is accumulating evidence that CMT1A is a risk factor of MS. Together with the findings of a previous report of anti-MOG-positive optic neuritis (6), the present results raise the possibility that CMT1A is also a risk factor for B-cell-mediated CNS demyelination. Further clinical and basic immunological studies are needed to elucidate the mechanisms underlying the immune cross-reaction between the peripheral nervous system and the CNS.
The authors state that they have no Conflict of Interest (COI). | METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33361678 | 19,517,386 | 2021-05-15 |
What was the administration route of drug 'PREDNISOLONE'? | Aquaporin-4-antibody-positive Neuromyelitis Optica Spectrum Disorder in a Patient with Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy, and its involvement in the central nervous system (CNS) is very rare. We herein report a 51-year-old woman with CMT1A who suffered from recurrent optic neuritis and myelopathy. Under the diagnosis of anti-aquaporin-4 (anti-AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD), we treated her successfully with corticosteroids. This is the first report of CMT1A complicated with anti-AQP4-positive NMOSD. Although the coexistence of the two disorders may simply be a coincidence, we speculated that immune cross-reaction between overexpressed peripheral myelin protein 22 and CNS myelin may have caused concomitant CMT1A and NMOSD.
Introduction
Charcot-Marie-Tooth disease (CMT) is a group of inherited motor sensory neuropathies. Demyelination in the central nervous system (CNS) is a rare complication of CMT, except for in its X-linked subtype (CMTX), in which CNS involvement has occasionally been reported (1).
We herein report a patient with CMT type 1A (CMT1A) who suffered from recurrent optic neuritis and myelopathy. We discuss the immune mechanisms underlying the concomitant involvement of the peripheral nervous system and the CNS.
Case Report
A 51-year-old Japanese woman was admitted to our hospital because of left ophthalmic pain and progressive blindness during the previous 9 days. One year before this presentation, she had experienced repeated numbness and pain in the lower extremities, which spontaneously remitted after a couple of weeks. One month before the admission, she had experienced blurred vision and discomfort of the right eye, which improved spontaneously after several days. She had experienced gait disturbance since childhood and had developed atrophy and paresthesia of the distal lower extremities during adolescence. She had a family history of peripheral neuropathy with the autosomal dominant form of inheritance (Fig. 1). The disease onset was in adolescence in all affected members, except for in a sister of the patient, whose onset was at elementary school age.
Figure 1. Pedigree tree of the family. Filled symbols indicate individuals with peripheral neuropathy and pes cavus. The father of the patient (I-1) had had difficulty running since he was a teenager. The older sister of the patient (II-1) had suffered from neuropathy since elementary school. Two siblings (II-3, 4), two nephews (III-2, 4), and one niece (III-5) of the patient had developed neuropathy in their teenage years. No family members had disorders involving the central nervous system, including optic neuritis. The arrow indicates the proband. Squares and circles indicate men and women, respectively.
On admission, her left eye was blind with a dilated pupil and an absent light reflex. A fundoscopic examination revealed redness of the left optic nerve papilla. The right eye had visual acuity of 0.80 (Snellen fraction of 20/25) with a normal light reflex and a normal fundoscopic appearance. The critical flicker fusion threshold (CFF) was unmeasurable in the left eye and 34 Hz in the right eye. Distal extremities exhibited wasting and weakness, especially the lower extremities. There was sensory loss of all modalities in the distal lower limbs. All deep tendon reflexes were absent, and pathological reflexes were not elicited. Pes cavus and hammer toe were noticed. She could walk without support but exhibited high steppage due to foot drop. Magnetic resonance imaging (MRI) revealed T2 elongation in the left optic nerve, and multiple high-intensity T2-weighted lesions were present in the cerebral deep white matter. Long spinal cord lesions were also observed on MRI (Fig. 2). Gadolinium-enhanced images were not obtained.
Figure 2. MRI of the brain and spinal cord. (A) A coronal T2-weighted image shows high-intensity signals in the left optic nerve (arrowhead; TE=21.6 ms/TR=7,300 ms). (B) An axial FLAIR image of the brain shows multiple high-intensity spots in the white matter (TE=105.3 ms/TR=8,000 ms). (C) A midsagittal image of the spinal cord with axial sections at the levels indicated by the white lines (Th4, Th6, Th9, and Th10 from top to bottom). Longitudinal hyperintense lesions are evident in the spinal cord (TE=103.0 ms/TR=3,000 ms).
Nerve conduction studies indicated systemic demyelinating neuropathy (Table 1). Visual evoked potentials (VEPs) were not detectable on left eye stimulation, and the latency was mildly prolonged in the right eye. Blood test results were unremarkable except for serum positivity for aquaporin-4 antibody (anti-AQP4). Serum myelin oligodendrocyte glycoprotein antibody (anti-MOG) was negative. Autoantibodies, including antinuclear antibody, SS-A, SS-B, and Sm, were negative. Thyroid hormones were normal. Cerebrospinal fluid (CSF) showed a normal protein level (18 mg/dL) without pleocytosis or oligoclonal bands (OCB). The IgG index was mildly elevated (0.84; normal limit 0.65). A genetic analysis revealed duplication of the peripheral myelin protein 22 (PMP22) gene.
Table 1. Electrophysiological Findings.
Nerve Amp (mV, μV) DL (ms) CV (m/s)
MCSs Median 7.8* 11.4* 24*
Ulnar 4.2* 8.4* 24*
Tibial 0.05* 13.2* 18*
SCSs Median 1.0* 7.04* 18*
Ulnar 0.6* 5.66* 20*
Sural 0.5* 8.52* 18*
Side P100 latency (ms)
VEPs Right 121.2*
Left Not evoked*
Nerve conduction studies were performed on the right median, ulnar, tibial, and sural nerves. Asterisks indicate significant results with reference to the standard values in our institute. Unit for amplitude is mv for MCSs and μV for SCSs. Amp: amplitude, CV: conduction velocity, DL: distal latency, MCSs: motor nerve conduction studies, SCSs: sensory nerve conduction studies, VEPs: visual evoked potentials
We diagnosed the patient with anti-AQP4-positive neuromyelitis optica spectrum disorder (NMOSD) plus underlying CMT1A. We treated her with three courses of methylprednisolone pulse therapy and seven plasma exchanges. The visual acuity of the left eye recovered to 0.03 (Snellen fraction of 20/630), and the CFF became measurable (20 Hz).
During maintenance therapy with 30 mg oral prednisolone, the patient experienced worsening of paresthesia of the extremities, hand tremor, and gastric ulcer. These symptoms subsided after reducing oral prednisolone and adding azathioprine.
Discussion
We encountered a case of recurrent optic neuritis and myelitis with long-standing sensorimotor polyneuropathy. The clinical picture of the chronic neuropathy in this patient was typical of CMT1A, and the diagnosis was confirmed genetically. Patients with CMT1A typically do not present with visual symptoms. However, subclinical prolongation of VEP is reported in 10-16% of CMT1A patients, which may be associated with asymptomatic optic neuropathy (2). Apart from the above-mentioned degenerative optic neuropathy, acute inflammatory processes in the CNS are an extremely rare complication of CMT1A.
To our knowledge, only eight cases of acute CNS inflammatory lesions have been reported in association with CMT1A (3-8). Of these, four cases of CMT1A with optic neuritis are summarized in Table 2. In one case, antibodies to the proteolipid protein (PLP) and MOG were positive, but anti-APQ4 was not reported in these previous cases. A CSF analysis was positive for OCB in three cases, and protein-cell dissociation was present in two cases. Neither OCB nor protein-cell dissociation was present in our patient. The IgG index was often elevated including our patient, suggesting inflammation in the CNS. These reports raise the possibility that the abnormal expression of PMP22 in peripheral nerve and demyelination of the CNS are causally related. One hypothesis is that PMP22 shares homology with other CNS myelin proteins, such as the PLP, and that the PMP22 overexpression in CMT1A induces an autoimmune response in the CNS (1,6). PLP has been studied extensively as a relevant primary antigen in multiple sclerosis (MS), and the T-cell response to PLP epitope induces experimental autoimmune encephalomyelitis (9,10). Wakerley et al. (6) observed increased immunity against PLP and MOG epitopes in their patient, supporting the immune cross-reactivity hypothesis. There are clinical conditions that suggest a pathophysiological link between peripheral and central myelin; (i) Pelizeus-Merzbacher disease is a leukodystrophy caused by the overexpression of PLP protein gene and is known to be associated with CMT-like neuropathy (11), (ii) hereditary neuropathy with liability to pressure palsy is caused by a deletion or mutation in PMP22 and known to manifest CNS white matter lesions (12).
Table 2. Previously Reported Cases of Optic Neuritis with CMT1A.
Reference Age
(years)/
Sex Diagnosis OCB IgG
index CSF
cell CSF
protein
(mg/dL) Demyelination on MRI VEPs
3 38/F MS + 0.89 ND ND ND Prolonged
3 30/F MS + 0.98 ND ND Cerebral white matter and spinal cord Prolonged
6 57/M Optic neuritis
(anti-MOG) + ND Normal 1,290 Only optic nerve Prolonged
1 31/M MS – 0.65 Normal 52 Cerebral white matter and spinal cord ND
Present case 51/F NMOSD
(anti-AQP4) – 0.84 Normal 18 Optic nerve, cerebral white matter and spinal cord Prolonged
F: female, M: male, anti-MOG: anti-myelin oligodendrocyte glycoprotein antibody, MS: multiple sclerosis, ND: not described, OCB: oligoclonal band, CSF: cerebrospinal fluid, VEPs: visual evoked potentials, anti-AQP4: anti-aquaporin-4 antibody, NMOSD: neuromyelitis optica spectrum disorder
NMOSD was previously considered a variant of MS but is now recognized as a distinct clinical entity. In MS, T cells are thought to target PLP expressed in oligodendrocytes. In contrast, NMOSD is primarily mediated by B-cell autoimmunity to AQP4, with AQP4-IgG antibodies binding to AQP4 expressed on astrocytes and activating the complement pathway (13). However, T-cell immunity in NMOSD is receiving increasing attention. For example, Matsuya et al. reported that PLP induced a significant T-cell response in NMOSD, suggesting that immunity to myelin proteins plays a pathological role (14). Michalski et al. reported that small amounts of PLP were expressed in astrocytes in mice (15). To our knowledge, the present report is the first of CMT1A complicated with anti-AQP4-positive NMOSD. Thus, the coexistence may simply be coincidental. However, an immune cross-reaction remains a potential explanation, and further research is needed.
Our patient experienced exacerbation of paresthesia in the lower extremities after corticosteroid maintenance therapy was initiated, which we attributed to peripheral neuropathy based on the sensory distribution. It is unclear why corticosteroid therapy elicited sensory neuropathy in this CMT1A patient. We speculated that methylprednisolone up-regulated the already-overexpressed PMP22 via its effect as a progesterone receptor agonist and consequently worsened the CMT1A symptoms. Progesterone is known to regulate the expression of PMP22; for example, a progesterone antagonist reduced PMP22 overexpression in a mouse model of CMT1A and improved the severity of the symptoms (16).
There is accumulating evidence that CMT1A is a risk factor of MS. Together with the findings of a previous report of anti-MOG-positive optic neuritis (6), the present results raise the possibility that CMT1A is also a risk factor for B-cell-mediated CNS demyelination. Further clinical and basic immunological studies are needed to elucidate the mechanisms underlying the immune cross-reaction between the peripheral nervous system and the CNS.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33361678 | 19,517,386 | 2021-05-15 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Aquaporin-4-antibody-positive Neuromyelitis Optica Spectrum Disorder in a Patient with Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy, and its involvement in the central nervous system (CNS) is very rare. We herein report a 51-year-old woman with CMT1A who suffered from recurrent optic neuritis and myelopathy. Under the diagnosis of anti-aquaporin-4 (anti-AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD), we treated her successfully with corticosteroids. This is the first report of CMT1A complicated with anti-AQP4-positive NMOSD. Although the coexistence of the two disorders may simply be a coincidence, we speculated that immune cross-reaction between overexpressed peripheral myelin protein 22 and CNS myelin may have caused concomitant CMT1A and NMOSD.
Introduction
Charcot-Marie-Tooth disease (CMT) is a group of inherited motor sensory neuropathies. Demyelination in the central nervous system (CNS) is a rare complication of CMT, except for in its X-linked subtype (CMTX), in which CNS involvement has occasionally been reported (1).
We herein report a patient with CMT type 1A (CMT1A) who suffered from recurrent optic neuritis and myelopathy. We discuss the immune mechanisms underlying the concomitant involvement of the peripheral nervous system and the CNS.
Case Report
A 51-year-old Japanese woman was admitted to our hospital because of left ophthalmic pain and progressive blindness during the previous 9 days. One year before this presentation, she had experienced repeated numbness and pain in the lower extremities, which spontaneously remitted after a couple of weeks. One month before the admission, she had experienced blurred vision and discomfort of the right eye, which improved spontaneously after several days. She had experienced gait disturbance since childhood and had developed atrophy and paresthesia of the distal lower extremities during adolescence. She had a family history of peripheral neuropathy with the autosomal dominant form of inheritance (Fig. 1). The disease onset was in adolescence in all affected members, except for in a sister of the patient, whose onset was at elementary school age.
Figure 1. Pedigree tree of the family. Filled symbols indicate individuals with peripheral neuropathy and pes cavus. The father of the patient (I-1) had had difficulty running since he was a teenager. The older sister of the patient (II-1) had suffered from neuropathy since elementary school. Two siblings (II-3, 4), two nephews (III-2, 4), and one niece (III-5) of the patient had developed neuropathy in their teenage years. No family members had disorders involving the central nervous system, including optic neuritis. The arrow indicates the proband. Squares and circles indicate men and women, respectively.
On admission, her left eye was blind with a dilated pupil and an absent light reflex. A fundoscopic examination revealed redness of the left optic nerve papilla. The right eye had visual acuity of 0.80 (Snellen fraction of 20/25) with a normal light reflex and a normal fundoscopic appearance. The critical flicker fusion threshold (CFF) was unmeasurable in the left eye and 34 Hz in the right eye. Distal extremities exhibited wasting and weakness, especially the lower extremities. There was sensory loss of all modalities in the distal lower limbs. All deep tendon reflexes were absent, and pathological reflexes were not elicited. Pes cavus and hammer toe were noticed. She could walk without support but exhibited high steppage due to foot drop. Magnetic resonance imaging (MRI) revealed T2 elongation in the left optic nerve, and multiple high-intensity T2-weighted lesions were present in the cerebral deep white matter. Long spinal cord lesions were also observed on MRI (Fig. 2). Gadolinium-enhanced images were not obtained.
Figure 2. MRI of the brain and spinal cord. (A) A coronal T2-weighted image shows high-intensity signals in the left optic nerve (arrowhead; TE=21.6 ms/TR=7,300 ms). (B) An axial FLAIR image of the brain shows multiple high-intensity spots in the white matter (TE=105.3 ms/TR=8,000 ms). (C) A midsagittal image of the spinal cord with axial sections at the levels indicated by the white lines (Th4, Th6, Th9, and Th10 from top to bottom). Longitudinal hyperintense lesions are evident in the spinal cord (TE=103.0 ms/TR=3,000 ms).
Nerve conduction studies indicated systemic demyelinating neuropathy (Table 1). Visual evoked potentials (VEPs) were not detectable on left eye stimulation, and the latency was mildly prolonged in the right eye. Blood test results were unremarkable except for serum positivity for aquaporin-4 antibody (anti-AQP4). Serum myelin oligodendrocyte glycoprotein antibody (anti-MOG) was negative. Autoantibodies, including antinuclear antibody, SS-A, SS-B, and Sm, were negative. Thyroid hormones were normal. Cerebrospinal fluid (CSF) showed a normal protein level (18 mg/dL) without pleocytosis or oligoclonal bands (OCB). The IgG index was mildly elevated (0.84; normal limit 0.65). A genetic analysis revealed duplication of the peripheral myelin protein 22 (PMP22) gene.
Table 1. Electrophysiological Findings.
Nerve Amp (mV, μV) DL (ms) CV (m/s)
MCSs Median 7.8* 11.4* 24*
Ulnar 4.2* 8.4* 24*
Tibial 0.05* 13.2* 18*
SCSs Median 1.0* 7.04* 18*
Ulnar 0.6* 5.66* 20*
Sural 0.5* 8.52* 18*
Side P100 latency (ms)
VEPs Right 121.2*
Left Not evoked*
Nerve conduction studies were performed on the right median, ulnar, tibial, and sural nerves. Asterisks indicate significant results with reference to the standard values in our institute. Unit for amplitude is mv for MCSs and μV for SCSs. Amp: amplitude, CV: conduction velocity, DL: distal latency, MCSs: motor nerve conduction studies, SCSs: sensory nerve conduction studies, VEPs: visual evoked potentials
We diagnosed the patient with anti-AQP4-positive neuromyelitis optica spectrum disorder (NMOSD) plus underlying CMT1A. We treated her with three courses of methylprednisolone pulse therapy and seven plasma exchanges. The visual acuity of the left eye recovered to 0.03 (Snellen fraction of 20/630), and the CFF became measurable (20 Hz).
During maintenance therapy with 30 mg oral prednisolone, the patient experienced worsening of paresthesia of the extremities, hand tremor, and gastric ulcer. These symptoms subsided after reducing oral prednisolone and adding azathioprine.
Discussion
We encountered a case of recurrent optic neuritis and myelitis with long-standing sensorimotor polyneuropathy. The clinical picture of the chronic neuropathy in this patient was typical of CMT1A, and the diagnosis was confirmed genetically. Patients with CMT1A typically do not present with visual symptoms. However, subclinical prolongation of VEP is reported in 10-16% of CMT1A patients, which may be associated with asymptomatic optic neuropathy (2). Apart from the above-mentioned degenerative optic neuropathy, acute inflammatory processes in the CNS are an extremely rare complication of CMT1A.
To our knowledge, only eight cases of acute CNS inflammatory lesions have been reported in association with CMT1A (3-8). Of these, four cases of CMT1A with optic neuritis are summarized in Table 2. In one case, antibodies to the proteolipid protein (PLP) and MOG were positive, but anti-APQ4 was not reported in these previous cases. A CSF analysis was positive for OCB in three cases, and protein-cell dissociation was present in two cases. Neither OCB nor protein-cell dissociation was present in our patient. The IgG index was often elevated including our patient, suggesting inflammation in the CNS. These reports raise the possibility that the abnormal expression of PMP22 in peripheral nerve and demyelination of the CNS are causally related. One hypothesis is that PMP22 shares homology with other CNS myelin proteins, such as the PLP, and that the PMP22 overexpression in CMT1A induces an autoimmune response in the CNS (1,6). PLP has been studied extensively as a relevant primary antigen in multiple sclerosis (MS), and the T-cell response to PLP epitope induces experimental autoimmune encephalomyelitis (9,10). Wakerley et al. (6) observed increased immunity against PLP and MOG epitopes in their patient, supporting the immune cross-reactivity hypothesis. There are clinical conditions that suggest a pathophysiological link between peripheral and central myelin; (i) Pelizeus-Merzbacher disease is a leukodystrophy caused by the overexpression of PLP protein gene and is known to be associated with CMT-like neuropathy (11), (ii) hereditary neuropathy with liability to pressure palsy is caused by a deletion or mutation in PMP22 and known to manifest CNS white matter lesions (12).
Table 2. Previously Reported Cases of Optic Neuritis with CMT1A.
Reference Age
(years)/
Sex Diagnosis OCB IgG
index CSF
cell CSF
protein
(mg/dL) Demyelination on MRI VEPs
3 38/F MS + 0.89 ND ND ND Prolonged
3 30/F MS + 0.98 ND ND Cerebral white matter and spinal cord Prolonged
6 57/M Optic neuritis
(anti-MOG) + ND Normal 1,290 Only optic nerve Prolonged
1 31/M MS – 0.65 Normal 52 Cerebral white matter and spinal cord ND
Present case 51/F NMOSD
(anti-AQP4) – 0.84 Normal 18 Optic nerve, cerebral white matter and spinal cord Prolonged
F: female, M: male, anti-MOG: anti-myelin oligodendrocyte glycoprotein antibody, MS: multiple sclerosis, ND: not described, OCB: oligoclonal band, CSF: cerebrospinal fluid, VEPs: visual evoked potentials, anti-AQP4: anti-aquaporin-4 antibody, NMOSD: neuromyelitis optica spectrum disorder
NMOSD was previously considered a variant of MS but is now recognized as a distinct clinical entity. In MS, T cells are thought to target PLP expressed in oligodendrocytes. In contrast, NMOSD is primarily mediated by B-cell autoimmunity to AQP4, with AQP4-IgG antibodies binding to AQP4 expressed on astrocytes and activating the complement pathway (13). However, T-cell immunity in NMOSD is receiving increasing attention. For example, Matsuya et al. reported that PLP induced a significant T-cell response in NMOSD, suggesting that immunity to myelin proteins plays a pathological role (14). Michalski et al. reported that small amounts of PLP were expressed in astrocytes in mice (15). To our knowledge, the present report is the first of CMT1A complicated with anti-AQP4-positive NMOSD. Thus, the coexistence may simply be coincidental. However, an immune cross-reaction remains a potential explanation, and further research is needed.
Our patient experienced exacerbation of paresthesia in the lower extremities after corticosteroid maintenance therapy was initiated, which we attributed to peripheral neuropathy based on the sensory distribution. It is unclear why corticosteroid therapy elicited sensory neuropathy in this CMT1A patient. We speculated that methylprednisolone up-regulated the already-overexpressed PMP22 via its effect as a progesterone receptor agonist and consequently worsened the CMT1A symptoms. Progesterone is known to regulate the expression of PMP22; for example, a progesterone antagonist reduced PMP22 overexpression in a mouse model of CMT1A and improved the severity of the symptoms (16).
There is accumulating evidence that CMT1A is a risk factor of MS. Together with the findings of a previous report of anti-MOG-positive optic neuritis (6), the present results raise the possibility that CMT1A is also a risk factor for B-cell-mediated CNS demyelination. Further clinical and basic immunological studies are needed to elucidate the mechanisms underlying the immune cross-reaction between the peripheral nervous system and the CNS.
The authors state that they have no Conflict of Interest (COI). | 3 COURSES OF PULSE THERAPY | DrugDosageText | CC BY-NC-ND | 33361678 | 19,517,386 | 2021-05-15 |
What was the dosage of drug 'PREDNISOLONE'? | Aquaporin-4-antibody-positive Neuromyelitis Optica Spectrum Disorder in a Patient with Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy, and its involvement in the central nervous system (CNS) is very rare. We herein report a 51-year-old woman with CMT1A who suffered from recurrent optic neuritis and myelopathy. Under the diagnosis of anti-aquaporin-4 (anti-AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD), we treated her successfully with corticosteroids. This is the first report of CMT1A complicated with anti-AQP4-positive NMOSD. Although the coexistence of the two disorders may simply be a coincidence, we speculated that immune cross-reaction between overexpressed peripheral myelin protein 22 and CNS myelin may have caused concomitant CMT1A and NMOSD.
Introduction
Charcot-Marie-Tooth disease (CMT) is a group of inherited motor sensory neuropathies. Demyelination in the central nervous system (CNS) is a rare complication of CMT, except for in its X-linked subtype (CMTX), in which CNS involvement has occasionally been reported (1).
We herein report a patient with CMT type 1A (CMT1A) who suffered from recurrent optic neuritis and myelopathy. We discuss the immune mechanisms underlying the concomitant involvement of the peripheral nervous system and the CNS.
Case Report
A 51-year-old Japanese woman was admitted to our hospital because of left ophthalmic pain and progressive blindness during the previous 9 days. One year before this presentation, she had experienced repeated numbness and pain in the lower extremities, which spontaneously remitted after a couple of weeks. One month before the admission, she had experienced blurred vision and discomfort of the right eye, which improved spontaneously after several days. She had experienced gait disturbance since childhood and had developed atrophy and paresthesia of the distal lower extremities during adolescence. She had a family history of peripheral neuropathy with the autosomal dominant form of inheritance (Fig. 1). The disease onset was in adolescence in all affected members, except for in a sister of the patient, whose onset was at elementary school age.
Figure 1. Pedigree tree of the family. Filled symbols indicate individuals with peripheral neuropathy and pes cavus. The father of the patient (I-1) had had difficulty running since he was a teenager. The older sister of the patient (II-1) had suffered from neuropathy since elementary school. Two siblings (II-3, 4), two nephews (III-2, 4), and one niece (III-5) of the patient had developed neuropathy in their teenage years. No family members had disorders involving the central nervous system, including optic neuritis. The arrow indicates the proband. Squares and circles indicate men and women, respectively.
On admission, her left eye was blind with a dilated pupil and an absent light reflex. A fundoscopic examination revealed redness of the left optic nerve papilla. The right eye had visual acuity of 0.80 (Snellen fraction of 20/25) with a normal light reflex and a normal fundoscopic appearance. The critical flicker fusion threshold (CFF) was unmeasurable in the left eye and 34 Hz in the right eye. Distal extremities exhibited wasting and weakness, especially the lower extremities. There was sensory loss of all modalities in the distal lower limbs. All deep tendon reflexes were absent, and pathological reflexes were not elicited. Pes cavus and hammer toe were noticed. She could walk without support but exhibited high steppage due to foot drop. Magnetic resonance imaging (MRI) revealed T2 elongation in the left optic nerve, and multiple high-intensity T2-weighted lesions were present in the cerebral deep white matter. Long spinal cord lesions were also observed on MRI (Fig. 2). Gadolinium-enhanced images were not obtained.
Figure 2. MRI of the brain and spinal cord. (A) A coronal T2-weighted image shows high-intensity signals in the left optic nerve (arrowhead; TE=21.6 ms/TR=7,300 ms). (B) An axial FLAIR image of the brain shows multiple high-intensity spots in the white matter (TE=105.3 ms/TR=8,000 ms). (C) A midsagittal image of the spinal cord with axial sections at the levels indicated by the white lines (Th4, Th6, Th9, and Th10 from top to bottom). Longitudinal hyperintense lesions are evident in the spinal cord (TE=103.0 ms/TR=3,000 ms).
Nerve conduction studies indicated systemic demyelinating neuropathy (Table 1). Visual evoked potentials (VEPs) were not detectable on left eye stimulation, and the latency was mildly prolonged in the right eye. Blood test results were unremarkable except for serum positivity for aquaporin-4 antibody (anti-AQP4). Serum myelin oligodendrocyte glycoprotein antibody (anti-MOG) was negative. Autoantibodies, including antinuclear antibody, SS-A, SS-B, and Sm, were negative. Thyroid hormones were normal. Cerebrospinal fluid (CSF) showed a normal protein level (18 mg/dL) without pleocytosis or oligoclonal bands (OCB). The IgG index was mildly elevated (0.84; normal limit 0.65). A genetic analysis revealed duplication of the peripheral myelin protein 22 (PMP22) gene.
Table 1. Electrophysiological Findings.
Nerve Amp (mV, μV) DL (ms) CV (m/s)
MCSs Median 7.8* 11.4* 24*
Ulnar 4.2* 8.4* 24*
Tibial 0.05* 13.2* 18*
SCSs Median 1.0* 7.04* 18*
Ulnar 0.6* 5.66* 20*
Sural 0.5* 8.52* 18*
Side P100 latency (ms)
VEPs Right 121.2*
Left Not evoked*
Nerve conduction studies were performed on the right median, ulnar, tibial, and sural nerves. Asterisks indicate significant results with reference to the standard values in our institute. Unit for amplitude is mv for MCSs and μV for SCSs. Amp: amplitude, CV: conduction velocity, DL: distal latency, MCSs: motor nerve conduction studies, SCSs: sensory nerve conduction studies, VEPs: visual evoked potentials
We diagnosed the patient with anti-AQP4-positive neuromyelitis optica spectrum disorder (NMOSD) plus underlying CMT1A. We treated her with three courses of methylprednisolone pulse therapy and seven plasma exchanges. The visual acuity of the left eye recovered to 0.03 (Snellen fraction of 20/630), and the CFF became measurable (20 Hz).
During maintenance therapy with 30 mg oral prednisolone, the patient experienced worsening of paresthesia of the extremities, hand tremor, and gastric ulcer. These symptoms subsided after reducing oral prednisolone and adding azathioprine.
Discussion
We encountered a case of recurrent optic neuritis and myelitis with long-standing sensorimotor polyneuropathy. The clinical picture of the chronic neuropathy in this patient was typical of CMT1A, and the diagnosis was confirmed genetically. Patients with CMT1A typically do not present with visual symptoms. However, subclinical prolongation of VEP is reported in 10-16% of CMT1A patients, which may be associated with asymptomatic optic neuropathy (2). Apart from the above-mentioned degenerative optic neuropathy, acute inflammatory processes in the CNS are an extremely rare complication of CMT1A.
To our knowledge, only eight cases of acute CNS inflammatory lesions have been reported in association with CMT1A (3-8). Of these, four cases of CMT1A with optic neuritis are summarized in Table 2. In one case, antibodies to the proteolipid protein (PLP) and MOG were positive, but anti-APQ4 was not reported in these previous cases. A CSF analysis was positive for OCB in three cases, and protein-cell dissociation was present in two cases. Neither OCB nor protein-cell dissociation was present in our patient. The IgG index was often elevated including our patient, suggesting inflammation in the CNS. These reports raise the possibility that the abnormal expression of PMP22 in peripheral nerve and demyelination of the CNS are causally related. One hypothesis is that PMP22 shares homology with other CNS myelin proteins, such as the PLP, and that the PMP22 overexpression in CMT1A induces an autoimmune response in the CNS (1,6). PLP has been studied extensively as a relevant primary antigen in multiple sclerosis (MS), and the T-cell response to PLP epitope induces experimental autoimmune encephalomyelitis (9,10). Wakerley et al. (6) observed increased immunity against PLP and MOG epitopes in their patient, supporting the immune cross-reactivity hypothesis. There are clinical conditions that suggest a pathophysiological link between peripheral and central myelin; (i) Pelizeus-Merzbacher disease is a leukodystrophy caused by the overexpression of PLP protein gene and is known to be associated with CMT-like neuropathy (11), (ii) hereditary neuropathy with liability to pressure palsy is caused by a deletion or mutation in PMP22 and known to manifest CNS white matter lesions (12).
Table 2. Previously Reported Cases of Optic Neuritis with CMT1A.
Reference Age
(years)/
Sex Diagnosis OCB IgG
index CSF
cell CSF
protein
(mg/dL) Demyelination on MRI VEPs
3 38/F MS + 0.89 ND ND ND Prolonged
3 30/F MS + 0.98 ND ND Cerebral white matter and spinal cord Prolonged
6 57/M Optic neuritis
(anti-MOG) + ND Normal 1,290 Only optic nerve Prolonged
1 31/M MS – 0.65 Normal 52 Cerebral white matter and spinal cord ND
Present case 51/F NMOSD
(anti-AQP4) – 0.84 Normal 18 Optic nerve, cerebral white matter and spinal cord Prolonged
F: female, M: male, anti-MOG: anti-myelin oligodendrocyte glycoprotein antibody, MS: multiple sclerosis, ND: not described, OCB: oligoclonal band, CSF: cerebrospinal fluid, VEPs: visual evoked potentials, anti-AQP4: anti-aquaporin-4 antibody, NMOSD: neuromyelitis optica spectrum disorder
NMOSD was previously considered a variant of MS but is now recognized as a distinct clinical entity. In MS, T cells are thought to target PLP expressed in oligodendrocytes. In contrast, NMOSD is primarily mediated by B-cell autoimmunity to AQP4, with AQP4-IgG antibodies binding to AQP4 expressed on astrocytes and activating the complement pathway (13). However, T-cell immunity in NMOSD is receiving increasing attention. For example, Matsuya et al. reported that PLP induced a significant T-cell response in NMOSD, suggesting that immunity to myelin proteins plays a pathological role (14). Michalski et al. reported that small amounts of PLP were expressed in astrocytes in mice (15). To our knowledge, the present report is the first of CMT1A complicated with anti-AQP4-positive NMOSD. Thus, the coexistence may simply be coincidental. However, an immune cross-reaction remains a potential explanation, and further research is needed.
Our patient experienced exacerbation of paresthesia in the lower extremities after corticosteroid maintenance therapy was initiated, which we attributed to peripheral neuropathy based on the sensory distribution. It is unclear why corticosteroid therapy elicited sensory neuropathy in this CMT1A patient. We speculated that methylprednisolone up-regulated the already-overexpressed PMP22 via its effect as a progesterone receptor agonist and consequently worsened the CMT1A symptoms. Progesterone is known to regulate the expression of PMP22; for example, a progesterone antagonist reduced PMP22 overexpression in a mouse model of CMT1A and improved the severity of the symptoms (16).
There is accumulating evidence that CMT1A is a risk factor of MS. Together with the findings of a previous report of anti-MOG-positive optic neuritis (6), the present results raise the possibility that CMT1A is also a risk factor for B-cell-mediated CNS demyelination. Further clinical and basic immunological studies are needed to elucidate the mechanisms underlying the immune cross-reaction between the peripheral nervous system and the CNS.
The authors state that they have no Conflict of Interest (COI). | 30 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33361678 | 19,517,386 | 2021-05-15 |
What was the outcome of reaction 'Paraesthesia'? | Aquaporin-4-antibody-positive Neuromyelitis Optica Spectrum Disorder in a Patient with Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy, and its involvement in the central nervous system (CNS) is very rare. We herein report a 51-year-old woman with CMT1A who suffered from recurrent optic neuritis and myelopathy. Under the diagnosis of anti-aquaporin-4 (anti-AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD), we treated her successfully with corticosteroids. This is the first report of CMT1A complicated with anti-AQP4-positive NMOSD. Although the coexistence of the two disorders may simply be a coincidence, we speculated that immune cross-reaction between overexpressed peripheral myelin protein 22 and CNS myelin may have caused concomitant CMT1A and NMOSD.
Introduction
Charcot-Marie-Tooth disease (CMT) is a group of inherited motor sensory neuropathies. Demyelination in the central nervous system (CNS) is a rare complication of CMT, except for in its X-linked subtype (CMTX), in which CNS involvement has occasionally been reported (1).
We herein report a patient with CMT type 1A (CMT1A) who suffered from recurrent optic neuritis and myelopathy. We discuss the immune mechanisms underlying the concomitant involvement of the peripheral nervous system and the CNS.
Case Report
A 51-year-old Japanese woman was admitted to our hospital because of left ophthalmic pain and progressive blindness during the previous 9 days. One year before this presentation, she had experienced repeated numbness and pain in the lower extremities, which spontaneously remitted after a couple of weeks. One month before the admission, she had experienced blurred vision and discomfort of the right eye, which improved spontaneously after several days. She had experienced gait disturbance since childhood and had developed atrophy and paresthesia of the distal lower extremities during adolescence. She had a family history of peripheral neuropathy with the autosomal dominant form of inheritance (Fig. 1). The disease onset was in adolescence in all affected members, except for in a sister of the patient, whose onset was at elementary school age.
Figure 1. Pedigree tree of the family. Filled symbols indicate individuals with peripheral neuropathy and pes cavus. The father of the patient (I-1) had had difficulty running since he was a teenager. The older sister of the patient (II-1) had suffered from neuropathy since elementary school. Two siblings (II-3, 4), two nephews (III-2, 4), and one niece (III-5) of the patient had developed neuropathy in their teenage years. No family members had disorders involving the central nervous system, including optic neuritis. The arrow indicates the proband. Squares and circles indicate men and women, respectively.
On admission, her left eye was blind with a dilated pupil and an absent light reflex. A fundoscopic examination revealed redness of the left optic nerve papilla. The right eye had visual acuity of 0.80 (Snellen fraction of 20/25) with a normal light reflex and a normal fundoscopic appearance. The critical flicker fusion threshold (CFF) was unmeasurable in the left eye and 34 Hz in the right eye. Distal extremities exhibited wasting and weakness, especially the lower extremities. There was sensory loss of all modalities in the distal lower limbs. All deep tendon reflexes were absent, and pathological reflexes were not elicited. Pes cavus and hammer toe were noticed. She could walk without support but exhibited high steppage due to foot drop. Magnetic resonance imaging (MRI) revealed T2 elongation in the left optic nerve, and multiple high-intensity T2-weighted lesions were present in the cerebral deep white matter. Long spinal cord lesions were also observed on MRI (Fig. 2). Gadolinium-enhanced images were not obtained.
Figure 2. MRI of the brain and spinal cord. (A) A coronal T2-weighted image shows high-intensity signals in the left optic nerve (arrowhead; TE=21.6 ms/TR=7,300 ms). (B) An axial FLAIR image of the brain shows multiple high-intensity spots in the white matter (TE=105.3 ms/TR=8,000 ms). (C) A midsagittal image of the spinal cord with axial sections at the levels indicated by the white lines (Th4, Th6, Th9, and Th10 from top to bottom). Longitudinal hyperintense lesions are evident in the spinal cord (TE=103.0 ms/TR=3,000 ms).
Nerve conduction studies indicated systemic demyelinating neuropathy (Table 1). Visual evoked potentials (VEPs) were not detectable on left eye stimulation, and the latency was mildly prolonged in the right eye. Blood test results were unremarkable except for serum positivity for aquaporin-4 antibody (anti-AQP4). Serum myelin oligodendrocyte glycoprotein antibody (anti-MOG) was negative. Autoantibodies, including antinuclear antibody, SS-A, SS-B, and Sm, were negative. Thyroid hormones were normal. Cerebrospinal fluid (CSF) showed a normal protein level (18 mg/dL) without pleocytosis or oligoclonal bands (OCB). The IgG index was mildly elevated (0.84; normal limit 0.65). A genetic analysis revealed duplication of the peripheral myelin protein 22 (PMP22) gene.
Table 1. Electrophysiological Findings.
Nerve Amp (mV, μV) DL (ms) CV (m/s)
MCSs Median 7.8* 11.4* 24*
Ulnar 4.2* 8.4* 24*
Tibial 0.05* 13.2* 18*
SCSs Median 1.0* 7.04* 18*
Ulnar 0.6* 5.66* 20*
Sural 0.5* 8.52* 18*
Side P100 latency (ms)
VEPs Right 121.2*
Left Not evoked*
Nerve conduction studies were performed on the right median, ulnar, tibial, and sural nerves. Asterisks indicate significant results with reference to the standard values in our institute. Unit for amplitude is mv for MCSs and μV for SCSs. Amp: amplitude, CV: conduction velocity, DL: distal latency, MCSs: motor nerve conduction studies, SCSs: sensory nerve conduction studies, VEPs: visual evoked potentials
We diagnosed the patient with anti-AQP4-positive neuromyelitis optica spectrum disorder (NMOSD) plus underlying CMT1A. We treated her with three courses of methylprednisolone pulse therapy and seven plasma exchanges. The visual acuity of the left eye recovered to 0.03 (Snellen fraction of 20/630), and the CFF became measurable (20 Hz).
During maintenance therapy with 30 mg oral prednisolone, the patient experienced worsening of paresthesia of the extremities, hand tremor, and gastric ulcer. These symptoms subsided after reducing oral prednisolone and adding azathioprine.
Discussion
We encountered a case of recurrent optic neuritis and myelitis with long-standing sensorimotor polyneuropathy. The clinical picture of the chronic neuropathy in this patient was typical of CMT1A, and the diagnosis was confirmed genetically. Patients with CMT1A typically do not present with visual symptoms. However, subclinical prolongation of VEP is reported in 10-16% of CMT1A patients, which may be associated with asymptomatic optic neuropathy (2). Apart from the above-mentioned degenerative optic neuropathy, acute inflammatory processes in the CNS are an extremely rare complication of CMT1A.
To our knowledge, only eight cases of acute CNS inflammatory lesions have been reported in association with CMT1A (3-8). Of these, four cases of CMT1A with optic neuritis are summarized in Table 2. In one case, antibodies to the proteolipid protein (PLP) and MOG were positive, but anti-APQ4 was not reported in these previous cases. A CSF analysis was positive for OCB in three cases, and protein-cell dissociation was present in two cases. Neither OCB nor protein-cell dissociation was present in our patient. The IgG index was often elevated including our patient, suggesting inflammation in the CNS. These reports raise the possibility that the abnormal expression of PMP22 in peripheral nerve and demyelination of the CNS are causally related. One hypothesis is that PMP22 shares homology with other CNS myelin proteins, such as the PLP, and that the PMP22 overexpression in CMT1A induces an autoimmune response in the CNS (1,6). PLP has been studied extensively as a relevant primary antigen in multiple sclerosis (MS), and the T-cell response to PLP epitope induces experimental autoimmune encephalomyelitis (9,10). Wakerley et al. (6) observed increased immunity against PLP and MOG epitopes in their patient, supporting the immune cross-reactivity hypothesis. There are clinical conditions that suggest a pathophysiological link between peripheral and central myelin; (i) Pelizeus-Merzbacher disease is a leukodystrophy caused by the overexpression of PLP protein gene and is known to be associated with CMT-like neuropathy (11), (ii) hereditary neuropathy with liability to pressure palsy is caused by a deletion or mutation in PMP22 and known to manifest CNS white matter lesions (12).
Table 2. Previously Reported Cases of Optic Neuritis with CMT1A.
Reference Age
(years)/
Sex Diagnosis OCB IgG
index CSF
cell CSF
protein
(mg/dL) Demyelination on MRI VEPs
3 38/F MS + 0.89 ND ND ND Prolonged
3 30/F MS + 0.98 ND ND Cerebral white matter and spinal cord Prolonged
6 57/M Optic neuritis
(anti-MOG) + ND Normal 1,290 Only optic nerve Prolonged
1 31/M MS – 0.65 Normal 52 Cerebral white matter and spinal cord ND
Present case 51/F NMOSD
(anti-AQP4) – 0.84 Normal 18 Optic nerve, cerebral white matter and spinal cord Prolonged
F: female, M: male, anti-MOG: anti-myelin oligodendrocyte glycoprotein antibody, MS: multiple sclerosis, ND: not described, OCB: oligoclonal band, CSF: cerebrospinal fluid, VEPs: visual evoked potentials, anti-AQP4: anti-aquaporin-4 antibody, NMOSD: neuromyelitis optica spectrum disorder
NMOSD was previously considered a variant of MS but is now recognized as a distinct clinical entity. In MS, T cells are thought to target PLP expressed in oligodendrocytes. In contrast, NMOSD is primarily mediated by B-cell autoimmunity to AQP4, with AQP4-IgG antibodies binding to AQP4 expressed on astrocytes and activating the complement pathway (13). However, T-cell immunity in NMOSD is receiving increasing attention. For example, Matsuya et al. reported that PLP induced a significant T-cell response in NMOSD, suggesting that immunity to myelin proteins plays a pathological role (14). Michalski et al. reported that small amounts of PLP were expressed in astrocytes in mice (15). To our knowledge, the present report is the first of CMT1A complicated with anti-AQP4-positive NMOSD. Thus, the coexistence may simply be coincidental. However, an immune cross-reaction remains a potential explanation, and further research is needed.
Our patient experienced exacerbation of paresthesia in the lower extremities after corticosteroid maintenance therapy was initiated, which we attributed to peripheral neuropathy based on the sensory distribution. It is unclear why corticosteroid therapy elicited sensory neuropathy in this CMT1A patient. We speculated that methylprednisolone up-regulated the already-overexpressed PMP22 via its effect as a progesterone receptor agonist and consequently worsened the CMT1A symptoms. Progesterone is known to regulate the expression of PMP22; for example, a progesterone antagonist reduced PMP22 overexpression in a mouse model of CMT1A and improved the severity of the symptoms (16).
There is accumulating evidence that CMT1A is a risk factor of MS. Together with the findings of a previous report of anti-MOG-positive optic neuritis (6), the present results raise the possibility that CMT1A is also a risk factor for B-cell-mediated CNS demyelination. Further clinical and basic immunological studies are needed to elucidate the mechanisms underlying the immune cross-reaction between the peripheral nervous system and the CNS.
The authors state that they have no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33361678 | 19,517,386 | 2021-05-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | Calciphylaxis: The potential diagnostic role of radiologists.
Calciphylaxis is a deadly disease that is currently diagnosed through a skin biopsy of resultant necrotic lesions despite many cases lacking this characteristic finding. Recently, research has demonstrated the ability of various radiologic techniques to detect calciphylaxis and have promoted their capabilities in earlier diagnosis without tissue invasion. In this case, an obese 55-year-old female with end stage renal disease, and a long history of dialysis, complained of weeks of persistent abdominal pain that was accompanied by a mottled, lacey, net-like rash that resembled livedo reticularis. Computed tomography of the abdomen revealed extensive arterial calcification and subcutaneous calcium deposition. These radiologic findings, coupled to a high clinical suspicion, prompted treatment for suspected calciphylaxis. Remarkably, after 1 week the patient reported substantial improvement. Hopefully, this publication in conjunction with previous and future research will raise awareness on the role Radiologists can play in expediting the diagnostic process for a lethal disease, especially when a tissue biopsy is not a feasible option.
Introduction
Calciphylaxis, also known as calcific uremic arteriolopathy, is a poorly understood condition characterized by arteriolar calcium deposition with resultant ischemia and possible necrosis of the skin and subcutaneous tissues [1]. The condition is primarily seen in end-stage renal disease patients on hemodialysis and has a reported annual incidence of 0.35% in this population [2]. Other factors shown to have an association include a longer history of dialysis, elevated parathyroid hormone, use of calcium containing binders, diabetes, obesity, and female sex [3]. Although rare, the disease carries a high mortality with an estimated 6-month survival rate of 50% [4]. Currently, a tissue biopsy is recommended to make the diagnosis. However, recent publications [5], [6], [7] have shown the ability of computed tomography (CT), X-ray and ultrasound to detect subcutaneous vascular calcifications in order to make the diagnosis of calciphylaxis. Another study found the diagnosis could be made with skeletal scintigraphy through technetium-99m methyl diphosphonate radiotracer uptake in subcutaneous tissues [8]. This case will support previous research and suggest radiologic findings, coupled to a high clinical suspicion, can play a vital role in the prompt recognition and diagnosis of calciphylaxis, especially when a characteristic lesion is unavailable for biopsy.
Case report
A 55-year-old obese female with a past medical history of end-stage renal disease requiring hemodialysis via right upper extremity arteriovenous fistula over the past 9 years, secondary hyperparathyroidism, insulin dependent type 2 diabetes mellitus, New York Heart Association Stage 4 diastolic heart failure, atrial fibrillation, and peripheral artery disease presented to the emergency department over concerns of weakness and fatigue after missing over 1 week of hemodialysis sessions that followed a Monday, Wednesday, Friday regimen. On presentation her weight was 246 lbs (BMI 45 kg/m2) despite her baseline averaging around ~220 lbs (BMI ~40 kg/m2). On examination, her abdomen was distended, and she had pitting edema extending to her thighs bilaterally. Electrocardiogram showed she was in atrial fibrillation with rapid ventricular response. A basic metabolic panel revealed hyperkalemia, so she was given emergent hemodialysis. Soon she developed hypoxemia and severe hypotension with systolic readings as low as 70 mm Hg. She was placed on BiPAP and transferred to the medical intensive care unit where pressor support with Norepinephrine was started. Although she remained afebrile, complete blood count revealed neutrophil predominant leukocytosis and blood cultures grew Acinetobacter baumannii of unknown origin. After 1 week, with antibiotics, the patient's infection had resolved and she was weaned off intravenous pressor support. She was transferred to the floors where her fluid status and labile blood pressures were further managed and monitored. While on the floors, the patient's primary complaint was persistent 9-10/10 left lower quadrant abdominal pain. Examination of the area of pain revealed a mottled, lacey, net-like rash that resembled livedo reticularis as shown in Fig. 1. The pain was investigated via CT abdomen that reported anasarca and extensive arterial calcifications (Fig. 2). The imaging also showed lower abdominal subcutaneous soft tissue densities and calcification as shown in Fig. 3. For pain management, the patient was given Oxycodone that would bring her pain down to a 6/10. A short course of steroids was also tried but provided no benefit. Nine days after being transferred to the floors, the patient again developed hypotension in the setting of suspected gastrointestinal bleed supported by hemoptysis, tarry stools, and a positive fecal occult blood test. A CT abdomen with contrast revealed splenic infarction but no signs of active bleeding (Fig. 4). The patient received a couple units of packed red blood cells and fresh frozen plasma. Fortunately, her hemoglobin and hematocrit stabilized, and no further investigative studies were undertaken. Despite persistent abdominal pain, with her fluid status and weight back to baseline, she was discharged to a long-term acute care facility. At the facility, her dialysis sessions were doubled taking place every day apart from Sunday. Despite these efforts, she again began retaining fluid and was re-admitted 6 days after being discharged for heart failure exacerbation. Physical exam showed the rash from previous admission (Fig. 1) and she still complained of 9-10/10 abdominal pain. This pain and rash coupled to the previous radiologic findings (Fig. 2) prompted the decision to withhold her phosphate binder (calcium acetate) and incorporate Cinacalcet to her medicinal regimen for suspected calciphylaxis. After 1 week, the patient reported resolution of her abdominal pain, at which time she was discharged back to long-term acute care.Fig. 1 Red circle showing a mottled, lacey, net-like rash resembling livedo reticularis in the region of pain.
Fig. 1 –Fig. 2 CT abdomen coronal view. Superior to inferior the red arrows demonstrate calcification of: splenic artery, bilateral renal arteries, abdominal aorta and branches of the iliac artery.
Fig. 2 –Fig. 3 CT abdomen showing two sagittal views. Red arrow on the left highlighting subcutaneous calcifications and the right arrow showing subcutaneous soft tissue densities.
Fig. 3 –Fig. 4 CT abdomen with contrast showing two transverse views. Red arrow superior cut showing calcification of the hepatic and splenic artery. Inferior arrow showing consequent splenic infarction.
Fig. 4 –
Discussion
Previous studies have suggested a deep skin biopsy with subcutaneous adipose tissue is required in order to make the diagnosis of calciphylaxis [9]. More recently, the literature seems to be shifting its frame of thought. Prompt recognition of calciphylaxis is crucial for prognosis. It has been shown that approximately 80% of skin manifestations never form the classic indurated necrotic lesion targeted for biopsy [10]. In addition, obtaining a biopsy of viable tissue may serve as a catalyst for the development of extensive necrosis and its subsequent complications [11]. For these reasons, there is interest in exploring more timely, less invasive diagnostic techniques. In this case, the patient had a textbook presentation that included pain in the region of a mottled, lacey, net-like rash that resembled livedo reticularis, arterial and subcutaneous calcium deposition on radiologic imaging, a long history of dialysis, elevated parathyroid hormone, use of calcium containing binders, diabetes, obesity, and female sex. [3] She had an extensive work up investigating other etiologies without success. Although her presentation preached calciphylaxis, she had to suffer from severe 9-10/10 abdominal pain for weeks before receiving appropriately targeted therapy due to the lack of a necrotic lesion for biopsy – as research suggests is the case for the majority of calciphylaxis patients [10]. Fortunately, clinical suspicion coupled with radiologic evidence was of enough persuasion to treat for calciphylaxis by holding the patients Calcium Acetate and incorporate Cinacalcet to her medicinal regimen. Remarkably, the patient reported improvement in her symptoms just over 1 week later. Hopefully, this publication, in conjunction with previous [5], [6], [7], [8] and future research, will raise awareness on the role Radiologists can play in expediting the diagnostic process for a lethal disease, especially when a tissue biopsy is not a feasible option.
Competing interest: Author has no competing interests to report. | CALCIUM ACETATE, NOREPINEPHRINE | DrugsGivenReaction | CC BY-NC-ND | 33363673 | 18,705,870 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Splenic infarction'. | Calciphylaxis: The potential diagnostic role of radiologists.
Calciphylaxis is a deadly disease that is currently diagnosed through a skin biopsy of resultant necrotic lesions despite many cases lacking this characteristic finding. Recently, research has demonstrated the ability of various radiologic techniques to detect calciphylaxis and have promoted their capabilities in earlier diagnosis without tissue invasion. In this case, an obese 55-year-old female with end stage renal disease, and a long history of dialysis, complained of weeks of persistent abdominal pain that was accompanied by a mottled, lacey, net-like rash that resembled livedo reticularis. Computed tomography of the abdomen revealed extensive arterial calcification and subcutaneous calcium deposition. These radiologic findings, coupled to a high clinical suspicion, prompted treatment for suspected calciphylaxis. Remarkably, after 1 week the patient reported substantial improvement. Hopefully, this publication in conjunction with previous and future research will raise awareness on the role Radiologists can play in expediting the diagnostic process for a lethal disease, especially when a tissue biopsy is not a feasible option.
Introduction
Calciphylaxis, also known as calcific uremic arteriolopathy, is a poorly understood condition characterized by arteriolar calcium deposition with resultant ischemia and possible necrosis of the skin and subcutaneous tissues [1]. The condition is primarily seen in end-stage renal disease patients on hemodialysis and has a reported annual incidence of 0.35% in this population [2]. Other factors shown to have an association include a longer history of dialysis, elevated parathyroid hormone, use of calcium containing binders, diabetes, obesity, and female sex [3]. Although rare, the disease carries a high mortality with an estimated 6-month survival rate of 50% [4]. Currently, a tissue biopsy is recommended to make the diagnosis. However, recent publications [5], [6], [7] have shown the ability of computed tomography (CT), X-ray and ultrasound to detect subcutaneous vascular calcifications in order to make the diagnosis of calciphylaxis. Another study found the diagnosis could be made with skeletal scintigraphy through technetium-99m methyl diphosphonate radiotracer uptake in subcutaneous tissues [8]. This case will support previous research and suggest radiologic findings, coupled to a high clinical suspicion, can play a vital role in the prompt recognition and diagnosis of calciphylaxis, especially when a characteristic lesion is unavailable for biopsy.
Case report
A 55-year-old obese female with a past medical history of end-stage renal disease requiring hemodialysis via right upper extremity arteriovenous fistula over the past 9 years, secondary hyperparathyroidism, insulin dependent type 2 diabetes mellitus, New York Heart Association Stage 4 diastolic heart failure, atrial fibrillation, and peripheral artery disease presented to the emergency department over concerns of weakness and fatigue after missing over 1 week of hemodialysis sessions that followed a Monday, Wednesday, Friday regimen. On presentation her weight was 246 lbs (BMI 45 kg/m2) despite her baseline averaging around ~220 lbs (BMI ~40 kg/m2). On examination, her abdomen was distended, and she had pitting edema extending to her thighs bilaterally. Electrocardiogram showed she was in atrial fibrillation with rapid ventricular response. A basic metabolic panel revealed hyperkalemia, so she was given emergent hemodialysis. Soon she developed hypoxemia and severe hypotension with systolic readings as low as 70 mm Hg. She was placed on BiPAP and transferred to the medical intensive care unit where pressor support with Norepinephrine was started. Although she remained afebrile, complete blood count revealed neutrophil predominant leukocytosis and blood cultures grew Acinetobacter baumannii of unknown origin. After 1 week, with antibiotics, the patient's infection had resolved and she was weaned off intravenous pressor support. She was transferred to the floors where her fluid status and labile blood pressures were further managed and monitored. While on the floors, the patient's primary complaint was persistent 9-10/10 left lower quadrant abdominal pain. Examination of the area of pain revealed a mottled, lacey, net-like rash that resembled livedo reticularis as shown in Fig. 1. The pain was investigated via CT abdomen that reported anasarca and extensive arterial calcifications (Fig. 2). The imaging also showed lower abdominal subcutaneous soft tissue densities and calcification as shown in Fig. 3. For pain management, the patient was given Oxycodone that would bring her pain down to a 6/10. A short course of steroids was also tried but provided no benefit. Nine days after being transferred to the floors, the patient again developed hypotension in the setting of suspected gastrointestinal bleed supported by hemoptysis, tarry stools, and a positive fecal occult blood test. A CT abdomen with contrast revealed splenic infarction but no signs of active bleeding (Fig. 4). The patient received a couple units of packed red blood cells and fresh frozen plasma. Fortunately, her hemoglobin and hematocrit stabilized, and no further investigative studies were undertaken. Despite persistent abdominal pain, with her fluid status and weight back to baseline, she was discharged to a long-term acute care facility. At the facility, her dialysis sessions were doubled taking place every day apart from Sunday. Despite these efforts, she again began retaining fluid and was re-admitted 6 days after being discharged for heart failure exacerbation. Physical exam showed the rash from previous admission (Fig. 1) and she still complained of 9-10/10 abdominal pain. This pain and rash coupled to the previous radiologic findings (Fig. 2) prompted the decision to withhold her phosphate binder (calcium acetate) and incorporate Cinacalcet to her medicinal regimen for suspected calciphylaxis. After 1 week, the patient reported resolution of her abdominal pain, at which time she was discharged back to long-term acute care.Fig. 1 Red circle showing a mottled, lacey, net-like rash resembling livedo reticularis in the region of pain.
Fig. 1 –Fig. 2 CT abdomen coronal view. Superior to inferior the red arrows demonstrate calcification of: splenic artery, bilateral renal arteries, abdominal aorta and branches of the iliac artery.
Fig. 2 –Fig. 3 CT abdomen showing two sagittal views. Red arrow on the left highlighting subcutaneous calcifications and the right arrow showing subcutaneous soft tissue densities.
Fig. 3 –Fig. 4 CT abdomen with contrast showing two transverse views. Red arrow superior cut showing calcification of the hepatic and splenic artery. Inferior arrow showing consequent splenic infarction.
Fig. 4 –
Discussion
Previous studies have suggested a deep skin biopsy with subcutaneous adipose tissue is required in order to make the diagnosis of calciphylaxis [9]. More recently, the literature seems to be shifting its frame of thought. Prompt recognition of calciphylaxis is crucial for prognosis. It has been shown that approximately 80% of skin manifestations never form the classic indurated necrotic lesion targeted for biopsy [10]. In addition, obtaining a biopsy of viable tissue may serve as a catalyst for the development of extensive necrosis and its subsequent complications [11]. For these reasons, there is interest in exploring more timely, less invasive diagnostic techniques. In this case, the patient had a textbook presentation that included pain in the region of a mottled, lacey, net-like rash that resembled livedo reticularis, arterial and subcutaneous calcium deposition on radiologic imaging, a long history of dialysis, elevated parathyroid hormone, use of calcium containing binders, diabetes, obesity, and female sex. [3] She had an extensive work up investigating other etiologies without success. Although her presentation preached calciphylaxis, she had to suffer from severe 9-10/10 abdominal pain for weeks before receiving appropriately targeted therapy due to the lack of a necrotic lesion for biopsy – as research suggests is the case for the majority of calciphylaxis patients [10]. Fortunately, clinical suspicion coupled with radiologic evidence was of enough persuasion to treat for calciphylaxis by holding the patients Calcium Acetate and incorporate Cinacalcet to her medicinal regimen. Remarkably, the patient reported improvement in her symptoms just over 1 week later. Hopefully, this publication, in conjunction with previous [5], [6], [7], [8] and future research, will raise awareness on the role Radiologists can play in expediting the diagnostic process for a lethal disease, especially when a tissue biopsy is not a feasible option.
Competing interest: Author has no competing interests to report. | CALCIUM ACETATE | DrugsGivenReaction | CC BY-NC-ND | 33363673 | 18,722,566 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematoma muscle'. | Psoas muscle hematoma presenting as painful monoplegia.
I present here a case of psoas (retroperitoneal) hematoma; which is a rare, but potentially life-threatening acute condition, with a 30-day mortality of 10% from bleeding in the retroperitoneal space without associated trauma or iatrogenic intervention. A 59-year-old man who was on long-term anticoagulation for his atrial fibrillation presented to our facility with worsening pain in the left groin and being unable to move the left leg and walk. Computed tomography showed a large left psoas hematoma. He was treated conservatively which included reversal of his anticoagulation state. This case highlights the need for early diagnosis of psoas hematoma by computed tomography scan of the abdomen and pelvis to promptly initiate treatment to improve functional outcome.
Case report
A 59-year-old-man with a history of hypertension, hyperlipidemia, morbid obesity, obstructive sleep apnea on bi-pap, and on chronic anticoagulation for atrial fibrillation and recurrent leg deep vein thrombosis presented with cellulitis of both legs. The following day he complained of sudden, progressively worsening discomfort in the left groin with being unable to move the left leg. When left leg was moved voluntarily, he screamed with excruciating pain. Neurological examination showed decreased muscle strength in the left hip flexors and adductors and knee extensors, decreased reflexes, and decrease light-touch and pin-prick sensation in lumbar 1-4 distribution. His admission INR was 4.4 (therapeutic INR range for atrial fibrillation 2.0-3.0). Computed tomography of the abdomen and pelvis showed large left psoas hematoma (Fig. 1a-c, denoted by asterisk). Patient's coumadin was held and he received vitamin K replacement, analgesics for pain and antibiotics for cellulitis. Patient was transferred to in-house rehabilitation facility where he received physical and occupational therapies and was able to safely transfer and ambulate by himself and discharged home 2-months later.Fig. 1 (a) Coronal abdominal CT showing a large left retroperitoneal (psoas) hematoma (*). (b) Sagittal abdominal CT showing a large left retroperitoneal (psoas) hematoma (*). (b) Axial abdominal CT showing a large left retroperitoneal (psoas) hematoma (*).
Fig 1
Discussion
The psoas muscle is in the lower lumbar region of the spine (retro-peritoneal space) and extends through the pelvis to the femur. This muscle flexes the hip joints, a movement essential in walking. Incidence of psoas hematoma in patients undergoing therapeutic anticoagulation is 0.6%-6.6% [1,2].Warfarin, unfractionated and low-molecular weight heparin have been mainly implicated [1], [2], [3]. Clinical features are varied and vague [4]. Abdominal and pelvis computed tomography scan is more sensitive in diagnosing this condition. [5]. All patients, whatever the underlying etiology, should be closely monitored and managed with fluid resuscitation, blood transfusion and normalization of coagulation factors [6]. Surgical drainage of the hematoma reduces the effect of tamponade but damages the lumbar nerve plexus and worsens leg weakness. There is a single case report of percutaneous hematoma drainage to restore femoral nerve function after being compressed by heparin-induced retroperitoneal hematoma [7].Psoas hematoma needs to be differentiated from other conditions which cause abdominal, flank or groin pain such as acute pancreatitis, ruptured aortic aneurysm, laparoscopic urologic intervention, or penetrating injuries.
Patient Consent
This could not be obtained as veteran as transferred out of state close to his other family members following his diagnosis and completion of treatment.
Author Contributions
Dr. Meheroz H. Rabadi - Study concept and design, Data acquisition, Analysis and interpretation, Write-up of the manuscript for intellectual content, Study supervision
Funding: None.
Competing Interests: None. | WARFARIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33363683 | 18,813,994 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'International normalised ratio increased'. | Psoas muscle hematoma presenting as painful monoplegia.
I present here a case of psoas (retroperitoneal) hematoma; which is a rare, but potentially life-threatening acute condition, with a 30-day mortality of 10% from bleeding in the retroperitoneal space without associated trauma or iatrogenic intervention. A 59-year-old man who was on long-term anticoagulation for his atrial fibrillation presented to our facility with worsening pain in the left groin and being unable to move the left leg and walk. Computed tomography showed a large left psoas hematoma. He was treated conservatively which included reversal of his anticoagulation state. This case highlights the need for early diagnosis of psoas hematoma by computed tomography scan of the abdomen and pelvis to promptly initiate treatment to improve functional outcome.
Case report
A 59-year-old-man with a history of hypertension, hyperlipidemia, morbid obesity, obstructive sleep apnea on bi-pap, and on chronic anticoagulation for atrial fibrillation and recurrent leg deep vein thrombosis presented with cellulitis of both legs. The following day he complained of sudden, progressively worsening discomfort in the left groin with being unable to move the left leg. When left leg was moved voluntarily, he screamed with excruciating pain. Neurological examination showed decreased muscle strength in the left hip flexors and adductors and knee extensors, decreased reflexes, and decrease light-touch and pin-prick sensation in lumbar 1-4 distribution. His admission INR was 4.4 (therapeutic INR range for atrial fibrillation 2.0-3.0). Computed tomography of the abdomen and pelvis showed large left psoas hematoma (Fig. 1a-c, denoted by asterisk). Patient's coumadin was held and he received vitamin K replacement, analgesics for pain and antibiotics for cellulitis. Patient was transferred to in-house rehabilitation facility where he received physical and occupational therapies and was able to safely transfer and ambulate by himself and discharged home 2-months later.Fig. 1 (a) Coronal abdominal CT showing a large left retroperitoneal (psoas) hematoma (*). (b) Sagittal abdominal CT showing a large left retroperitoneal (psoas) hematoma (*). (b) Axial abdominal CT showing a large left retroperitoneal (psoas) hematoma (*).
Fig 1
Discussion
The psoas muscle is in the lower lumbar region of the spine (retro-peritoneal space) and extends through the pelvis to the femur. This muscle flexes the hip joints, a movement essential in walking. Incidence of psoas hematoma in patients undergoing therapeutic anticoagulation is 0.6%-6.6% [1,2].Warfarin, unfractionated and low-molecular weight heparin have been mainly implicated [1], [2], [3]. Clinical features are varied and vague [4]. Abdominal and pelvis computed tomography scan is more sensitive in diagnosing this condition. [5]. All patients, whatever the underlying etiology, should be closely monitored and managed with fluid resuscitation, blood transfusion and normalization of coagulation factors [6]. Surgical drainage of the hematoma reduces the effect of tamponade but damages the lumbar nerve plexus and worsens leg weakness. There is a single case report of percutaneous hematoma drainage to restore femoral nerve function after being compressed by heparin-induced retroperitoneal hematoma [7].Psoas hematoma needs to be differentiated from other conditions which cause abdominal, flank or groin pain such as acute pancreatitis, ruptured aortic aneurysm, laparoscopic urologic intervention, or penetrating injuries.
Patient Consent
This could not be obtained as veteran as transferred out of state close to his other family members following his diagnosis and completion of treatment.
Author Contributions
Dr. Meheroz H. Rabadi - Study concept and design, Data acquisition, Analysis and interpretation, Write-up of the manuscript for intellectual content, Study supervision
Funding: None.
Competing Interests: None. | WARFARIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33363683 | 18,813,994 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breast necrosis'. | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | CAPECITABINE, TEMOZOLOMIDE | DrugsGivenReaction | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematotoxicity'. | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | CAPECITABINE, TEMOZOLOMIDE | DrugsGivenReaction | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mastitis'. | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | CAPECITABINE, TEMOZOLOMIDE | DrugsGivenReaction | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | CAPECITABINE, TEMOZOLOMIDE | DrugsGivenReaction | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancytopenia'. | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | CAPECITABINE, TEMOZOLOMIDE | DrugsGivenReaction | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the administration route of drug 'CAPECITABINE'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the administration route of drug 'EDOTREOTIDE LUTETIUM LU-177'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33363730 | 18,826,407 | 2021-01 |
What was the administration route of drug 'TEMOZOLOMIDE'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the dosage of drug 'EDOTREOTIDE LUTETIUM LU-177'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | FOR 4 CYCLES | DrugDosageText | CC BY-NC-ND | 33363730 | 18,826,407 | 2021-01 |
What was the dosage of drug 'TEMOZOLOMIDE'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | 150 MILLIGRAM/SQ. METER | DrugDosageText | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the outcome of reaction 'Breast necrosis'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the outcome of reaction 'Haematotoxicity'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the outcome of reaction 'Mastitis'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the outcome of reaction 'Myelosuppression'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
What was the outcome of reaction 'Pancytopenia'? | A rare case of a patient with a high grade neuroendocrine tumor developing neutropenic sepsis after receiving PRRT combined with Capecitabine or Temozolomide: A case report.
Neuroendocrine tumors (NET) are rare and demonstrate variable clinical behavior depending on the degree of tumor differentiation. Patients with poorly differentiated tumors (NET G3) have a poor prognosis. Systemic treatment with cytotoxic chemotherapy is considered to be the treatment of choice. In patients that are refractory or intolerant to first-line therapy, experts recommend peptide receptor radionuclide therapy (PRRT) in tumors that express somatostatin receptors. Recently, combinations of PRRT and chemotherapy were tested in patients with NET. Available data have reported promising tumor control rates and an excellent toxicity profile in cases where PRRT had been administered with capecitabine/temozolomide, even when administered as salvage therapy. The current study reported an exceptional case of advanced NET G3 with severe toxicity upon receiving PRRT in combination with capecitabine/temozolomide as third line therapy. The patient developed a life-threatening neutropenic fever, fungal pneumonia and necrotizing mastitis 23 days after the first cycle of therapy was administered. However, the treatment led to a significant reduction in tumor size. A total of 5 months after treatment initiation, the patient was alive and in excellent clinical condition with sustained tumor response. In summary, the current study presented a rare case of high grade NET exhibiting an almost complete response to PRRT in combination capecitabine/temozolomide, despite facing unexpected severe toxicity.
Introduction
Neuroendocrine neoplasia (NEN) are a rare and heterogeneous group of tumors. According to the World Health Organization (WHO) classification, NEN are stratified into low/moderate-[grade (G) 1/2] or high-grade (G3) neuroendocrine tumors (NET) and neuroendocrine carcinoma (NEC) (1). Well-differentiated NET (G1 and G2) are characterized by a low proliferative index, retain the expression of somatostatin receptors (SSTR) and are associated with a good prognosis compared with that in other malignancies. By contrast, G3 NET feature a high Ki-67 proliferation index of >20% and are associated with a poor prognosis.
The systemic treatment of patients with G3 NET has been under investigated. To date, no data from prospective clinical trials are available, and current recommendations for the treatment of G3 NET primarily relies on retrospective analyses and case series. Overall, G3 NET show low objective response rates to platinum-based therapies, when compared with that in NECs (2). Therefore, alternative, less toxic chemotherapy regimens, such as capecitabine/temozolomide are recommended (3). Data on second- or third-line therapy in the treatment of G3 NET are even rarer, and current recommendations are primarily based on expert opinions rather than on systematic clinical studies. In the case of SSR-positive tumors, peptide receptor radionuclide therapy (PRRT) has been recommended by several expert research groups. PRRT is a tumor-targeted systemic radiotherapy that enables the specific delivery of radionuclides directly into tumor cells inducing tumor cell death. The high-level expression of SSR on the tumor cell surface in NEN provides the rational for a therapy with radioisotope-labeled somatostatin analogs (4). While PRRT has emerged as a highly effective and well-tolerated treatment in SSR-positive, well-differentiated NET (5-7), few data exist on patients with high-grade NET. Zhang et al (8) reported a median progression-free survival (PFS) time of 9.6 months and a median overall survival (OS) time of 19.9 months in 69 patients with G3 NET treated with PRRT. Notably, in these patients PRRT was well-tolerated without any decline in renal function, hepatotoxicity or grade 3/4 hematotoxicity. Combinations of PRRT with systemic chemotherapy (e.g. capecetabine with and without temzolomide) might be associated with both additive and synergistic effects, since chemotherapeutic agents might serve as a radiosensitizer, as well as targeting cells non-responsive to PRRT (9). However, at present, there are only a few case reports and small number of case series, which have reported the outcome of patients treated with a combination of PRRT and chemotherapy. In the present case study, a patient with disease progression following 4 cycles of PRRT, who was subsequently treated with a combination of PRRT and capecitabine/temozolomide at our institution has been described.
Case report
The case of a 58-year-old female patient who was diagnosed with a G3 NET of unknown primary location and synchronous liver metastases in October 2017 (Table I) has been described. The proliferation according to Ki-67 was high (20%). Multi-slice computed tomography (CT) and DOTATOC-positron emission tomography (PET)/CT revealed multiple SSR-positive liver metastases; however, it did not provide any evidence of a primary tumor. Immunohistochemical analysis of a biopsy obtained from a liver metastasis showed strong expression of synaptophysin and a slightly weaker expression of chromogranin. Staining for serotonin, CDX2 and TTF1 were negative and membranous PD-L1 expression was found in <1% of tumor cells.
Treatment with lanreotide Autogel (120 mg) was administered every 28 days. In addition, the patient underwent 4 cycles of PRRT with 7.4 gigabecquerel (GBq) 177LU LU-DOTATOC over a period of 6 months (last dose June 2018). Notably, this treatment resulted in a partial remission lasting until December 2018 (Fig. 1A-C). At this time point a follow-up DOTATOC-PET/CT scan revealed disease progression in the liver (only in the right lobe, with stable disease on the left-hand side). No other distant metastases was evident. Based on the short duration of tumor control, another systemic treatment was not administered; however, the patient was admitted to undergo hemihepatectomy to resect the progressive lesions. Histopathological analysis of the resected tumor confirmed the diagnosis of NET with Ki-67 >20%, leading to the diagnosis of G3 NET (Fig. 2A-C). However, a DOTATOC-PET/CT scan performed four months following surgery showed further hepatic and lymphatic progression with an increase in tumor size of >20% according to the Response Evaluation Criteria in Solid Tumors (RECIST). Considering the initial partial response to PRRT and the systemic progression at that time point, systemic therapy was not administered but simultaneously continuation of PRRT sessions. Capecitabine/temzolomide was chosen as the chemotherapeutic agent due to the high response rates observed in patients with NET (10,11) and since it represents the most common therapy regime used in studies investigating PRRT in combination with chemotherapy (12-14). At the time point of treatment initiation, the patient was in good general condition [Eastern Cooperative Oncology Group (ECOG) 0] and had recovered from the side effects of previous therapies. Nevertheless, the therapy was administered at a reduced dose, since (reversible) anemia and a lower platelet and leucocyte count had occurred, as some of the side effects from the initial 4 cycles of PRRT (Fig. 3A and B).
As timing between chemotherapy and PRRT has been found to have an impact on outcome parameters in animal studies, wean already established protocol was used (15,16). Of note, this particular protocol was selected, as it has been reported that therapy was only accompanied by modest reversible myelosuppression, which was not greater than that in conventional PRRT therapies. Therefore, the combination of PRRT plus capecitabine/temozolomide was administered according to the protocol recently published by Strosberg et al (10) using 750 mg/m2 capecitabine (which was reduced to 538 mg/m2) and temzolomide 200 mg/m2 (which was reduced to 150 mg/m2). Chemotherapy with oral capecitabine started five days prior to PRRT. In particular, 7.0 GBq 177-LU-DOTATOC was administered intravenously, followed by oral temozolamide in the last five days of the 14-day period of the capecitabine cycle. Dosimetric calculations revealed that the radiation absorbed doses were 1.09 milligrays (mGy)/megaBq (MBq) for the kidneys, 0.288 mGy/MBq for the liver, 0.41 mGy/MBq for the spleen and 0.03 mGy/MBq for bone marrow, while hepatic metastases demonstrated a higher uptake of 4.56 mGy/MBq, which was in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17).
The treatment was initially well-tolerated without any side effects. However, 23 days after PRRT, the patient was hospitalized due to recurrent episodes of fever, dyspnea, as well as pain, redness and swelling in the right mamma. Laboratory testing revealed pancytopenia and slightly elevated inflammatory markers, while an ultrasound of the mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. Chest CT revealed a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground glass opacity, suggesting fungal pneumonia (Fig. 4A and B).
Blood, sputum and swab cultures did not identify any pathogens. For further evaluation of the pancytopenia, a bone marrow puncture was performed, which revealed toxic bone marrow damage (Fig. 5). As a result of the clinical investigations, neutropenic fever, a right-sided necrotizing mastitis and fungal pneumonia, as clinical complications of toxic bone marrow aplasia (most likely due to hematoxicity of PRRT and chemotherapy) was diagnosed. The patient, treated in an external rural hospital at that time, was then sent to an Oncology unit in a tertiary University hospital. An empirical combination therapy with piperacillin/tazobactam, vancomycin, aciclovir and Caspofungin was initiated and was later changed to a combination of vancomycin, ciprofloxacin and voriconazole. Furthermore, stimulation therapy with granulocyte-colony stimulating factor was performed, along with the administration of several red blood cell and platelet transfusions. After 11 days, the blood cells started to regenerate (Fig. 3A and 3B). Follow-up imaging two weeks later revealed a clear regression of the infiltrations in the right upper lobe. The inflammatory markers decreased, along with an improvement in the healing process of the wound tissue of the mamma (Fig. 6).
Despite the critical clinical condition caused by combination PRRT, CT staging conducted one month following PPRT plus capecitabine/temozolomide showed a liver tumor mass reduction of at least 55% according to RECIST, without any signs of pathological lymph node enlargement. Subsequent magnetic resonance imaging four months later revealed a further tumor reduction of at least 68% according to RECIST (Fig. 1D and E).
In consideration of the severe bone marrow damage and the critical condition of the patient, the combination of PRRT plus capecitabine/temozolomide was discontinued and somatostatin analogue (SSA)-therapy was restarted again. The blood count stabilized and remained normal. The following staging investigations in October 2019 revealed further sustained tumor response. To date, the patient is alive and fully recovered from the therapy-related side effects.
Discussion
The present case report described the case of a patient diagnosed with a G3 NET of unknown primary origin accompanied by synchronous liver metastases. The patient received a combination of PRRT and capecitabine/temozolomide chemotherapy, as part of a multi-modal treatment concept at our institution. After receiving only one cycle of therapy, the patient exhibited severe bone marrow toxicity, as well as neutropenic fever and critical infectious complications (necrotizing mastitis and fungal pneumonia); however, demonstrated an effective tumor response. The patient in the present case report provides several notable aspects: First, the combination of chemotherapy and PRRT was associated with an effective tumor response, leading to a sustained tumor control >5 months after only one cycle; second, this response was achieved in a patient with high-grade NET, representing a cohort of patients with limited treatment options; third, the toxicity of the treatment exceeded the toxicity reported in the current literature by far, highlighting the requirement for careful patient selection and close monitoring of patients receiving PRRT in combination with chemotherapy.
Until now, different experimental approaches and strategies have been investigated to optimize the effectiveness of PRRT and to minimize potential side effects (18). Research groups, such as Claringbold et al (12-14) have tried to combine PRRT with chemotherapy (capecitabine with and without temzolomidect) in cases of patients with advanced low-grade GNETs, in which either of the two treatment options alone failed (12-14,16). With the intention to use chemotherapy, as a radiosensitizing agent to enhance the efficacy of PRRT, effective tumor control rates were achieved, with disease control in up to 55% of the patients (13,19). A study, investigating pNET in particular, revealed an overall response rate of 80%, including complete remission in 13% and partial response in 70% of the cases (14). Accordingly, the effective tumor response of at least 68% tumor reduction was in line with previous studies.
Both combined PRRT and PRRT alone have been presented as procedures leading to an increase in long-term survival with a low complication rate (20-28). The patient in the present case study received the combination of 177Lu-octreotate and capecitabinec and temozolomide, which was considered feasible and safe, regarding the acute and subacute side effects (12-14). According to previous studies, acute side effects are typically mild and self-limiting (most commonly nausea), whereas long-term side effects include loss of renal function, myelodysplastic syndrome and acute leukemia. However, hematological toxicity was the most significant potential adverse event following PRRT, caused by irradiation of the bone marrow and primarily presenting as reversible, limited grade cytopenia. Current research studies suggest that WHO grade 3 or 4 toxicity could only occur in up to 15% of patients. According to Kesavan et al (16) this number was not significantly increased in patients receiving PRRT in combination with radiosensitizing chemotherapy, which has the potential to enhance the efficiency of the therapy. Research by Kesavan et al (16) retrospectively analyzed long-term outcomes of the two cohorts from their 177Lu-octreotate and chemotherapy study (37 patients treated with capecitabine/temzolomide and 28 patients treated with 177Lu-octreotate and capecitabine). In both cohorts, only modest reversible myelosuppression was observed. In patients treated with capecitabine/temzolomide, long-term follow-up revealed significant thrombocytopenia in 2.7% (n=1), neutropenia in 2.7% (n=1) and anemia in 10.8% (n=4), while no short-term hematological toxicity grade 3/4 (n=0) was reported. In patients receiving 177Lu-octreotate and capecitabine, long-term hematotoxicity, such as anemia and thrombytopenia was only detected in 3.5% of the cases (n=1). However, an exact measure of the adverse events due to PRRT plus chemotherapy can be challenging, which is why the procedure is still considered investigational (29).
The patient in the present case report developed severe bone marrow toxicity, along with critical infectious complications (necrotizing mastitis and fungal pneumonia) after only one session of PRRT in combination with capecitabine/temzolomidect at a reduced dose. Despite the fact that only one cycle of combined PRRT, at a reduced dose was administered, severe bone marrow damage was observed, leading to myelotoxic cytopenia most likely caused by prior therapy with PRRT, which was not seen in association with previous SSA therapy (30,31). Fig. 3A and B revealed the myelotoxic damage after two PRRT sessions causing a lower platelet and leucocyte count,counts as well as persistent anemia after several months. However, an increased radiation uptake can be excluded, as dosimetric calculations revealed the radiation absorption doses, which were in line with previously published results from patients receiving combinations of chemotherapy and PRRT (17). Therefore, it was concluded Therefore, we can conclude that the patient in the current study was already predisposed to develop pancytopenia during PRRT in combination with capecitabine/temzolomide. Pretreatment with radiation-based therapy or alkylating agents has also been considered a significant factor to predict myelotoxicity, as research by Kesavan et al (16) showed a significant differencesignificance between increased risk of short- and long-term toxicity and the presence and number of previous treatments. Thus, a reduced dose of capecitabine/temzolomide was administered to the patient in the present case report.
As aforementioned, there are several approaches to prevent adverse effects of PRRT, such as using amino acid infusion or gelofusine and optimization of antiemetic regimens (32-35). Furthermore, it has been suggested that early therapy with PRRT-containing regimens could not only improve the outcome, but also reduce myelotoxicity (36). However, early treatment with PRRT was not successful in preventing severe bone marrow damage in the patient in the present case report, suggesting the requirement for additional approaches to prevent myelotoxicity. In this regard, establishment of specific algorithms incorporating predictors for myelotoxicity are highly desirable to select optimal treatment strategies, with respect to dosage and the number of cycles for each individual patient.
Another primary finding of the present case report was that the tumor reduced in size by at least 55% after only one month, followed by a further reduction of up to 68% (Fig. 1D). This supports several previous studies, which consider PRRT in combination with radiosensitizing chemotherapy an effective therapeutic option in this challenging disease (12-14). The rapid response seen in the patient in the current case report indicates the requirement for close clinical and radiological monitoring in patients treated with such regimens, to adjust the therapeutic strategy according to its efficacy and toxicity. Long-term follow-up would be a requirement to investigate sustainability of the tumor response after one cycle, as well as the occurrence of long-term adverse effects.
However, the present case report has some limitations, as only one patient with radiosensitizing chemotherapy in combination with PRRT was treated at our institute, which makes further conclusions difficult. Furthermore, the primary tumor in the patient is still unknown. However, there is a high incidence of, CUP (10-15%) in patients with NET (37-40) and no correlation between an improveda therapy response and/or higher toxicity with respect to tumor origin after PRRT combinationcombined with chemotherapy has been analyzed or reported yet (12-14,19).
Despite the high tumor reduction rate and several successful approaches to reduce the side effect profile in the field of radio sensitizing chemotherapy in combination with PRRT, the serious problem of myelotoxicity could not be addressed. Clinical trials on this type of therapy are rare, but are urgently required to further investigate the toxicity, as well as to develop preventive measures and predictors of response and long-term survival in patients receiving a combination of PRRT and systemic chemotherapy.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
BÖ, HA, IS, PEG, MTM, UF, FT, HJ and CR were involved treated the patient. BÖ, HJ and CR wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
The patient provided written informed consent for the publication of patient data and images according to the Declaration of Helsinki.
Competing interests
The authors declare that they have no competing interests.
Figure 1 Hepatic metastases in axial abdominal CT and MRI scans during the course of treatment in a 58-year-old female patient with neuroendocrine CUP and synchronous hepatic metastases. Tumor lesions are indicated by yellow arrows. (A) Axial non-contrast-enhanced CT scan demonstrates multiple hepatic metastases at initial diagnosis (November 2017). (B) Axial-contrast enhanced (venous phase) CT scan displays a reduction in the size of hepatic metastases after 4 cycles of PRRT (July 2018). (C) Axial-contrast enhanced (venous phase) CT scan demonstrates progression in the size of hepatic metastases primarily in the right liver lobe (December 2018). (D) Axial contrast-enhanced (venous phase) CT scan demonstrates tumor reduction of at least 55% (according to RECIST v11.1) 1 month after PRRT in combination with capecitabine/temzolomide (July 2019). (E) Axial contrast-enhanced (venous phase) MRI depicts a hepatic tumor reduction of at least 68% (according to RECIST v11.1) after one cycle of PRRT in combination with capecitabine/temozolomide (October 2019). CUP, cancer of unknown primary; PRRT, peptide receptor radionuclide therapy; RECIST, Response Evaluation Criteria in Solid Tumors.
Figure 2 Immunohistochemical expression of cells from hepatic metastasis (hemihepatectomy resection from January 2019). Pathological analysis and immunohistochemical expression of cells from hepatic metastasis obtained following hemihepatectomy resection. (A) Ki-67 expression was >20%. (B) Synaptophysin expression of tumor cells. (C) Chromogranin expression of the tumor cells (all, magnification x20).
Figure 3 Platelet and leucocyte count during the course of treatment. (A) Platelet (blue curve) and leukocyte count (green curve) during the course of treatment. The graph illustrates a large decrease in leucocyte and platelet count 23 days after PRRT in combination with capecitabin/temzolomid. The results also exhibit a decline in platelet and leucocyte count after the administration of four cycles of PRRT, which rapidly increased subsequently, and stabilized during partial remission, with a decrease as the disease progressed. (B) Hemoglobin levels during the course of treatment. The graph illustrates a progressive decrease in hemoglobin levels after initial diagnosis resulting in chronic anemia. Despite a decrease in hemoglobin levels after four cycles of PRRT, the anemia may have been cancer-related, showing a decline with progressive disease. Subsequent to granulocyte-colony stimulating factor stimulation and the administration of erythrocyte concentrates during hospitalization in July 2019, hemoglobin levels normalized. PRRT, peptide receptor radionuclide therapy.
Figure 4 Axial contrast-enhanced CT scan of the chest, suggesting fungal pneumonia. (A) Axial- and (B) coronal contrast-enhanced CT scan of the chest demonstrated a mass-like pulmonary infiltrate in the right upper lobe with surrounding ground class opacity, suggesting fungal pneumonia.
Figure 5 Bone marrow aspirate stained with H&E showing severe bone marrow hypoplasia. For further evaluation of the unexplained pancytopenia, a bone marrow puncture was performed. Results suggested that toxic bone marrow damage most likely due to hematoxicity of PRRT and chemotherapy.
Figure 6 Necrotizing mastitis (with cutis and subcutis involvement) of the right mamma prior to and during treatment. (A) Mastitis before treatment initiation, showing erythema, edema and necrosis. Previous ultrasound imaging of the patient's mamma showed distinct edema with induration of the tissue without evidence of an abscess formation. (B) Mastitis of the right mamma during the healing process after treatment initiation. As a result of therapy, edema and erythema regressed, while necrosis could still be detected.
Table I Course of disease.
Year Month Therapy Staging
2017 October - G3 NET CUP with synchronous hepatic metastases: First biopsy of a hepatic metastasis, Ki 67 20%, Synaptophysin+++, CGA++, SSTR-2A+++
November SSA therapy (Somatuline 120 mg) every 28 days Staging CT and DOTATOC-PET: SSR-positive multiple hepatic metastases primarily in the right liver lobe. No evidence of primary tumor
- Second biopsy of a hepatic metastasis: Ki67 35-40%, Synaptophysin+++, CGA++, SSTR-2A+++, ISLET1-positive, TTF1- and CDX2-negative
December First cycle PRRT 7,4 GBq 177LU-DOTATOC -
2018 February Second cycle PRRT 7,4 GBq 177LU-DOTATOC -
April Third cycle PRRT 7,6 GBq 177LU-DOTATOC Staging CT: Hepatic progressive disease
- Staging CT and DOTATOC-PET: Hepatic progressive disease
June Fourth cycle PRRT 7,7 GBq 177LU-DOTATOC -
July Continuation of SSA therapy Staging CT: Partial remission with hepatic tumor size reduction
September - Staging CT and DOTATOC-PET: Partial further hepatic tumor size reduction
December - Staging CT and DOTATOC-PET: Hepatic progressive disease (progress of right lobe liver metastasis). No pathological lymph node enlargement
2019 January Right hemihepatectomy Histopathology of liver specimen: Ki 67 >20%, synaptophysin +++, CGA++, MLH1+, MSH2+, MSH6+, PMS2+serotonin, CDDX2 and TTF1 negative. PD-L1+
May - Staging CT and DOTATOC-PET: Hepatic and lymphatic progressive disease (>20% according to RECIST)
June Fifth PRRT 6,941 GBq 177Lu-DOTATOC in combination with capecitabine (540 mg/m2) and temzolomide (150 mg/m2) -
July Hospitalization due to clinical complications (neutropenic fever, transfusion obligatory pancytopenia, right sided necrotizing mastitis, fungal pneumonia) after PRRT in combination with capecitabine/temzolomide Staging CT: Partial remission (55% according to RECIST). No pathological lymph node enlargement. No primary tumor detectable
August Continuation of SSA therapy -
October - MR: Partial remission (68% according to RECIST)
PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analogue therapy; CT, computer tomography; MR, magnetic resonance; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33363730 | 18,672,294 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | A rare case of extensive Staphylococcus aureus sternoclavicular septic arthritis treated without surgical intervention.
This is a rare case of a 55 year-old immunocompetent female who developed Methicillin sensitive Staphylococcus aureus sternoclavicular septic arthritis. The infection was not limited to the joint space but extended into adjacent bones and superior mediastinum. However the patient was successfully treated without surgical intervention and preservation of joint function was obtained with only intravenous antibiotic therapy.
Introduction
The sternoclavicular (SC) joint is a mobile joint with significant movement and rotation abilities [1]. This joint functions similar to sacroiliac and pubic symphysis joints [1]. Septic arthritis of the SC joint is a rare form of septic arthritis occurring in less than 1% of all cases [2]. The most common risk factors are intravenous (IV) drug use, diabetes, immunosuppression and rheumatological diseases but approximately one-fifth of patients do not have any risk factors [2,3]. SC septic arthritis can occur from contiguous spread or hematogenous seeding of the joint. The majority of cases are hematogenous in etiology with Staphylococcus aureus being the most common pathogen [2,3].
Early diagnosis and treatment is required to prevent spread into the mediastinum, great vessels and thoracic cavity [3]. The most common treatment is surgical irrigation and debridement combined with antibiotic therapy [4,5]. More extensive surgical resection of the joint and clavicle head with reconstructive surgery have been advocated for extensive disease [[4], [5], [6]]. This case presents an unusual case of an immunocompetent female who developed extensive methicillin sensitive Staphylococcus aureus (MSSA) SC septic arthritis with extension to the adjacent ribs, clavicle and superior mediastinum. This was successfully treated without surgical intervention but rather with only IV oxacillin therapy and graded physical therapy.
Case
A 55 year-old healthy female with no significant past medical history was in her normal state of health until she started to have pain in her right clavicle. She was evaluated by her primary care physician who prescribed a nonsteroidal anti-inflammatory drug for pain management. However the pain, swelling and erythema intensified. She then presented to her local emergency room where a CT scan of the chest showed SC septic arthritis, osteomyelitis of the clavicle and 2nd rib and a superior mediastinal abscess. The patient was admitted to the local hospital and blood cultures and percutaneous aspiration of the abscess were obtained. She was started on IV vancomycin 1.25 g every 12 h and pipercillin/tazobactam 3.375 g every 6 h. Both blood and aspiration cultures grew MSSA. Antibiotics were subsequently changed to oxacillin 2 g IV every 4 h. After the 3rd dose the patient complained of severe burning in her peripheral vein and oxacillin was changed to cefazolin 2 g IV every 8 h. Unfortunately after 2 days on cefazolin she developed a diffuse rash and cefazolin was changed back to vancomycin 1.25 g IV every 12 h. Repeat blood cultures 2 days after starting intravenous antibiotics did not have any further bacterial growth and transthoracic echocardiogram did not show evidence of endocarditis. A peripheral inserted central catheter (PICC) was inserted and she was discharged home on IV vancomycin 1.25 g every 12 h with plan for 6 weeks of therapy.
For the next 5 days, she continued to have pain, swelling and erythema over her right sternoclavicular joint and therefore presented to the University of Maryland Medical Center for a second opinion. On physical exam, she had limited range of motion of her right upper extremity due to pain. CT scan of the chest with IV contrast showed SC septic arthritis, osteomyelitis of the clavicle head, adjacent ribs and inflammatory changes extending into superior mediastinum with a small superior mediastinal abscess (Fig. 1). Given the growth of MSSA on previous cultures, vancomycin was changed to IV oxacillin 2 g every 4 h through the PICC. Repeat transthoracic echocardiogram did not show evidence of endocarditis. Recommendation for surgical intervention with debridement of SC joint and probable resection of right clavicle head were discussed with the patient. However alternative treatment option was discussed which entailed IV oxacillin therapy and graded physical therapy with close clinical monitoring with plan for surgical intervention if improvement did not occur.Fig. 1 CT chest with axial images. A) Superior mediastinal abscess and developing anterior phlegmon without discrete abscess B) Right clavicular head osteomyelitis and right sternoclavicular septic arthritis joint.
Fig. 1
The patient elected to forgo surgical intervention and attempt salvage therapy with IV oxacillin and graded physical therapy. She tolerated IV oxacillin therapy with no burning and therefore was discharged home on IV oxacillin 2 g every 4 h via an infusion pump. Over the next 6 weeks she was followed in clinic every 2 weeks. Her swelling, erythema and pain slowly improved as well as her range of motion, which increased from 90 degrees to 150 degrees. Serum inflammatory markers (CRP and ESR) decreased over the course of therapy (Fig. 2). After 6 weeks of IV oxacillin therapy, the patient was changed to oral doxycycline 100 mg twice a day for an additional 4 weeks. During these 4 weeks the patient continued her graded physical therapy and she regained full range of motion of her right arm. She had no further swelling, erythema or pain over the SC joint and therefore antibiotics were stopped. She was followed clinically off antibiotics for 3 months and no clinical recurrence was seen. Workup for underlying immunodeficiency (CD4, complement, IgA, IgG, IgM, IgE, myeloperoxidase level, neutrophil function assay and leukocyte adhesion deficiency panel) did not reveal any underlying abnormalities. One year later the patient is back to her normal activities that include swimming and hiking with no limitations.Fig. 2 Trends of ESR and CRP over course of antibiotic therapy. Blue arrow indicates when IV oxacillin was started and Black arrow shows when oral doxycycline therapy was started and was continued until week 11 when all antibiotics were stopped. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 2
Discussion
In this case the patient had no known cause for her MSSA bacteremia. In fact she was a healthy, physically fit 55 year-old female. It is unknown how long she was bacteremic before presenting to the local hospital but after 48 h of intravenous antibiotics her blood cultures showed sterility. The patient was evaluated for underlying immunodeficiency but no deficiency was found. It is well known that risk factors associated with Staphylococcus bacteremia are IV drug use, long term intravenous access devices, immunodeficiency (especially neutrophil dysfunction), diabetes and chronic kidney disease [7]. However, in approximately 25 % of cases a cause of staphylococcus bacteremia is never found [7]. In this case, it is unknown why she developed MSSA bacteremia but the patient’s SC septic arthritis and associated adjacent infection was undoubtedly caused from hematogenous seeding of MSSA to these locations.
Her treatment at the outside hospital was limited given the phlebitis that occurred with IV oxacillin use through a peripheral vein. It is unknown if this patient had mechanical or chemical phlebitis given administration was conducted at a local hospital. Oxacillin can be associated with phlebitis but with larger gauge catheters incidence can be less [8]. At the University of Maryland Medical center, she was challenged with oxacillin through her PICC and this was not associated with phlebitis suggesting that her phlebitis was likely secondary to mechanical inflammation and not chemical phlebitis from oxacillin. This reinforces that phlebitis is not an absolute contraindication to continued use of a medication but rather suggests needing to use alternative mitigation strategies such as diluting medication, slowing the rate of the infusion or using larger gauge catheter to prevent further inflammation of the vein [8]. In this case the local hospital did not try any of those measures, but rather changed her therapy to cefazolin which has similar efficacy to oxacillin in MSSA bacteremia [9]. However cefazolin caused her to have a diffuse rash and therefore the patient was discharged on IV vancomycin which has been shown to potentially be inferior to oxacillin or cefazolin for MSSA bacteremia [10].
Unfortunately, the patient did not improve clinically while on IV vancomycin as seen with continued erythema, pain, swelling and loss of function forcing her to seek a second opinion. Imaging of the chest continued to show extensive SC septic arthritis with extension to adjacent ribs, clavicle head and posteriorly into superior mediastinum (Fig. 1). In this case only diagnostic aspiration of the superior mediastinal abscess was conducted. Given the extensive nature of her infection, surgical intervention was recommended and the need for resection of the clavicle head was discussed. Resection of the clavicle head can be associated with chronic pain and instability if the supporting ligamentous structures are damaged [6]. This patient was an active 55 year old female and she did not want to risk the chance of joint instability and permanent pain. Therefore she elected to attempt to salvage her SC joint with only IV oxacillin therapy and close clinical monitoring every 2 weeks with the plan to undergo surgical intervention if improvements with respect to her range of motion and symptomology did not occur. In SC septic arthritis with limited disease, antimicrobial therapy alone has been shown to be curative in case reports [11]. When extensive disease is present, as seen with extension into mediastinum or clavicular head, surgical intervention is almost universally recommended [[4], [5], [6]].
In this case, this patient had extensive infection beyond the SC joint but antimicrobial therapy alone was able to successfully treat her infection without surgical intervention. This was seen with the resolution of her clinical symptoms, normalization of inflammatory markers (Fig. 2) and the lack of clinical recurrence of her MSSA infection after 1 year of clinical follow up. It is well known that neutrophils play an important role staphylococcal infections [[12], [13], [14]]. Disease states (diabetes, chronic granulomatous disease and others) that inhibit neutrophil function predispose patients to staphylococcal infections (13). The patient in this case did not have an immunodeficiency or underlying medical problem that inhibited her innate immune response from functioning properly. Therefore her innate immune system was able to work in correlation with antibiotic therapy to clear her MSSA infection. However joint damage can occur when inflammatory cytokines, enzymes and bacterial toxins cause erosive damage of bone and cartilage resulting in permanent debility [15]. No such permanent changes occurred in her treatment course but her graded physical therapy regimen potentially allowed her to improve her range of motion and prevent permanent limited mobility. It should be noted that over the course of her therapy slow incremental improvements in range of function occurred. While this encouraged this patient, the lack of more immediate pronounced clinical improvements in range of motion may not be as well received in other patients. Potential prospective studies are warranted to evaluate if intravenous antimicrobial, physical therapy and close clinical follow up may prevent the need for surgical intervention in immunocompetent patients with SC septic arthritis. However given the rarity of this condition, such a study would need to be multicenter with a prolonged accrual period.
In conclusion, this patient was successfully treated for extensive SC joint septic arthritis with only antibiotic therapy. While this is a single case report it does suggest that aggressive intravenous antibiotic therapy in lieu of surgical intervention for SC septic arthritis in immunocompetent patients may be beneficial. Only prospective studies will be able to definitively determine if this approach has efficacy and potential to reduce medical costs, anesthesia risks and reduce potential long term ramifications of surgical interventions.
Funding
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request
Author contribution
Dr. James Doub conducted the study design and writing of the manuscript.
Declaration of Competing Interest
The authors report no declarations of interest. | CEFAZOLIN | DrugsGivenReaction | CC BY-NC-ND | 33364169 | 19,703,399 | 2021 |
What was the administration route of drug 'CEFAZOLIN'? | A rare case of extensive Staphylococcus aureus sternoclavicular septic arthritis treated without surgical intervention.
This is a rare case of a 55 year-old immunocompetent female who developed Methicillin sensitive Staphylococcus aureus sternoclavicular septic arthritis. The infection was not limited to the joint space but extended into adjacent bones and superior mediastinum. However the patient was successfully treated without surgical intervention and preservation of joint function was obtained with only intravenous antibiotic therapy.
Introduction
The sternoclavicular (SC) joint is a mobile joint with significant movement and rotation abilities [1]. This joint functions similar to sacroiliac and pubic symphysis joints [1]. Septic arthritis of the SC joint is a rare form of septic arthritis occurring in less than 1% of all cases [2]. The most common risk factors are intravenous (IV) drug use, diabetes, immunosuppression and rheumatological diseases but approximately one-fifth of patients do not have any risk factors [2,3]. SC septic arthritis can occur from contiguous spread or hematogenous seeding of the joint. The majority of cases are hematogenous in etiology with Staphylococcus aureus being the most common pathogen [2,3].
Early diagnosis and treatment is required to prevent spread into the mediastinum, great vessels and thoracic cavity [3]. The most common treatment is surgical irrigation and debridement combined with antibiotic therapy [4,5]. More extensive surgical resection of the joint and clavicle head with reconstructive surgery have been advocated for extensive disease [[4], [5], [6]]. This case presents an unusual case of an immunocompetent female who developed extensive methicillin sensitive Staphylococcus aureus (MSSA) SC septic arthritis with extension to the adjacent ribs, clavicle and superior mediastinum. This was successfully treated without surgical intervention but rather with only IV oxacillin therapy and graded physical therapy.
Case
A 55 year-old healthy female with no significant past medical history was in her normal state of health until she started to have pain in her right clavicle. She was evaluated by her primary care physician who prescribed a nonsteroidal anti-inflammatory drug for pain management. However the pain, swelling and erythema intensified. She then presented to her local emergency room where a CT scan of the chest showed SC septic arthritis, osteomyelitis of the clavicle and 2nd rib and a superior mediastinal abscess. The patient was admitted to the local hospital and blood cultures and percutaneous aspiration of the abscess were obtained. She was started on IV vancomycin 1.25 g every 12 h and pipercillin/tazobactam 3.375 g every 6 h. Both blood and aspiration cultures grew MSSA. Antibiotics were subsequently changed to oxacillin 2 g IV every 4 h. After the 3rd dose the patient complained of severe burning in her peripheral vein and oxacillin was changed to cefazolin 2 g IV every 8 h. Unfortunately after 2 days on cefazolin she developed a diffuse rash and cefazolin was changed back to vancomycin 1.25 g IV every 12 h. Repeat blood cultures 2 days after starting intravenous antibiotics did not have any further bacterial growth and transthoracic echocardiogram did not show evidence of endocarditis. A peripheral inserted central catheter (PICC) was inserted and she was discharged home on IV vancomycin 1.25 g every 12 h with plan for 6 weeks of therapy.
For the next 5 days, she continued to have pain, swelling and erythema over her right sternoclavicular joint and therefore presented to the University of Maryland Medical Center for a second opinion. On physical exam, she had limited range of motion of her right upper extremity due to pain. CT scan of the chest with IV contrast showed SC septic arthritis, osteomyelitis of the clavicle head, adjacent ribs and inflammatory changes extending into superior mediastinum with a small superior mediastinal abscess (Fig. 1). Given the growth of MSSA on previous cultures, vancomycin was changed to IV oxacillin 2 g every 4 h through the PICC. Repeat transthoracic echocardiogram did not show evidence of endocarditis. Recommendation for surgical intervention with debridement of SC joint and probable resection of right clavicle head were discussed with the patient. However alternative treatment option was discussed which entailed IV oxacillin therapy and graded physical therapy with close clinical monitoring with plan for surgical intervention if improvement did not occur.Fig. 1 CT chest with axial images. A) Superior mediastinal abscess and developing anterior phlegmon without discrete abscess B) Right clavicular head osteomyelitis and right sternoclavicular septic arthritis joint.
Fig. 1
The patient elected to forgo surgical intervention and attempt salvage therapy with IV oxacillin and graded physical therapy. She tolerated IV oxacillin therapy with no burning and therefore was discharged home on IV oxacillin 2 g every 4 h via an infusion pump. Over the next 6 weeks she was followed in clinic every 2 weeks. Her swelling, erythema and pain slowly improved as well as her range of motion, which increased from 90 degrees to 150 degrees. Serum inflammatory markers (CRP and ESR) decreased over the course of therapy (Fig. 2). After 6 weeks of IV oxacillin therapy, the patient was changed to oral doxycycline 100 mg twice a day for an additional 4 weeks. During these 4 weeks the patient continued her graded physical therapy and she regained full range of motion of her right arm. She had no further swelling, erythema or pain over the SC joint and therefore antibiotics were stopped. She was followed clinically off antibiotics for 3 months and no clinical recurrence was seen. Workup for underlying immunodeficiency (CD4, complement, IgA, IgG, IgM, IgE, myeloperoxidase level, neutrophil function assay and leukocyte adhesion deficiency panel) did not reveal any underlying abnormalities. One year later the patient is back to her normal activities that include swimming and hiking with no limitations.Fig. 2 Trends of ESR and CRP over course of antibiotic therapy. Blue arrow indicates when IV oxacillin was started and Black arrow shows when oral doxycycline therapy was started and was continued until week 11 when all antibiotics were stopped. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 2
Discussion
In this case the patient had no known cause for her MSSA bacteremia. In fact she was a healthy, physically fit 55 year-old female. It is unknown how long she was bacteremic before presenting to the local hospital but after 48 h of intravenous antibiotics her blood cultures showed sterility. The patient was evaluated for underlying immunodeficiency but no deficiency was found. It is well known that risk factors associated with Staphylococcus bacteremia are IV drug use, long term intravenous access devices, immunodeficiency (especially neutrophil dysfunction), diabetes and chronic kidney disease [7]. However, in approximately 25 % of cases a cause of staphylococcus bacteremia is never found [7]. In this case, it is unknown why she developed MSSA bacteremia but the patient’s SC septic arthritis and associated adjacent infection was undoubtedly caused from hematogenous seeding of MSSA to these locations.
Her treatment at the outside hospital was limited given the phlebitis that occurred with IV oxacillin use through a peripheral vein. It is unknown if this patient had mechanical or chemical phlebitis given administration was conducted at a local hospital. Oxacillin can be associated with phlebitis but with larger gauge catheters incidence can be less [8]. At the University of Maryland Medical center, she was challenged with oxacillin through her PICC and this was not associated with phlebitis suggesting that her phlebitis was likely secondary to mechanical inflammation and not chemical phlebitis from oxacillin. This reinforces that phlebitis is not an absolute contraindication to continued use of a medication but rather suggests needing to use alternative mitigation strategies such as diluting medication, slowing the rate of the infusion or using larger gauge catheter to prevent further inflammation of the vein [8]. In this case the local hospital did not try any of those measures, but rather changed her therapy to cefazolin which has similar efficacy to oxacillin in MSSA bacteremia [9]. However cefazolin caused her to have a diffuse rash and therefore the patient was discharged on IV vancomycin which has been shown to potentially be inferior to oxacillin or cefazolin for MSSA bacteremia [10].
Unfortunately, the patient did not improve clinically while on IV vancomycin as seen with continued erythema, pain, swelling and loss of function forcing her to seek a second opinion. Imaging of the chest continued to show extensive SC septic arthritis with extension to adjacent ribs, clavicle head and posteriorly into superior mediastinum (Fig. 1). In this case only diagnostic aspiration of the superior mediastinal abscess was conducted. Given the extensive nature of her infection, surgical intervention was recommended and the need for resection of the clavicle head was discussed. Resection of the clavicle head can be associated with chronic pain and instability if the supporting ligamentous structures are damaged [6]. This patient was an active 55 year old female and she did not want to risk the chance of joint instability and permanent pain. Therefore she elected to attempt to salvage her SC joint with only IV oxacillin therapy and close clinical monitoring every 2 weeks with the plan to undergo surgical intervention if improvements with respect to her range of motion and symptomology did not occur. In SC septic arthritis with limited disease, antimicrobial therapy alone has been shown to be curative in case reports [11]. When extensive disease is present, as seen with extension into mediastinum or clavicular head, surgical intervention is almost universally recommended [[4], [5], [6]].
In this case, this patient had extensive infection beyond the SC joint but antimicrobial therapy alone was able to successfully treat her infection without surgical intervention. This was seen with the resolution of her clinical symptoms, normalization of inflammatory markers (Fig. 2) and the lack of clinical recurrence of her MSSA infection after 1 year of clinical follow up. It is well known that neutrophils play an important role staphylococcal infections [[12], [13], [14]]. Disease states (diabetes, chronic granulomatous disease and others) that inhibit neutrophil function predispose patients to staphylococcal infections (13). The patient in this case did not have an immunodeficiency or underlying medical problem that inhibited her innate immune response from functioning properly. Therefore her innate immune system was able to work in correlation with antibiotic therapy to clear her MSSA infection. However joint damage can occur when inflammatory cytokines, enzymes and bacterial toxins cause erosive damage of bone and cartilage resulting in permanent debility [15]. No such permanent changes occurred in her treatment course but her graded physical therapy regimen potentially allowed her to improve her range of motion and prevent permanent limited mobility. It should be noted that over the course of her therapy slow incremental improvements in range of function occurred. While this encouraged this patient, the lack of more immediate pronounced clinical improvements in range of motion may not be as well received in other patients. Potential prospective studies are warranted to evaluate if intravenous antimicrobial, physical therapy and close clinical follow up may prevent the need for surgical intervention in immunocompetent patients with SC septic arthritis. However given the rarity of this condition, such a study would need to be multicenter with a prolonged accrual period.
In conclusion, this patient was successfully treated for extensive SC joint septic arthritis with only antibiotic therapy. While this is a single case report it does suggest that aggressive intravenous antibiotic therapy in lieu of surgical intervention for SC septic arthritis in immunocompetent patients may be beneficial. Only prospective studies will be able to definitively determine if this approach has efficacy and potential to reduce medical costs, anesthesia risks and reduce potential long term ramifications of surgical interventions.
Funding
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request
Author contribution
Dr. James Doub conducted the study design and writing of the manuscript.
Declaration of Competing Interest
The authors report no declarations of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33364169 | 19,703,399 | 2021 |
What was the dosage of drug 'CEFAZOLIN'? | A rare case of extensive Staphylococcus aureus sternoclavicular septic arthritis treated without surgical intervention.
This is a rare case of a 55 year-old immunocompetent female who developed Methicillin sensitive Staphylococcus aureus sternoclavicular septic arthritis. The infection was not limited to the joint space but extended into adjacent bones and superior mediastinum. However the patient was successfully treated without surgical intervention and preservation of joint function was obtained with only intravenous antibiotic therapy.
Introduction
The sternoclavicular (SC) joint is a mobile joint with significant movement and rotation abilities [1]. This joint functions similar to sacroiliac and pubic symphysis joints [1]. Septic arthritis of the SC joint is a rare form of septic arthritis occurring in less than 1% of all cases [2]. The most common risk factors are intravenous (IV) drug use, diabetes, immunosuppression and rheumatological diseases but approximately one-fifth of patients do not have any risk factors [2,3]. SC septic arthritis can occur from contiguous spread or hematogenous seeding of the joint. The majority of cases are hematogenous in etiology with Staphylococcus aureus being the most common pathogen [2,3].
Early diagnosis and treatment is required to prevent spread into the mediastinum, great vessels and thoracic cavity [3]. The most common treatment is surgical irrigation and debridement combined with antibiotic therapy [4,5]. More extensive surgical resection of the joint and clavicle head with reconstructive surgery have been advocated for extensive disease [[4], [5], [6]]. This case presents an unusual case of an immunocompetent female who developed extensive methicillin sensitive Staphylococcus aureus (MSSA) SC septic arthritis with extension to the adjacent ribs, clavicle and superior mediastinum. This was successfully treated without surgical intervention but rather with only IV oxacillin therapy and graded physical therapy.
Case
A 55 year-old healthy female with no significant past medical history was in her normal state of health until she started to have pain in her right clavicle. She was evaluated by her primary care physician who prescribed a nonsteroidal anti-inflammatory drug for pain management. However the pain, swelling and erythema intensified. She then presented to her local emergency room where a CT scan of the chest showed SC septic arthritis, osteomyelitis of the clavicle and 2nd rib and a superior mediastinal abscess. The patient was admitted to the local hospital and blood cultures and percutaneous aspiration of the abscess were obtained. She was started on IV vancomycin 1.25 g every 12 h and pipercillin/tazobactam 3.375 g every 6 h. Both blood and aspiration cultures grew MSSA. Antibiotics were subsequently changed to oxacillin 2 g IV every 4 h. After the 3rd dose the patient complained of severe burning in her peripheral vein and oxacillin was changed to cefazolin 2 g IV every 8 h. Unfortunately after 2 days on cefazolin she developed a diffuse rash and cefazolin was changed back to vancomycin 1.25 g IV every 12 h. Repeat blood cultures 2 days after starting intravenous antibiotics did not have any further bacterial growth and transthoracic echocardiogram did not show evidence of endocarditis. A peripheral inserted central catheter (PICC) was inserted and she was discharged home on IV vancomycin 1.25 g every 12 h with plan for 6 weeks of therapy.
For the next 5 days, she continued to have pain, swelling and erythema over her right sternoclavicular joint and therefore presented to the University of Maryland Medical Center for a second opinion. On physical exam, she had limited range of motion of her right upper extremity due to pain. CT scan of the chest with IV contrast showed SC septic arthritis, osteomyelitis of the clavicle head, adjacent ribs and inflammatory changes extending into superior mediastinum with a small superior mediastinal abscess (Fig. 1). Given the growth of MSSA on previous cultures, vancomycin was changed to IV oxacillin 2 g every 4 h through the PICC. Repeat transthoracic echocardiogram did not show evidence of endocarditis. Recommendation for surgical intervention with debridement of SC joint and probable resection of right clavicle head were discussed with the patient. However alternative treatment option was discussed which entailed IV oxacillin therapy and graded physical therapy with close clinical monitoring with plan for surgical intervention if improvement did not occur.Fig. 1 CT chest with axial images. A) Superior mediastinal abscess and developing anterior phlegmon without discrete abscess B) Right clavicular head osteomyelitis and right sternoclavicular septic arthritis joint.
Fig. 1
The patient elected to forgo surgical intervention and attempt salvage therapy with IV oxacillin and graded physical therapy. She tolerated IV oxacillin therapy with no burning and therefore was discharged home on IV oxacillin 2 g every 4 h via an infusion pump. Over the next 6 weeks she was followed in clinic every 2 weeks. Her swelling, erythema and pain slowly improved as well as her range of motion, which increased from 90 degrees to 150 degrees. Serum inflammatory markers (CRP and ESR) decreased over the course of therapy (Fig. 2). After 6 weeks of IV oxacillin therapy, the patient was changed to oral doxycycline 100 mg twice a day for an additional 4 weeks. During these 4 weeks the patient continued her graded physical therapy and she regained full range of motion of her right arm. She had no further swelling, erythema or pain over the SC joint and therefore antibiotics were stopped. She was followed clinically off antibiotics for 3 months and no clinical recurrence was seen. Workup for underlying immunodeficiency (CD4, complement, IgA, IgG, IgM, IgE, myeloperoxidase level, neutrophil function assay and leukocyte adhesion deficiency panel) did not reveal any underlying abnormalities. One year later the patient is back to her normal activities that include swimming and hiking with no limitations.Fig. 2 Trends of ESR and CRP over course of antibiotic therapy. Blue arrow indicates when IV oxacillin was started and Black arrow shows when oral doxycycline therapy was started and was continued until week 11 when all antibiotics were stopped. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 2
Discussion
In this case the patient had no known cause for her MSSA bacteremia. In fact she was a healthy, physically fit 55 year-old female. It is unknown how long she was bacteremic before presenting to the local hospital but after 48 h of intravenous antibiotics her blood cultures showed sterility. The patient was evaluated for underlying immunodeficiency but no deficiency was found. It is well known that risk factors associated with Staphylococcus bacteremia are IV drug use, long term intravenous access devices, immunodeficiency (especially neutrophil dysfunction), diabetes and chronic kidney disease [7]. However, in approximately 25 % of cases a cause of staphylococcus bacteremia is never found [7]. In this case, it is unknown why she developed MSSA bacteremia but the patient’s SC septic arthritis and associated adjacent infection was undoubtedly caused from hematogenous seeding of MSSA to these locations.
Her treatment at the outside hospital was limited given the phlebitis that occurred with IV oxacillin use through a peripheral vein. It is unknown if this patient had mechanical or chemical phlebitis given administration was conducted at a local hospital. Oxacillin can be associated with phlebitis but with larger gauge catheters incidence can be less [8]. At the University of Maryland Medical center, she was challenged with oxacillin through her PICC and this was not associated with phlebitis suggesting that her phlebitis was likely secondary to mechanical inflammation and not chemical phlebitis from oxacillin. This reinforces that phlebitis is not an absolute contraindication to continued use of a medication but rather suggests needing to use alternative mitigation strategies such as diluting medication, slowing the rate of the infusion or using larger gauge catheter to prevent further inflammation of the vein [8]. In this case the local hospital did not try any of those measures, but rather changed her therapy to cefazolin which has similar efficacy to oxacillin in MSSA bacteremia [9]. However cefazolin caused her to have a diffuse rash and therefore the patient was discharged on IV vancomycin which has been shown to potentially be inferior to oxacillin or cefazolin for MSSA bacteremia [10].
Unfortunately, the patient did not improve clinically while on IV vancomycin as seen with continued erythema, pain, swelling and loss of function forcing her to seek a second opinion. Imaging of the chest continued to show extensive SC septic arthritis with extension to adjacent ribs, clavicle head and posteriorly into superior mediastinum (Fig. 1). In this case only diagnostic aspiration of the superior mediastinal abscess was conducted. Given the extensive nature of her infection, surgical intervention was recommended and the need for resection of the clavicle head was discussed. Resection of the clavicle head can be associated with chronic pain and instability if the supporting ligamentous structures are damaged [6]. This patient was an active 55 year old female and she did not want to risk the chance of joint instability and permanent pain. Therefore she elected to attempt to salvage her SC joint with only IV oxacillin therapy and close clinical monitoring every 2 weeks with the plan to undergo surgical intervention if improvements with respect to her range of motion and symptomology did not occur. In SC septic arthritis with limited disease, antimicrobial therapy alone has been shown to be curative in case reports [11]. When extensive disease is present, as seen with extension into mediastinum or clavicular head, surgical intervention is almost universally recommended [[4], [5], [6]].
In this case, this patient had extensive infection beyond the SC joint but antimicrobial therapy alone was able to successfully treat her infection without surgical intervention. This was seen with the resolution of her clinical symptoms, normalization of inflammatory markers (Fig. 2) and the lack of clinical recurrence of her MSSA infection after 1 year of clinical follow up. It is well known that neutrophils play an important role staphylococcal infections [[12], [13], [14]]. Disease states (diabetes, chronic granulomatous disease and others) that inhibit neutrophil function predispose patients to staphylococcal infections (13). The patient in this case did not have an immunodeficiency or underlying medical problem that inhibited her innate immune response from functioning properly. Therefore her innate immune system was able to work in correlation with antibiotic therapy to clear her MSSA infection. However joint damage can occur when inflammatory cytokines, enzymes and bacterial toxins cause erosive damage of bone and cartilage resulting in permanent debility [15]. No such permanent changes occurred in her treatment course but her graded physical therapy regimen potentially allowed her to improve her range of motion and prevent permanent limited mobility. It should be noted that over the course of her therapy slow incremental improvements in range of function occurred. While this encouraged this patient, the lack of more immediate pronounced clinical improvements in range of motion may not be as well received in other patients. Potential prospective studies are warranted to evaluate if intravenous antimicrobial, physical therapy and close clinical follow up may prevent the need for surgical intervention in immunocompetent patients with SC septic arthritis. However given the rarity of this condition, such a study would need to be multicenter with a prolonged accrual period.
In conclusion, this patient was successfully treated for extensive SC joint septic arthritis with only antibiotic therapy. While this is a single case report it does suggest that aggressive intravenous antibiotic therapy in lieu of surgical intervention for SC septic arthritis in immunocompetent patients may be beneficial. Only prospective studies will be able to definitively determine if this approach has efficacy and potential to reduce medical costs, anesthesia risks and reduce potential long term ramifications of surgical interventions.
Funding
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request
Author contribution
Dr. James Doub conducted the study design and writing of the manuscript.
Declaration of Competing Interest
The authors report no declarations of interest. | 2 g (grams). | DrugDosage | CC BY-NC-ND | 33364169 | 19,703,399 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse drug reaction'. | Ovarian teratoma with pituitary tissue: A case report.
Ovarian cysts and specifically ovarian teratomas are a common finding in young patients. These cysts display histological cell types from all three cells lines: endodermal, ectodermal and mesodermal origins. A 22-year-old woman who displayed classic signs of cortisol excess - excessive weight gain, difficultly losing weight and abdominal striae - was found to have a 10 cm mature teratoma cyst. This patient presented with ovarian torsion, a common complication of ovarian cysts, and was treated surgically. Pathology was significant for an ovarian teratoma with pituitary secreting cells, most significantly cells secreting adrenocorticotropic hormone (ACTH).
1 Introduction
This is a unique case of an ovarian dermoid with mature pituitary tissue, which was positive for cells secreting growth hormone, prolactin and adrenocorticotropic hormone (ACTH), a rare pathological finding. Dermoid cysts, also known as benign cystic mature teratomas, are the most common ovarian tumor in women in the second and third decades of life. These cysts contain mature tissue of ectodermal, mesodermal, and endodermal origin; therefore, they are highly variable in form and histology [1]. Ovarian dermoid cysts most commonly exhibit several different types of tissue, such as bone, muscle and skin. It is rare to find more complex tissues within an ovarian dermoid such as brain, spinal cord, or eye tissue.
The pituitary glands' cell line precursor is the ectoderm, and it is able to secrete a variety of hormones that in turn may exert an effect on many other endocrine glands [2]. The pituitary gland is responsible for secreting endocrine hormones such as ACTH, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, thyroid stimulating hormone (TSH), Melanocyte-stimulating hormone (MSH) and growth hormone. Given that dermoid cysts can continue ectodermal tissue, it is possible that a dermoid cyst could contain pituitary tissue, but it is so rare that there is no current data available to give a rate of occurrence.
Often ovarian dermoid cysts are discovered when patients begin to exhibit pelvic or abdominal pain, bloat or constipation or present acutely with ovarian torsion [3]. Ovarian torsion occurs when the weight of an adnexal mass causes the ovary and fallopian tube to twist around the infundibulopelvic ligament, causing restriction of its blood supply. Patients often present with acute onset of unremitting unilateral pelvic pain, nausea, vomiting and an adnexal mass [4].
2 Case Presentation
A 22-year-old woman presented to the emergency room with worsening lower left pelvic pain, nausea, vomiting and vaginal bleeding.
Her medical history was significant for a rapid weight gain the year prior, which prompted outpatient evaluation by an endocrinologist. She was reporting regular menses and sleep habits and denied hirsutism, acne or hair loss. Preliminary endocrine labs were reported as follows: HgbA1 4.8% [normal <5.7%], testosterone 29.9 [15–70 ng/dL], LH 8.1 [5–25 IU/L], FSH 4.1 [4.7–21.5 mIU/mL], TSH 2.41 [0.5–5.0 mIU/L], CMP normal, lipid panel normal. The patient attempted a trial of off-label metformin for weight loss with increasing exercise regimen; however, this was self-discontinued due to side-effects. Surgical and family history were noncontributory.
The patient attempted multiple therapies to lose weight, including injections of semaglutide, a GLP-1 receptor agonist, to aid an increase in insulin secretion. Endocrine visits were significant for abdominal striae; however, the patient was not tested for Cushing's syndrome as she did not display other symptoms, such as hirsutism, acne, buffalo hump, muscle wasting, heat intolerance or hypertension.
2.1 Diagnostic Assessment
On examination in the emergency room, the patient was found to be mildly tender over her left lower quadrant; however, no masses were appreciated secondary to body habitus. Transvaginal ultrasound and CT scan demonstrated a 10.6 cm multi-septated left adnexal mass, containing fat, fluid, and calcifications, consistent with suspected dermoid cyst.
During the course of her emergency room visit, her pain improved and as ultrasound revealed arterial and venous blood flow to both ovaries, a decision was made for outpatient follow-up that week with a surgeon.
Shortly after her visit to the emergency room, the patient was seen in the outpatient clinic and scheduled for laparoscopic ovarian cystectomy. Upon laparoscopic entry, the left ovary was found to be torsed two times around its vascular pedicle with a large dermoid cyst. The dermoid was removed laparoscopically and residual ovarian parenchyma was repaired.
2.2 Follow-up and Outcome
The final pathology was a mature cystic teratoma (dermoid cyst) with a small focus of mature pituitary tissue. Per pathology review, identification of pituitary tissue was supported by a positive pancytokeratin, CAM 5.2, S100, and synaptophysin [seen in Fig. 1, Fig. 2]. Stains for tropic hormones were positive for growth hormone, prolactin and ACTH [seen in Fig. 3].Fig. 1 Low-power view (4×), H&E: Showing well circumscribed nodule consisting of oncocytic cells.
Fig. 1Fig. 2 Low-power view (4×): Positive staining for S-100 immunohistochemistry.
Fig. 2Fig. 3 Low-power view (100×) showing ACTH positive staining tumor cells (in brown). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
The patient was seen one month after her surgery, when was she was doing well and was noted to have modest weight loss since her operation. The patient was advised to have a repeat sonogram in 6 months, to check for a possible redevelopment of a teratoma. The patient has not been back to see her endocrinologist to date.
3 Discussion
Ovarian torsion affects women of all ages and is considered one of the more common gynecologic emergencies. This diagnosis encompasses either complete or partial rotation of the adnexa, which results in changes in the blood supply of the ovary, causing ischemia [3]. Risk factors include ovarian cysts, ovarian tumors, and fertility treatment [7]. Ovarian torsion has been reported to occur with masses ranging from 1 to 30 cm (mean 9.5 cm) in size, and often presents with acute lower abdominal or pelvic pain along with nausea and vomiting [5]. Treatment often includes laparoscopy to untwist the ovary or the adnexa and restore blood flow with a possible cystectomy to prevent torsion from recurring.
Mature ovarian teratomas are one of the most common benign ovarian neoplasms and include differentiated germ cell layers (ectoderm, mesoderm, endoderm) and often are identified at the time of surgery after a patient presents with an ovarian torsion [6]. This is a case of ovarian torsion secondary to an ovarian mature teratoma that was later found to mature pituitary tissue with ACTH-secreting cells. ACTH normally is secreted by the pituitary gland, but has been found to be secreted from ectopic sources [8]. ACTH stimulates the adrenal gland to produce cortisol [2]. If ACTH is secreted in excess it can cause an increase in cortisol secretion, which can be associated with the symptoms this patient was experiencing, including acute weight gain and abdominal striae [2].
A limitation of this case report is that there was no laboratory confirmation of systemic ACTH or cortisol excess; rather, this patient's diagnosis was from clinical exam findings alone. When managing endocrine disorders, it is of value to remember that benign and malignant tumors can secrete ectopic hormones that can impact the entire hormonal axis. This case report adds value to clinical practice because this patient's symptoms were secondary to a very rare presentation of ectopic ACTH secretion.
Contributors
Sarah Werner drafted the article.
Cristina Zottola contributed to revision of the article.
Jordan Steinberg contributed the pathology slides.
Barry Pearson contributed the pathology review.
Adi Katz was the surgeon involved in the case and contributed to revision of the article.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Written informed consent for publication of her details was obtained from the patient prior to the writing of this case report.
Provenance and Peer Review
This case report was peer reviewed. | METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33364180 | 20,870,128 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Ovarian teratoma with pituitary tissue: A case report.
Ovarian cysts and specifically ovarian teratomas are a common finding in young patients. These cysts display histological cell types from all three cells lines: endodermal, ectodermal and mesodermal origins. A 22-year-old woman who displayed classic signs of cortisol excess - excessive weight gain, difficultly losing weight and abdominal striae - was found to have a 10 cm mature teratoma cyst. This patient presented with ovarian torsion, a common complication of ovarian cysts, and was treated surgically. Pathology was significant for an ovarian teratoma with pituitary secreting cells, most significantly cells secreting adrenocorticotropic hormone (ACTH).
1 Introduction
This is a unique case of an ovarian dermoid with mature pituitary tissue, which was positive for cells secreting growth hormone, prolactin and adrenocorticotropic hormone (ACTH), a rare pathological finding. Dermoid cysts, also known as benign cystic mature teratomas, are the most common ovarian tumor in women in the second and third decades of life. These cysts contain mature tissue of ectodermal, mesodermal, and endodermal origin; therefore, they are highly variable in form and histology [1]. Ovarian dermoid cysts most commonly exhibit several different types of tissue, such as bone, muscle and skin. It is rare to find more complex tissues within an ovarian dermoid such as brain, spinal cord, or eye tissue.
The pituitary glands' cell line precursor is the ectoderm, and it is able to secrete a variety of hormones that in turn may exert an effect on many other endocrine glands [2]. The pituitary gland is responsible for secreting endocrine hormones such as ACTH, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, thyroid stimulating hormone (TSH), Melanocyte-stimulating hormone (MSH) and growth hormone. Given that dermoid cysts can continue ectodermal tissue, it is possible that a dermoid cyst could contain pituitary tissue, but it is so rare that there is no current data available to give a rate of occurrence.
Often ovarian dermoid cysts are discovered when patients begin to exhibit pelvic or abdominal pain, bloat or constipation or present acutely with ovarian torsion [3]. Ovarian torsion occurs when the weight of an adnexal mass causes the ovary and fallopian tube to twist around the infundibulopelvic ligament, causing restriction of its blood supply. Patients often present with acute onset of unremitting unilateral pelvic pain, nausea, vomiting and an adnexal mass [4].
2 Case Presentation
A 22-year-old woman presented to the emergency room with worsening lower left pelvic pain, nausea, vomiting and vaginal bleeding.
Her medical history was significant for a rapid weight gain the year prior, which prompted outpatient evaluation by an endocrinologist. She was reporting regular menses and sleep habits and denied hirsutism, acne or hair loss. Preliminary endocrine labs were reported as follows: HgbA1 4.8% [normal <5.7%], testosterone 29.9 [15–70 ng/dL], LH 8.1 [5–25 IU/L], FSH 4.1 [4.7–21.5 mIU/mL], TSH 2.41 [0.5–5.0 mIU/L], CMP normal, lipid panel normal. The patient attempted a trial of off-label metformin for weight loss with increasing exercise regimen; however, this was self-discontinued due to side-effects. Surgical and family history were noncontributory.
The patient attempted multiple therapies to lose weight, including injections of semaglutide, a GLP-1 receptor agonist, to aid an increase in insulin secretion. Endocrine visits were significant for abdominal striae; however, the patient was not tested for Cushing's syndrome as she did not display other symptoms, such as hirsutism, acne, buffalo hump, muscle wasting, heat intolerance or hypertension.
2.1 Diagnostic Assessment
On examination in the emergency room, the patient was found to be mildly tender over her left lower quadrant; however, no masses were appreciated secondary to body habitus. Transvaginal ultrasound and CT scan demonstrated a 10.6 cm multi-septated left adnexal mass, containing fat, fluid, and calcifications, consistent with suspected dermoid cyst.
During the course of her emergency room visit, her pain improved and as ultrasound revealed arterial and venous blood flow to both ovaries, a decision was made for outpatient follow-up that week with a surgeon.
Shortly after her visit to the emergency room, the patient was seen in the outpatient clinic and scheduled for laparoscopic ovarian cystectomy. Upon laparoscopic entry, the left ovary was found to be torsed two times around its vascular pedicle with a large dermoid cyst. The dermoid was removed laparoscopically and residual ovarian parenchyma was repaired.
2.2 Follow-up and Outcome
The final pathology was a mature cystic teratoma (dermoid cyst) with a small focus of mature pituitary tissue. Per pathology review, identification of pituitary tissue was supported by a positive pancytokeratin, CAM 5.2, S100, and synaptophysin [seen in Fig. 1, Fig. 2]. Stains for tropic hormones were positive for growth hormone, prolactin and ACTH [seen in Fig. 3].Fig. 1 Low-power view (4×), H&E: Showing well circumscribed nodule consisting of oncocytic cells.
Fig. 1Fig. 2 Low-power view (4×): Positive staining for S-100 immunohistochemistry.
Fig. 2Fig. 3 Low-power view (100×) showing ACTH positive staining tumor cells (in brown). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
The patient was seen one month after her surgery, when was she was doing well and was noted to have modest weight loss since her operation. The patient was advised to have a repeat sonogram in 6 months, to check for a possible redevelopment of a teratoma. The patient has not been back to see her endocrinologist to date.
3 Discussion
Ovarian torsion affects women of all ages and is considered one of the more common gynecologic emergencies. This diagnosis encompasses either complete or partial rotation of the adnexa, which results in changes in the blood supply of the ovary, causing ischemia [3]. Risk factors include ovarian cysts, ovarian tumors, and fertility treatment [7]. Ovarian torsion has been reported to occur with masses ranging from 1 to 30 cm (mean 9.5 cm) in size, and often presents with acute lower abdominal or pelvic pain along with nausea and vomiting [5]. Treatment often includes laparoscopy to untwist the ovary or the adnexa and restore blood flow with a possible cystectomy to prevent torsion from recurring.
Mature ovarian teratomas are one of the most common benign ovarian neoplasms and include differentiated germ cell layers (ectoderm, mesoderm, endoderm) and often are identified at the time of surgery after a patient presents with an ovarian torsion [6]. This is a case of ovarian torsion secondary to an ovarian mature teratoma that was later found to mature pituitary tissue with ACTH-secreting cells. ACTH normally is secreted by the pituitary gland, but has been found to be secreted from ectopic sources [8]. ACTH stimulates the adrenal gland to produce cortisol [2]. If ACTH is secreted in excess it can cause an increase in cortisol secretion, which can be associated with the symptoms this patient was experiencing, including acute weight gain and abdominal striae [2].
A limitation of this case report is that there was no laboratory confirmation of systemic ACTH or cortisol excess; rather, this patient's diagnosis was from clinical exam findings alone. When managing endocrine disorders, it is of value to remember that benign and malignant tumors can secrete ectopic hormones that can impact the entire hormonal axis. This case report adds value to clinical practice because this patient's symptoms were secondary to a very rare presentation of ectopic ACTH secretion.
Contributors
Sarah Werner drafted the article.
Cristina Zottola contributed to revision of the article.
Jordan Steinberg contributed the pathology slides.
Barry Pearson contributed the pathology review.
Adi Katz was the surgeon involved in the case and contributed to revision of the article.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding from an external source supported the publication of this case report.
Patient Consent
Written informed consent for publication of her details was obtained from the patient prior to the writing of this case report.
Provenance and Peer Review
This case report was peer reviewed. | METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33364180 | 20,870,128 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood parathyroid hormone decreased'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Clavicle fracture'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Femur fracture'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fibula fracture'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foot fracture'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Humerus fracture'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypercalcaemia'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypercalciuria'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephrocalcinosis'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rebound effect'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tibia fracture'. | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | DENOSUMAB, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the administration route of drug 'DENOSUMAB'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Subcutaneous | DrugAdministrationRoute | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the outcome of reaction 'Clavicle fracture'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the outcome of reaction 'Femur fracture'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the outcome of reaction 'Fibula fracture'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the outcome of reaction 'Foot fracture'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the outcome of reaction 'Humerus fracture'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the outcome of reaction 'Hypercalcaemia'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
What was the outcome of reaction 'Tibia fracture'? | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes.
This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation.
She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures.
This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.
1 Introduction
Autosomal recessive osteopetrosis (ARO) is rare (1:250,000), usually presents in infancy, requiring prompt diagnosis to facilitate early haematopoietic stem cell transplantation (HSCT) where appropriate (Wu et al., 2017). Hypercalcaemia can emerge once HSCT for ARO restores osteoclast activity (Martinez et al., 2010). Whilst hypercalcaemia may occur in various types of ARO, it is especially the case in the osteoclast-poor forms and can be particularly severe in the OP-ARO subtype due to mutations in the Tumour Necrosis Factor Receptor Superfamily 11A (TNFRSF11A) gene, which encodes the protein Receptor Activator of NF-kB (RANK) (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019).
Rapid onset severe hypercalcaemia is a medical emergency: patients can be unwell, thirsty, dehydrated and have abdominal pain; complications include pre-renal renal failure, nephrocalcinosis and long-term renal impairment (Martinez et al., 2010). So, vigilance in calcium monitoring and appropriate management of hypercalcaemia is required.
The monoclonal antibody denosumab mimics osteoprotegerin action by blocking RANK ligand (RANKL) binding to RANK receptor, thus inhibiting osteoclast differentiation, activity, and bone resorption. The mean half-life of denosumab from adult data is 29 days (range 25–35 days). In vivo development of antibodies against denosumab that might influence efficacy has not been described. Functional inhibition of bone turnover rapidly reverses after drug discontinuation, in contrast to bisphosphonates which persist in bone (Boyce, 2017). Other case reports of denosumab use in children with refractory post-HSCT-hypercalcaemia with short to medium term follow-up (Shroff et al., 2012; Pangrazio et al., 2012; Paul et al., 2019) suggest hypercalcaemia may resolve by 9–12 months allowing denosumab discontinuation. We report an extremely unusual and challenging OP-ARO case with longer duration (2.5 years post-HSCT) of problematic hypercalcaemia despite 18 months of denosumab, then 12 months of adjuvant zoledronic acid. This case contributes new information on denosumab dose and frequency in a <10 kg patient. It demonstrates that rebound hypercalcaemia may occur despite concomitant bisphosphonate therapy, and may be prolonged in the setting of markedly elevated bone mass. Osteoclast remodelling of osteopetrotic bone post-HSCT should ultimately lessen excessive bone mass, but our case illustrates the attendant risk of deleterious severe hypercalcaemia and the fragility fractures (due to low-energy trauma) highlight the underlying abnormal bone quality. This TNFRSF11A OP-ARO case illustrates the complexity of a bone metabolism medication strategy which optimally controls osteoclasts to resolve hypercalcaemia whilst sufficiently permissive of skeletal remodelling post-HSCT. This case also adds evidence to the literature that craniosynostosis may constitute an early feature of ARO.
2 Case report
A now 5.9-year-old girl was referred to paediatric endocrine services aged 2.3 years due to poor linear growth and concern around low alkaline phosphatase. She had no bone pain and consumed a normal calcium content diet. She was born at 41 weeks gestation with normal birth weight (3.57 kg), of mixed White British and British Asian ethnicity. During her early months she was assessed for a left intermittent divergent squint, with otherwise normal developmental milestones and growth in infancy. She then presented aged 8 months with a bulging fontanelle and cranial imaging identified bilateral partial coronal craniosynostosis without hydrocephalus. Plain radiograph imaging did not give evidence of any skull vault or skull base density increase (Fig. 1A). Ophthalmology assessment revealed nystagmus, left visual impairment and optic nerve pallor. CT imaging (not shown) did not give any evidence of foraminal narrowing; it remained unclear whether the optic nerve dysfunction was due to raised intracranial pressure or a degree of foraminal narrowing or a combination thereof. Visual loss progressed. Craniofacial surgery was undertaken, involving posterior vault expansion, due to progressive suture involvement (lambdoid and squamous sutures). Clinical examination aged 2.3 years showed significant short stature (height z score −3.4 SDS, weight z score −4.9 SDS, BMI 14.14 kg/m2 [2nd centile], head circumference 46.6 cm[50th centile]), asymmetric pectus carinatum, mild facial asymmetry, markedly delayed primary dentition (only 3 erupted teeth), mild thickening and broadening of wrists and anterior tibia, but no significant bowing or marked other deformity. She had severe but stable visual impairment, bilateral optic atrophy and retained light perception in left eye.Fig. 1 Radiology: initial lateral skull plain radiograph aged 8 months on presentation with craniosynostosis; no increased density of either skull vault or skull base evident on this radiograph [A]. Remainder are skeletal survey plain radiographs at diagnosis of osteopetrosis aged 2.3 years; all show marked generalised increased density (B–J). B: Increased skull base density with skull vault sparing, previous skull vault surgical springs. C Chest X-ray: increased rib density, proximal humeral medullary lucencies. Spine shows mild platyspondyly and end-plate sclerosis and bone in bone appearance in the pelvis (lateral [D] and PA [E]). Hand and wrist [F]: increased density throughout all carpal, metacarpal and phalanges. Long bone images (humerus [G], radius and ulna [H], femur [I], tibia and fibula [J]) show loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses. (Image [I] of the femur also shown in Fig. 3(last panel) for comparison to illustrate long bone growth between baseline and 2.5 years post-HSCT).
Fig. 1
Investigations: initial testing prior to the craniosynostosis surgery had shown a normal array CGH (Comparative genomic hybridization) and a craniosynostosis gene panel had identified no causative variants, including extended sequencing of TCF12, FGFR2 and ERF genes. Biochemistry investigations aged 2 years indicated persistently mildly low alkaline phosphatase (94–139 IU/L, reference range 156–369), normal full blood count, electrolytes and liver function. A skeletal survey aged 2.3 years revealed marked generalised increased density of the appendicular and axial skeleton, bone in bone appearance in the pelvis, long bones showed loss of corticomedullary differentiation and undertubulation with prominent medullary lucencies in proximal and distal diaphyses, and spine showed mild platyspondyly and end-plate sclerosis (Fig. 1 panels B–J). This radiological evidence suggested a form of osteopetrosis or ‘sclerosing skeletal dysplasia’, highlighting that osteopetrosis and dysosteosclerosis are overlapping entities. This case was diagnostically challenging, as the absence of initial osteosclerosis on imaging under one year of age, and the lack of hepatosplenomegaly and hypogammaglobulinaemia were consistent with dysosteosclerosis, whereas in our opinion the platyspondyly was much more minimal than typical for dysosteosclerosis. Molecular genetic testing was undertaken on a clinical basis by the Bristol Genetics Laboratory with a bespoke panel for osteopetrosis and osteosclerosis using Agilent's Focused Exome custom target enrichment system SureSelectXT for the following 21 genes: ANKH, CA2, CLCN7, CTSK, FAM123B, FAM20C, FERMT3, IKBKG, LEMD3, LRP5, OSTM1, SNX10, SOST, TCIRG1, TGFB1, PLEKHM1, PTH1R, RASGRP2, TNFRSF11A, TNFSF11, TYROBP, and variants confirmed using Sanger Sequencing. This revealed two compound heterozygous variants in TNFRSF11A gene not reported in other patients: c.414_427 + 7del, p.(Gln140Alafs*17) (maternal, White British ethnicity) and c.1664del, p.(Ser555Cysfs*121) (paternal, British Asian ethnicity). These describe deletions predicted to cause frameshifts resulting in STOP codons 16 and 120 bps downstream respectively, resulting in reduced or absent TNFRSF11A expression and were classified as pathogenic and likely pathogenic respectively according to American College of Medical Genetics and Genomics (ACMG) Guidelines (Richards et al., 2015) and Association for Clinical Genomic Science (ACGS): c.414_427 + 7del [p.Gln140Alafs*17] (ACGS 2019 scoring PM2 (moderate pathogenicity) absent gnomAD reference population, PVS1 (Pathogenic Very Strong) nonsense mediated decay predicted due to disruption of donor site exon 4 of 10, not reported in other patients, pathogenic) and c.1664del [p.Ser555Cysfs*121] (ACGS 2019 scoring PM2 absent gnomAD reference population, PVS1_moderate nonsense mediated decay not predicted and <10% protein removed, not reported in other patients, likely pathogenic), consistent with Autosomal Recessive Osteopetrosis (OP-ARO) (All TNFRSF11A sequence information is based on GenBank reference sequence NM_003839.3). The pathogenic variants in this case are also in Xue et al focussed on separate subsequent functional work, under the descriptor dysosteosclerosis, on the osteopetrosis spectrum (Xue et al., 2020). A pre-transplant Dual energy X-ray absorptiometry (DXA) scan using Hologic C confirmed markedly elevated Lumbar (L1-L4) Bone Mineral Density (BMD), Z-score + 6.3.
Aged 3.1 years, she underwent a haploidentical-maternal HSCT, HLA matching 5/10, bone marrow stem cells (donor had normal bone mineral density). HSCT workup included IgG immunoglobulins 4.99 g/L normal for age. The conditioning regimen comprised rituximab, alemtuzumab, busulfan, fludarabine and cyclophosphamide. The CD34 cell dose administered was 4.29 × 106/kg. Hypercalcaemia (adjusted calcium 3.0 mmol/L [2.20–2.70]) occurred on Day 18 post-HSCT, four days ahead of engraftment (Day 22) defined by the first of three consecutive days of neutrophils >0.5 × 109/L. Hyperhydration and diuretics for 36 h were ineffective and hypercalcaemia (Fig. 2) worsened to adjusted calcium 4.09 mmol/L(16.4 mg/dL) with hypercalciuria (calcium creatinine ratio 12.30 [N < 0.8]). Denosumab 0.13 mg/kg (1.2 mg; weight 9.2 kg, open orange diamond in Fig. 2) subcutaneous injection was administered on Day 20 post-HSCT. Administration details involved denosumab 60 mg in 1 mL diluted to 10 mL with water-for-injection, of which 0.2 mL (=1.2 mg) was injected. Serum calcium reduced minimally (4.09 to 3.65 mmol/L), raising concern whether the denosumab dose was insufficient or involved incomplete delivery of the extremely small volume. An additional denosumab dose 0.2 mg/kg was administered 4 days later, creating an effective total denosumab dose 0.33 mg/kg which normalised serum calcium (2.51 mmol/L) for 3 weeks. Thereafter symptomatic hypercalcaemia (increased thirst and abdominal pain) continued to recur after several weeks. On some occasions despite weekly to twice weekly biochemical monitoring, symptomatic hypercalcaemia developed extremely rapidly only a few days after a reassuring calcium level. It was therefore challenging to identify the ideal denosumab dosage regimen. Denosumab 0.25 mg/kg (2.4 mg, shaded orange diamonds in Fig. 2) every 4 weeks proved adequate and was transitioned to larger (0.6 mg/kg: solid orange diamonds in Fig. 2) less frequent (every 8 weeks) doses to reduce injection frequency burden to the child. Unfortunately, the larger dose did not increase duration of efficacy and symptomatic severe hypercalcaemia developed rapidly on four occasions, each involving emergency department presentation and inpatient admission (Days 51, 103, 227 and 272 post-HSCT, varying from 6.5 to 7.5 weeks following previous denosumab injection). Denosumab was required and was consistently efficacious (hyperhydration achieved no improvement). From 9 months post-HSCT, dosing frequency was changed to denosumab 0.6 mg/kg (6 mg) every 6 weeks, which proved effective for the following 12 months (Fig. 2). Hypercalcaemia was accompanied by appropriately suppressed PTH 0.6 (normal range 1.6–6.9 pmol/L) and hypercalciuria (urine calcium:creatinine ratio 2.47 and 3.85 [normal range < 0.8]). Bone turnover markers (alkaline phosphatase [ALP], procollagen 1 N-Terminal Propeptide [P1NP] and C-terminal telopeptide of type 1 collagen [CTX]) are shown in Fig. 3. Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow; consistent with the intrinsic low turnover rate of osteopetrosis) rose during episodes of hypercalcaemia post-HSCT but overall remained subnormal for 2 years post-HSCT; it has been more consistently in normal range over the last 10 months. Evidence of excess bone breakdown as the cause of the hypercalcaemia was obtained during five instances of hypercalcaemia demonstrated by elevated CTX 0.94, 1.39, 0.99, 1.71 and 1.85 (normal range 0.1–0.5 μg/L) (see lower panel Fig. 3). CTX was assayed immediately prior and 48 h following denosumab falling from 0.99 μg/L (elevated) to 0.37 μg/L (normal), indicating expected response to denosumab (24 months post-HSCT). Tartrate Resistant Acid Phosphatase (TRAP5b) was 11.3 U/L (measured 27 months post-HSCT).Fig. 2 Episodes of post-HSCT hypercalcaemia, denosumab (orange diamonds ♦) and zoledronic acid (green squares ▪) administration and fractures (purple triangles ▲) plotted against time (labelled as both days post-HSCT and age of patient). Serial serum adjusted calcium levels (blue line) plotted against x-axis of Days post-HSCT and age of patient, normocalcaemia (2.2–2.7 mmol/L) indicated by shaded blue range. Calcium data commences 2 week prior to the HSCT, and declines during pre-conditioning phase as expected, falling to mild hypocalcaemia by the time of HSCT (marked as Day 0), then onset of hypercalcaemia with engraftment (D18), with 12 further episodes of hypercalcaemia. Upper section of the figure illustrates denosumab subcutaneous injections (orange diamonds ♦, appearance (open, shaded, solid) and position indicating increased doses) and zoledronic acid infusions (green squares) out to 2.75 years post-HSCT. Lower section of the figure illustrates fracture episodes (purple triangles ▲).
Fig. 2Fig. 3 Bone turnover markers: upper panel shows Alkaline phosphatase (ALP), which was low prior to HSCT (indicated by blue arrow) consistent with the intrinsic low turnover rate of osteopetrosis, then following HSCT rose at episodes of hypercalcaemia but overall remained subnormal for 2 years post-HSCT, then more consistently in normal range over last 10 months. The horizontal dashed orange line indicates the 26 months duration of denosumab and horizontal dashed green line indicates zoledronic acid which overlaps with 8 months of denosumab and indicates total zoledronic acid duration 11 months. Middle panel shows Procollagen N-Terminal Propeptide [P1NP] was normal on all occasions measured providing reassurance against excessive suppression. Lower panel shows C-terminal telopeptide of type 1 collagen [CTX] showed fluctuation with elevated results coinciding with episodes of hypercalcaemia (see text) with normalised levels after denosumab indicating appropriate osteoclast response to denosumab. Normal ranges indicated by green shading in all 3 panels.
Fig. 3
By 18 months post-HSCT, it was expected that the excessive osteoclast activity responsible for hypercalcaemia might have abated allowing denosumab to be withdrawn. We cautiously weaned denosumab, whilst overlapping with introduction of zoledronic acid intravenous infusions to mitigate the potential of the recognised phenomenon of rebound hypercalcaemia on denosumab withdrawal (Boyce, 2017). Despite serial zoledronic acid infusions and frequent monitoring, there was rapid onset of severe (3.81 mmol/L) and symptomatic hypercalcaemia 3 months after discontinuing denosumab (see Fig. 2). This rebound hypercalcaemia from denosumab-washout was treated with both denosumab and zoledronic acid, as was a further occurrence of rebound hypercalcaemia 6 weeks later (adjusted calcium 4.06 mmol/L) (see Fig. 2); both episodes were associated with hypercalciuria (calcium:creatinine ratio 3.49 and 2.47, at 666 and 722 days (22 and 24 months) post-HSCT respectively). Ultimately, denosumab was administered for 26 months, with zoledronic acid for the latter 8 months thereof. Subsequent to final denosumab injection, two further episodes of significant hypercalcaemia (3.47 and 3.49 mmol/L) required zoledronic acid 0.025 then 0.017 mg/kg infusions respectively. A further episode of mild hypercalcaemia (2.88 mmol/L) was monitored and resolved without intervention. The latest status is normocalcaemia for 3 months (6 months since last denosumab and 4 months since last zoledronic acid).
Nine fragility fractures occurred between 7 and 29 months post-HSCT (nil prior) (Fractures itemised in Table 1 and Radiology shown in Fig. 4). Fractures 1–8 were all low trauma fractures (fell from standing, or for fracture 6: twisted her foot), minimally displaced and managed conservatively. Fracture number 9 differed from previous in mechanism, location, type and intervention required: moderately greater trauma force (fell whilst slowly riding stability tricycle) resulted in an oblique fracture diagonally across an expanded remodelling diaphysis (encompassing diaphyseal new bone growth post-HSCT merging into pre-HSCT osteopetrotic diaphyseal region of femur). This displaced fracture required closed reduction under anaesthetic. All fractures demonstrated normal healing characteristics: clinical resolution within the usual timeframe for normal childhood fractures and with normal callus formation (Fig. 4 panel 2b).Table 1 Nine fragility fractures occurred between 7 and 29 months post-HSCT.
Table 1Fracture number Months post-HSCT Age (y) Fractures (nil pre-HSCT) Fracture details
1 7 3.7 Left Clavicle Transverse proximal third of diaphysis
2 12 4.1 Left humerus Transverse proximal third of diaphysis
3 14 4.3 Left fibula Transverse proximal third of diaphysis
4 16 4.4 Left tibia and fibula Transverse distal tibial diaphyses and minimal fracture lateral aspect of distal fibular diaphysis
5 20 4.8 Right tibia and fibula Oblique distal third of tibial diaphysis
Transverse distal third of fibula diaphysis
6 24 5.2 Right metatarsals Transverse distal third of diaphyses of second and third metatarsals
7 25 5.2 Right clavicle Transverse proximal third of diaphysis
8 27 5.3 Left tibia Anterior portion of distal tibial metadiaphyseal region
9 29 5.4 Left femur Oblique diagonal through distal-mid expanded region of diaphysis
Fig. 4 Fragility fractures post-HSCT. Plain radiographs numbering corresponds with fracture episode chronology listed in Table 1. Arrows mark the fracture sites, in addition, all images show evidence of the underlying osteopetrotic changes of intra-medullary lucencies and diffuse sclerotic appearance similar to pre-HSCT evident in Fig. 1 images. 1: Left clavicle: transverse minimally displaced fracture through the medial third of the left clavicle diaphysis. 2a: Left humerus: transverse lucency across proximal third of humeral diaphysis. 2b is 7 weeks after image 2 and demonstrates proximal left humeral fracture with cortical remodelling, alignment preserved, sclerosed fracture plane and callus formation, pronounced on medial aspect. 3: left tibia and fibula: transverse fracture at proximal third of fibular diaphysis linear. 4: left tibia and fibula: upper arrow against proximal third of fibular diaphysis shows healing fracture from panel 3 and lower two arrows show new minimally displaced fractures through distal tibial and fibular diaphyses. 5: Right tibia and fibula: minimally-displaced oblique fracture of distal tibial diaphysis and an undisplaced transverse fracture of distal fibular diaphysis. 6: Right foot: non-displaced fracture through 2nd & 3rd metatarsals. 7 Right clavicle: Transverse fracture across proximal third. 8a Left tibia: fracture not evident on this AP image (so no arrow) whereas 8b (lateral image) shows non-displaced linear lucency evident through anterior distal tibia. 9 Left Femur: two arrows show upper and lower margins of oblique displaced fracture through expanded distal femoral diaphysis. This images 2.5 years post-HSCT also demonstrates improvement of metaphyseal contour and quality in comparison to pre-HSCT image to its right, with lessening of the medullary lucencies and loss of Erlenmeyer flask type deformity. 10: (lower right) does not contain a fracture but shown here in addition to Fig. 1 (panel 1) to facilitate comparison of left femur diaphysis pre-HSCT against progressively changed in bone appearance post-transplant.
Fig. 4
Beyond the above calcium and bone complications, overall progress post-HSCT proceeds well: there has been persistent 100% donor chimerism, normal blood counts, and no other transplant-related complications. Aged 5.9 years, she attends mainstream school with visual impairment educational support. Residual vision has not deteriorated, and hearing remains stable. Linear growth demonstrates normal but not increased growth velocity, i.e. no catch-up growth has occurred: Height SDS -3.7 SDS both just prior to transplant and 2.6 years post-transplant. Appreciable reduction in BMD did not occur in the initial 1.5 years, but is evident 2.5 years post-HSCT (see Table 2). Lateral spine plain radiography 2.4 years post HSCT is unchanged, showing neither progression from mild platyspondyly nor evidence of vertebral fractures. Renal ultrasound was normal pre-transplant, but mild nephrocalcinosis was identified 6 months post-HSCT and remains stable (bilateral grade 1 nephrocalcinosis) on serial monitoring with normal renal function.Table 2 Serial bone mineral density DXA scans, performed using Hologic C.
Table 2Age (years) Years post-HSCT Whole body less head bone mineral density (g/cm2) Lumbar spine (L1–4) bone mineral density (g/cm2) Lumbar spine Z score
2.8 Unavailable 0.934 +6.3
4 0.9 Unavailable 1.052 +6.1
4.6 1.5 0.689 1.133 +6.1
5.6 2.5 0.625 1.055 +5.2
3 Discussion
Osteopetrosis is a heterogeneous group of rare skeletal disorders characterised by increased bone density due to defective osteoclast differentiation and function (Wu et al., 2017). Autosomal dominant forms can be relatively mild and usually diagnosed in adulthood, whereas autosomal recessive osteopetrosis (ARO) forms are more severe and typically present in infancy. Our case demonstrates several new learning points relevant to optimal clinical management of the ultrarare subtype of TNFRSF11A-related ARO (1–4% of cases of ARO). These include several notable ARO clinical features (failure to thrive, optic atrophy and dental abnormalities), unusual radiographic skeletal changes (specifically loss of corticomedullary differentiation, and prominent medullary lucencies in proximal and distal diaphyses), craniosynostosis and fragility fractures. Three clinical aspects to highlight for further discussion are the initial cranial vault abnormalities, the post-HSCT hypercalcaemia and the fragility fractures.
Recognised cranial abnormalities in ARO occur due to increased skull base bone mass causing hydrocephalus, which was not present in our case, and visual impairment from foraminal narrowing (Steward, 2003). Although craniosynostosis is not widely considered as a characteristic component of osteopetrosis, we identified 6 other individual case reports of craniosynostosis in ARO; genetic variants were reported for half the cases: TCIRG1 (n = 2) and OSTEM (n = 1), unreported (n = 3) (Driessen et al., 2003). We propose that craniosynostosis reflects reduced osteoclast activity giving abnormal bone modelling at cranial sutures and is relevant in identifying ARO, since craniosynostosis may present prior to obvious skeletal sclerosis. Our case highlights this diagnostic subtlety, as retrospective review of the initial skull radiographs confirmed no apparent increase density of either skull vault or base in early infancy.
The majority of ARO involve osteoclasts that are present but poorly functioning with compensatory positive feedback loops explaining the ‘osteoclast-rich’ appearances on bone biopsy; genes involved are CA2, TCIRG1, CLCN7, OSTM1, PLEKHM1, SNX10 (Penna et al., 2019). In the rarer subgroup of OP-ARO, loss-of-function mutations prevent osteoclast formation, for which two causative genes have been identified: TNFSF11 and TNFRSF11A. The cause of absent osteoclasts in TNFSF11-related ARO is the lack of RANKL to induce pre-osteoclast differentiation. By contrast, TNFRSF11A encodes the membrane-anchored RANK protein in the pre-osteoclast itself, without which pre-osteoclasts are intrinsically abnormal and unable to differentiate. This specific feature underpins the uniqueness of the TNFRSF11A-related OP-ARO as the type most likely to involve severe hypercalcaemia following HSCT, as the transition from completely non-functional pre-osteoclasts to the engraftment of normal well-functioning RANK-secreting pre-osteoclasts permits a sudden increase in osteoclast activity. Osteoclasts break down pre-existing excess bone, releasing significant circulating excess calcium.
Life-threatening hypercalcaemia post-HSCT for OP-ARO is a known complication. Reported overall prevalence ranges from 16 to 40%, with higher risk 60% in patients older than 2 years of age attributed to their higher bone mass (Martinez et al., 2010; Shroff et al., 2012; Pangrazio et al., 2012; Driessen et al., 2003). In the OP-ARO subset (due to TNFRSF11A mutations), hypercalcaemia post-HSCT seems to have an even higher prevalence, earlier onset, and be both recurrent and more severe (Martinez et al., 2010; Penna et al., 2019). This presents clinicians with significant challenges regarding effective treatment options which until recently were limited to hyperhydration, furosemide, calcitonin, glucocorticoids, bisphosphonates and haemofiltration (Basok et al., 2018).
The emergence of denosumab, first approved for use in adults in 2010, as a potent anti-resorptive agent has provided an exciting new therapeutic option which more directly targets the pathophysiology of the hypercalcaemia. This human monoclonal antibody binds the RANK receptor with high affinity and specificity. It blocks RANKL binding, preventing osteoclast differentiation and hence reducing bone resorption. Denosumab is licensed for use in adults for post-menopausal osteoporosis, giant cell tumours, and hypercalcemia due to malignancy and bone metastases (Boyce, 2017; Polyzos et al., 2019). There is emerging but cautious use of denosumab in paediatrics: clinical research trials in osteogenesis imperfecta (OI) and limited off-license use (Boyce, 2017; Polyzos et al., 2019). Paediatric doses have differed widely: most commonly 1 mg/kg every 6 months, shorter intervals of 10 weeks in Type VI OI to manage breakthrough hypercalcaemia (Trejo et al., 2018) and a range of doses in different bone conditions; along with this relatively frequent administration of 0.6 mg/kg every 6 weeks in post-HSCT hypercalcaemia in our case.
Shroff et al first described denosumab to treat post-HSCT hypercalcaemia in two paediatric patients with OP-ARO due to TNFRSF11A mutations (Shroff et al., 2012). These patients were treated with denosumab 0.13–0.27 mg/kg, appreciably lower doses than the 1 mg/kg regimen used in paediatric OI studies. In our small (<10 kg) patient, we elected to treat cautiously initially, using the lower dose 0.13 mg/kg (1.2 mg) subcutaneously. However, effective control of ongoing hypercalcaemia was not achieved until titration through several dosages to 0.6 mg/kg once every 6 weeks for 18–24 months. This clinical efficacy duration of 6 weeks fits with evidence that bone turnover markers return to pre-treatment levels 6–8 weeks post denosumab (Boyce, 2017). The degree of rebound hypercalcaemia appeared uninfluenced by denosumab dosage; the challenge was to reach duration of control that avoided overly frequent painful injections for this child. We propose use of denosumab 0.6 mg/kg at 6 week intervals, higher than previously reported, in severe cases in the unique cohort of OP-ARO post-HSCT for medium-term control of hypercalcaemia.
Commencing denosumab for RANK-related TNFRSF11A OP-ARO post-HSCT hypercalcaemia is an intuitive choice and is effective precisely because it directly targets the RANK signalling pathway now restored by HSCT. The temporary-reversible nature of denosumab was preferred over the potentially toxic bisphosphonate effect on engrafting stem cells. But this initial solution can be followed by the dilemma of how to safely discontinue. Upon ceasing denosumab, the monoclonal antibody no longer blocks the RANK pathway, unleashing a potentially amassed pool of pre-osteoclasts. Rebound hypercalcaemia is a recognised complication following denosumab discontinuation in adults and children, particularly in high bone turnover conditions, e.g. giant cell tumours, Paget's disease and fibrous dysplasia (Boyce, 2017). This rebound hypercalcaemia of denosumab washout was probably amplified by the underlying OP-ARO high bone mass, and hypothetically compensatory over-expression of RANKL proposed in RANK-related ARO (Sobacchi et al., 2013). These may all have contributed to severe hypercalcemia recurring whilst withdrawing denosumab, requiring 8 months concurrent zoledronic acid to control. Elevated bone turnover marker CTX indicates bone breakdown, inferring osteoclast activity, common to all mechanisms. The serum tartrate resistant acid phosphatase (TRAP5b) 11.3 U/L may indicate reasonable osteoclast numbers at 2.3 years post-HSCT; although there are neither reference ranges young children or young children with ARO post-HSCT, 11.3 is reassuringly close to 13–23 U/L (normal range 7.5-10 years (Whyte et al., 2010)). We hypothesise that longterm denosumab may have suppressed remodelling (ALP normalisation took 2 years post-HSCT). However, the medical reality was dramatic hypercalcaemia causing systemic symptoms, where prompt control was essential to reduce risk of nephrocalcinosis progressing to renal impairment. Lower doses may have minimised suppression, but they resulted in extremely frequent injections that were not tolerable for the child. Our case does raise the possibility that whilst denosumab is a rational solution for initial management it may perpetuate hypercalcaemia. So potentially addition of zoledronic acid earlier, e.g. after 8–12 months rather than 18 months, may be advisable. Overall, we attribute the extent of hypercalcaemia predominantly to the excessiveness of bone mass accumulated by the older age of transplant, a concept supported by the literature (Orchard et al., 2015).
Restoration of osteoclast activity is an important outcome of HSCT for osteopetrosis. Skeletal remodelling in our case is indicated by hypercalcaemia and bone turnover markers. Progressive reduction of elevated bone mass is expected, although no other reports used DXA to quantify bone density. Our case highlights that reduction in DXA bone density may take a longer time frame to emerge - evident by 2.5 years, but not at 1.5 years post-HSCT (Table 2). Long duration of skeletal remodelling offloading excessive calcium can be attributed to the extent of excessive bone mass accumulated by older age at transplant (Orchard et al., 2015). We had considered whether transplantation from a haploidentical donor rather than a homozygous normal donor did not achieve full bone correction. We discounted this hypothesis as HSCT is often done without apparent issue from parental or sibling carriers in other forms of osteopetrosis and secondly our maternal donor's normal bone mineral density provides reassurance. Functional studies on this child's pathogenic variants have very recently been published (Xue et al., 2020), giving some insight into osteoclast dysfunction mechanisms and highlighting that osteopetrosis and dysosteosclerosis comprise a spectrum. Subsequent studies could further elucidate our unique case in due course.
Our patient experienced 9 fragility fractures 7–29 months post-HSCT but none prior to transplant. This contrast pre and post HSCT may be coincidental, since fractures are a recognised feature of the natural history of osteopetrosis without stem cell transplant, due to the inherently brittle marble-like bone (Sobacchi et al., 2013). Comparative post-HSCT fracture data is an acknowledged gap in follow-up studies (Orchard et al., 2015). It is plausible that the post-HSCT fractures are a consequence of bone turnover with normalised osteoclast function and bone physiology. It is notable that the long bone fractures in our case occurred at the junction of new diaphyseal bone growth post-HSCT with pre-existing ‘marble-like’ diffuse sclerotic bone (Fig. 1, Fig. 4), potentially where now restored osteoclast aims to remodel that abnormal bone. This junctional location is similar to ‘stress-riser’ fractures with bisphosphonate treated bone and medication-naïve bone. There is no evidence to indicate whether denosumab osteoclast inhibition increases or attenuates fracture risk in OP-ARO. Nevertheless, the impact of recurring fragility fractures was significant for this young child and influenced our pragmatic clinical decision to attempt to wean denosumab and then zoledronic acid therapies to avoid ongoing bone suppression and inhibition of bone remodelling. Since discontinuing both therapies, one episode of mild self-resolving hypercalcaemia suggests bone remodelling off-loading calcium. Ongoing surveillance will monitor bone quality improvement over the coming years.
4 Conclusion
Post-HSCT for OP-ARO, intrinsic osteoclast drive breaks down calcium laden osteopetrotic bone, as remodelling strives to progressively normalise the skeleton. Our case demonstrates the challenge in achieving optimal treatment to permit sufficient bone turnover for skeletal remodelling, whilst sufficiently suppressing bone turnover to avoid life-threatening hypercalcaemia. Denosumab is effective for medium term use in OP-ARO post-HSCT to combat recurrent hypercalcaemia. Thereafter, withdrawal is relevant to permit engrafted osteoclasts to facilitate skeletal remodelling. Judicious withdrawal entails more than the single bisphosphonate administration to ‘seal in calcium’ effective in low bone mass conditions, e.g. OI, and involves prolonged concurrent zoledronic acid (8 months), during which vigilance for rapid onset severe hypercalcaemia must be maintained.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics statement
Our research complies with all relevant national regulations and institutional policies. Informed consent was obtained from the parents of the child for inclusion in this research.
CRediT authorship contribution statement
TTM: Writing - original draft, review & editing, PS: Resources, SFS: Resources, Writing - review & editing, CS: Resources, Writing - review & editing, CPB: Conceptualization, Resources, Supervision, Writing - review & editing, revisions, Visualization. All authors have approved the final version of the manuscript.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33364264 | 18,706,353 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Insomnia'. | Vitamin D deficiency in the pathogenesis of leiomyoma and intravascular leiomyomatosis: A case report and review of the literature.
This is a case of recurrent intravascular leiomyomatosis in a pre-menopausal woman of African-Caribbean heritage. She presented in 2006 with multiple uterine leiomyomata, tumour invading the inferior vena cava (IVC) extending into the right atrium, and pulmonary metastases. Her initial presentation was treated surgically. On recurrence she was treated by oestrogen suppression using a combination of goserelin and letrozole, with a substantial response. She subsequently reported further regression of disease following exposure to strong sunlight enabling her to discontinue oestrogen suppression without relapse. The hypothesis is that the benefit was due to vitamin D. The role of hypovitaminosis D in the pathogenesis of uterine leiomyomata is discussed, including epidemiology data demonstrating a link between ethnicity and risk and the proven mechanisms by which vitamin D controls oestrogen and progesterone receptor expression and influences other signalling pathways involved in the pathogenesis of leiomyomas. Data indicating the intermediate malignancy nature of intravascular leiomyomatosis, are discussed. We are not aware of other reports indicating a link between intravascular leiomyomatosis and a lack of vitamin D.
1 Case report
Herein we report a case of strong sunlight, supplemented with oral vitamin D3, causing stabilisation of uterine leiomyomas permitting withdrawal of oestrogen suppression therapy in a patient with uterine leiomyomas and intravascular leiomyomatosis.
A pre-menopausal woman of African-Caribbean heritage presented in 2006, at the age of 36, with pulmonary embolus, an intracardiac mass tumour thrombus extending from the pelvis up the inferior vena cava (IVC) to the right ventricle. She also had uterine leiomyomas. The intravascular tumour was resected on cardio-pulmonary bypass by a cardiothoracic surgeon and an abdominal surgeon with special expertise in renal surgery. The majority of the tumour was pulled out from the right ventricle as it was quite mobile. However an incision was also made in the IVC from the level of the left renal vein to remove the mass from the left renal vein and an incision was also made in the left renal vein itself. There was a small amount of tumour in the left ovarian vein and therefore the left ovarian vein was removed. The uterus, fallopian tubes and ovaries were not resected because the patient was unwilling to be rendered infertile. The histology of the mass removed from the right ventricle was reported as benign leiomyoma. Fig. 1A, Fig. 1B shows haematoxylin and eosin (H&E) a stained section of the resected specimen at two different magnifications. It was reported as follows: “Sections show an encapsulated, elongated spindle cell tumour with large areas of infarction. The tumour is composed of bland spindle cells arranged in loose fascicles, and admixed with thick-walled blood vessels, few of which show hyalinization. Myxoid change is noted focally, mitoses and nuclear pleomorphism is not seen. The tumours cells stain for ER, PgR, desmin, SMA, Bcl-2 and caldesmon and are negative for S100, CD34, CD117, calretinin, AE1/3 and HMB45.” We also note the presence of clear cells and both this and hyalinisation have been reported in intravascular leiomyomatosis together with the suggestion that the appearances of intravascular leiomyomatosis differ somewhat from benign leiomyoma (Han et al., 1998, Yaguchi et al., 2010).Fig. 1A H&E stained section of resected tumour from the right ventricle at 10X magnification showing a large thick-walled blood vessel, spindle cells loosely packed in a myxoid stroma. No mitoses are seen.
Fig. 1B Part of the same section is shown at 20x magnification.
No prophylaxis was offered following surgery and the patient was lost to follow-up. She re-presented in 2009 with large pelvic and abdominal masses (Fig. 2a), lung nodules (Fig. 2b) and a suspicion of recurrence in the IVC indicating a diagnosis of intravascular leiomyomatosis. The following year in 2010 a cardiac MRI scan confirmed the presence of tumour in the IVC and right atrium. Treatment with a combination of goserelin and letrozole was commenced in August 2010 resulting in a rapid reduction in the size of pelvic and abdominal leiomyomas (Fig. 3A and B), a slight reduction in the size of pulmonary metastases was also seen together with regression of disease in the IVC on cardiac MRI.Fig. 2 Axial contrast enhanced CT abdomen & pelvis performed in 2009 demonstrates large uterine leiomyomata (A) and pulmonary nodules (arrow B).
Fig. 3 Coronal CT reformat from a contrast enhanced CT performed in July 2010 (A), September 2010 (B) and 2012 (C) shows shrinkage of the masses.
There was a further slight reduction in the volume of intra-abdominal disease (Fig. 3C) in 2011. However, the patient was increasingly distressed by the side effects of oestrogen suppression, particularly by insomnia and reduced libido and discontinued treatment to relieve these symptoms in 2012. A CT in March 2013 showed slight progression in both the pelvic and abdominal disease and lung metastases. In June 2013 a repeat CT showed a further increase in the size of the pelvic disease and a cardiac MRI and echocardiogram showed possible recurrent disease in the IVC. Ulipristal acetate was commenced in March 2013 but has since been discontinued. Letrozole and goserelin treatment was recommenced in October 2013 and continued until 2015.
At an out-patient visit in August 2015 she reported that during a trip to the Southern USA in February 2013 to visit a relative, during which she had much more exposure to sunlight than in the UK, she experienced a significant reduction in the size of the abdominal masses and the associated abdominal bloating and discomfort. She was also taking oral vitamin D3 supplements in the form of cod liver oil and vitamin D3. Following this experience, noting that her tumours were smaller in the Summer, during the year 2015 she started regularly using a sunbed twice a week, when access to strong sunshine was not possible. She continued to take cod liver oil and vitamin D3. This combined strategy proved successful and she was able to stop the letrozole and goserelin in 2015 without suffering a relapse. Vitamin D blood levels were not examined following this new information, because we had no baseline prior to the start of self-medicated vitamin D supplementation. Fig. 4 shows a comparison between a representative tumour in 2013 and the same tumour in 2015 showing a small reduction in tumour volume. The patient remains well to this day with stable disease by RECIST, although a more recent scan may show slight progression, and has not needed to recommence treatment with letrozole and goserelin in the last 5 years.Fig. 4 Axial T2W MRI in 2013 (A) and 2015 (B) showing a large soft tissue mass centred on the uterus (*). Maximum axial dimension in 2013 was 24.2 × 13.9 cm compared with 22.4 × 12.2 cm in 2015.
2 Discussion
Uterine leiomyomas (fibroids) are extremely common. It is estimated that by the age of 50, nearly 70% of white women and >80% of African-American women will have ultrasound evidence of uterine fibroids. A recent study demonstrated a link between low blood levels of 25-hydroxyvitamin D (<20 ng/ml) and an increased risk of leiomyomata (Han et al., 1998). A study in Italy reported similar findings, demonstrating that women with at least one uterine leiomyoma had a significantly lower blood level of 25-hydroxyvitamin D3. In this study 25-hydroxyvitamin D3 deficiency was defined as <10 ng/ml and this was associated with an odds ratio for leiomyoma of 2.4 (95% confidence interval 1.2–4.9, P-0.16) compared with controls (Yaguchi et al., 2010). An American nutrition survey African-American women were 10 times more likely to have low vitamin D levels than white women (Baird et al., 2013). The increased incidence of uterine leiomyomas in African–American women has been identified as a public health issue (Eltoukhi et al., 2014; Paffoni et al., 2013). It has been shown that 1–25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates the expression of oestrogen and progesterone receptors in uterine leiomyoma cells (Al-Hendy et al., 2015; Nesby-O'Dell et al., 2002). Treating these cells with 1,25(OH)2D3 reduced the expression of oestrogen receptor-α, progesterone receptor-A and B and members of the steroid receptor coactivator (SRC) family. In addition, 1,25(OH)2D3 also reduces TGFβ3- induced fibrosis-related gene expression, e.g. collagen and fibronectin genes, in uterine leiomyoma cells (Halder et al., 2011; Sharan et al., 2011). Vitamin D3 has also been shown to inhibit the proliferation of uterine leiomyoma cells via inhibition of catechol-o-methyltransferase (Al-Hendy et al., 2016) and to inhibit WNT/β-catenin and mTOR signalling pathways in uterine leiomyoma cells (Ciavattini et al., 2016). There is a strong case for considering vitamin D supplementation in women of reproductive age and hypovitaminosis D as a preventive measure and some evidence that this can prevent the progression of pre-existing uterine leiomyomas (Ordulu et al., 2016).
3 Conclusions
The role of vitamin D in the pathogenesis of leiomyomas is still not universally recognised by gynecologists. Hypovitaminosis D is a significant problem in women of darker skin ethnicity living in Northern climates, since they require greater sun exposure to generate sufficient vitamin D in the skin, sometimes compounded by cultural factors. This case highlights the potential value of sunlight and vitamin D supplementation in controlling leiomyomas. What is particularly unusual is the fact that this woman was diagnosed with the potentially life-threatening situation of intravascular leiomyomatosis with tumour extending up the IVC into the right atrium prior to successful treatment with combined oestrogen deprivation. This is now recognised to be a disease of intermediate grade malignancy as reported by Ordulu et al. (2016), with a gene expression profile similar to that of leiomyosarcoma, rather than leiomyoma or normal myometrium and the frequent finding of a translocation der[14]t[12;14](q14.3;q24) as shown by co-localization of probes for HMGA2 (12q14.3) and 14q24 by FISH. In contrast, this study also showed no evidence in the intravenous leiomyomatosis cases of loss of 7q22, frequently deleted in uterine leiomyomata. This case is by no means proof, but it seems likely that this condition is also influenced by the same hormonal factors as common leiomyomas and hence its growth is potentially enhanced by lack of vitamin D and impeded by repletion.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Authorship
Both authors contributed to the manuscript, IJ was mainly responsible for the case report and discussion and was the physician who initially cared for the patient. CM was responsible for the choice and presentation of the images. Both authors reviewed the final manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding acknowledgements
We wish to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre, Clinical Research Facility in Imaging and the Cancer Research Network. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. | GOSERELIN, LETROZOLE | DrugsGivenReaction | CC BY-NC-ND | 33364287 | 18,880,673 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Libido decreased'. | Vitamin D deficiency in the pathogenesis of leiomyoma and intravascular leiomyomatosis: A case report and review of the literature.
This is a case of recurrent intravascular leiomyomatosis in a pre-menopausal woman of African-Caribbean heritage. She presented in 2006 with multiple uterine leiomyomata, tumour invading the inferior vena cava (IVC) extending into the right atrium, and pulmonary metastases. Her initial presentation was treated surgically. On recurrence she was treated by oestrogen suppression using a combination of goserelin and letrozole, with a substantial response. She subsequently reported further regression of disease following exposure to strong sunlight enabling her to discontinue oestrogen suppression without relapse. The hypothesis is that the benefit was due to vitamin D. The role of hypovitaminosis D in the pathogenesis of uterine leiomyomata is discussed, including epidemiology data demonstrating a link between ethnicity and risk and the proven mechanisms by which vitamin D controls oestrogen and progesterone receptor expression and influences other signalling pathways involved in the pathogenesis of leiomyomas. Data indicating the intermediate malignancy nature of intravascular leiomyomatosis, are discussed. We are not aware of other reports indicating a link between intravascular leiomyomatosis and a lack of vitamin D.
1 Case report
Herein we report a case of strong sunlight, supplemented with oral vitamin D3, causing stabilisation of uterine leiomyomas permitting withdrawal of oestrogen suppression therapy in a patient with uterine leiomyomas and intravascular leiomyomatosis.
A pre-menopausal woman of African-Caribbean heritage presented in 2006, at the age of 36, with pulmonary embolus, an intracardiac mass tumour thrombus extending from the pelvis up the inferior vena cava (IVC) to the right ventricle. She also had uterine leiomyomas. The intravascular tumour was resected on cardio-pulmonary bypass by a cardiothoracic surgeon and an abdominal surgeon with special expertise in renal surgery. The majority of the tumour was pulled out from the right ventricle as it was quite mobile. However an incision was also made in the IVC from the level of the left renal vein to remove the mass from the left renal vein and an incision was also made in the left renal vein itself. There was a small amount of tumour in the left ovarian vein and therefore the left ovarian vein was removed. The uterus, fallopian tubes and ovaries were not resected because the patient was unwilling to be rendered infertile. The histology of the mass removed from the right ventricle was reported as benign leiomyoma. Fig. 1A, Fig. 1B shows haematoxylin and eosin (H&E) a stained section of the resected specimen at two different magnifications. It was reported as follows: “Sections show an encapsulated, elongated spindle cell tumour with large areas of infarction. The tumour is composed of bland spindle cells arranged in loose fascicles, and admixed with thick-walled blood vessels, few of which show hyalinization. Myxoid change is noted focally, mitoses and nuclear pleomorphism is not seen. The tumours cells stain for ER, PgR, desmin, SMA, Bcl-2 and caldesmon and are negative for S100, CD34, CD117, calretinin, AE1/3 and HMB45.” We also note the presence of clear cells and both this and hyalinisation have been reported in intravascular leiomyomatosis together with the suggestion that the appearances of intravascular leiomyomatosis differ somewhat from benign leiomyoma (Han et al., 1998, Yaguchi et al., 2010).Fig. 1A H&E stained section of resected tumour from the right ventricle at 10X magnification showing a large thick-walled blood vessel, spindle cells loosely packed in a myxoid stroma. No mitoses are seen.
Fig. 1B Part of the same section is shown at 20x magnification.
No prophylaxis was offered following surgery and the patient was lost to follow-up. She re-presented in 2009 with large pelvic and abdominal masses (Fig. 2a), lung nodules (Fig. 2b) and a suspicion of recurrence in the IVC indicating a diagnosis of intravascular leiomyomatosis. The following year in 2010 a cardiac MRI scan confirmed the presence of tumour in the IVC and right atrium. Treatment with a combination of goserelin and letrozole was commenced in August 2010 resulting in a rapid reduction in the size of pelvic and abdominal leiomyomas (Fig. 3A and B), a slight reduction in the size of pulmonary metastases was also seen together with regression of disease in the IVC on cardiac MRI.Fig. 2 Axial contrast enhanced CT abdomen & pelvis performed in 2009 demonstrates large uterine leiomyomata (A) and pulmonary nodules (arrow B).
Fig. 3 Coronal CT reformat from a contrast enhanced CT performed in July 2010 (A), September 2010 (B) and 2012 (C) shows shrinkage of the masses.
There was a further slight reduction in the volume of intra-abdominal disease (Fig. 3C) in 2011. However, the patient was increasingly distressed by the side effects of oestrogen suppression, particularly by insomnia and reduced libido and discontinued treatment to relieve these symptoms in 2012. A CT in March 2013 showed slight progression in both the pelvic and abdominal disease and lung metastases. In June 2013 a repeat CT showed a further increase in the size of the pelvic disease and a cardiac MRI and echocardiogram showed possible recurrent disease in the IVC. Ulipristal acetate was commenced in March 2013 but has since been discontinued. Letrozole and goserelin treatment was recommenced in October 2013 and continued until 2015.
At an out-patient visit in August 2015 she reported that during a trip to the Southern USA in February 2013 to visit a relative, during which she had much more exposure to sunlight than in the UK, she experienced a significant reduction in the size of the abdominal masses and the associated abdominal bloating and discomfort. She was also taking oral vitamin D3 supplements in the form of cod liver oil and vitamin D3. Following this experience, noting that her tumours were smaller in the Summer, during the year 2015 she started regularly using a sunbed twice a week, when access to strong sunshine was not possible. She continued to take cod liver oil and vitamin D3. This combined strategy proved successful and she was able to stop the letrozole and goserelin in 2015 without suffering a relapse. Vitamin D blood levels were not examined following this new information, because we had no baseline prior to the start of self-medicated vitamin D supplementation. Fig. 4 shows a comparison between a representative tumour in 2013 and the same tumour in 2015 showing a small reduction in tumour volume. The patient remains well to this day with stable disease by RECIST, although a more recent scan may show slight progression, and has not needed to recommence treatment with letrozole and goserelin in the last 5 years.Fig. 4 Axial T2W MRI in 2013 (A) and 2015 (B) showing a large soft tissue mass centred on the uterus (*). Maximum axial dimension in 2013 was 24.2 × 13.9 cm compared with 22.4 × 12.2 cm in 2015.
2 Discussion
Uterine leiomyomas (fibroids) are extremely common. It is estimated that by the age of 50, nearly 70% of white women and >80% of African-American women will have ultrasound evidence of uterine fibroids. A recent study demonstrated a link between low blood levels of 25-hydroxyvitamin D (<20 ng/ml) and an increased risk of leiomyomata (Han et al., 1998). A study in Italy reported similar findings, demonstrating that women with at least one uterine leiomyoma had a significantly lower blood level of 25-hydroxyvitamin D3. In this study 25-hydroxyvitamin D3 deficiency was defined as <10 ng/ml and this was associated with an odds ratio for leiomyoma of 2.4 (95% confidence interval 1.2–4.9, P-0.16) compared with controls (Yaguchi et al., 2010). An American nutrition survey African-American women were 10 times more likely to have low vitamin D levels than white women (Baird et al., 2013). The increased incidence of uterine leiomyomas in African–American women has been identified as a public health issue (Eltoukhi et al., 2014; Paffoni et al., 2013). It has been shown that 1–25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates the expression of oestrogen and progesterone receptors in uterine leiomyoma cells (Al-Hendy et al., 2015; Nesby-O'Dell et al., 2002). Treating these cells with 1,25(OH)2D3 reduced the expression of oestrogen receptor-α, progesterone receptor-A and B and members of the steroid receptor coactivator (SRC) family. In addition, 1,25(OH)2D3 also reduces TGFβ3- induced fibrosis-related gene expression, e.g. collagen and fibronectin genes, in uterine leiomyoma cells (Halder et al., 2011; Sharan et al., 2011). Vitamin D3 has also been shown to inhibit the proliferation of uterine leiomyoma cells via inhibition of catechol-o-methyltransferase (Al-Hendy et al., 2016) and to inhibit WNT/β-catenin and mTOR signalling pathways in uterine leiomyoma cells (Ciavattini et al., 2016). There is a strong case for considering vitamin D supplementation in women of reproductive age and hypovitaminosis D as a preventive measure and some evidence that this can prevent the progression of pre-existing uterine leiomyomas (Ordulu et al., 2016).
3 Conclusions
The role of vitamin D in the pathogenesis of leiomyomas is still not universally recognised by gynecologists. Hypovitaminosis D is a significant problem in women of darker skin ethnicity living in Northern climates, since they require greater sun exposure to generate sufficient vitamin D in the skin, sometimes compounded by cultural factors. This case highlights the potential value of sunlight and vitamin D supplementation in controlling leiomyomas. What is particularly unusual is the fact that this woman was diagnosed with the potentially life-threatening situation of intravascular leiomyomatosis with tumour extending up the IVC into the right atrium prior to successful treatment with combined oestrogen deprivation. This is now recognised to be a disease of intermediate grade malignancy as reported by Ordulu et al. (2016), with a gene expression profile similar to that of leiomyosarcoma, rather than leiomyoma or normal myometrium and the frequent finding of a translocation der[14]t[12;14](q14.3;q24) as shown by co-localization of probes for HMGA2 (12q14.3) and 14q24 by FISH. In contrast, this study also showed no evidence in the intravenous leiomyomatosis cases of loss of 7q22, frequently deleted in uterine leiomyomata. This case is by no means proof, but it seems likely that this condition is also influenced by the same hormonal factors as common leiomyomas and hence its growth is potentially enhanced by lack of vitamin D and impeded by repletion.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Authorship
Both authors contributed to the manuscript, IJ was mainly responsible for the case report and discussion and was the physician who initially cared for the patient. CM was responsible for the choice and presentation of the images. Both authors reviewed the final manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding acknowledgements
We wish to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre, Clinical Research Facility in Imaging and the Cancer Research Network. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. | GOSERELIN, LETROZOLE | DrugsGivenReaction | CC BY-NC-ND | 33364287 | 18,880,673 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Vitamin D deficiency in the pathogenesis of leiomyoma and intravascular leiomyomatosis: A case report and review of the literature.
This is a case of recurrent intravascular leiomyomatosis in a pre-menopausal woman of African-Caribbean heritage. She presented in 2006 with multiple uterine leiomyomata, tumour invading the inferior vena cava (IVC) extending into the right atrium, and pulmonary metastases. Her initial presentation was treated surgically. On recurrence she was treated by oestrogen suppression using a combination of goserelin and letrozole, with a substantial response. She subsequently reported further regression of disease following exposure to strong sunlight enabling her to discontinue oestrogen suppression without relapse. The hypothesis is that the benefit was due to vitamin D. The role of hypovitaminosis D in the pathogenesis of uterine leiomyomata is discussed, including epidemiology data demonstrating a link between ethnicity and risk and the proven mechanisms by which vitamin D controls oestrogen and progesterone receptor expression and influences other signalling pathways involved in the pathogenesis of leiomyomas. Data indicating the intermediate malignancy nature of intravascular leiomyomatosis, are discussed. We are not aware of other reports indicating a link between intravascular leiomyomatosis and a lack of vitamin D.
1 Case report
Herein we report a case of strong sunlight, supplemented with oral vitamin D3, causing stabilisation of uterine leiomyomas permitting withdrawal of oestrogen suppression therapy in a patient with uterine leiomyomas and intravascular leiomyomatosis.
A pre-menopausal woman of African-Caribbean heritage presented in 2006, at the age of 36, with pulmonary embolus, an intracardiac mass tumour thrombus extending from the pelvis up the inferior vena cava (IVC) to the right ventricle. She also had uterine leiomyomas. The intravascular tumour was resected on cardio-pulmonary bypass by a cardiothoracic surgeon and an abdominal surgeon with special expertise in renal surgery. The majority of the tumour was pulled out from the right ventricle as it was quite mobile. However an incision was also made in the IVC from the level of the left renal vein to remove the mass from the left renal vein and an incision was also made in the left renal vein itself. There was a small amount of tumour in the left ovarian vein and therefore the left ovarian vein was removed. The uterus, fallopian tubes and ovaries were not resected because the patient was unwilling to be rendered infertile. The histology of the mass removed from the right ventricle was reported as benign leiomyoma. Fig. 1A, Fig. 1B shows haematoxylin and eosin (H&E) a stained section of the resected specimen at two different magnifications. It was reported as follows: “Sections show an encapsulated, elongated spindle cell tumour with large areas of infarction. The tumour is composed of bland spindle cells arranged in loose fascicles, and admixed with thick-walled blood vessels, few of which show hyalinization. Myxoid change is noted focally, mitoses and nuclear pleomorphism is not seen. The tumours cells stain for ER, PgR, desmin, SMA, Bcl-2 and caldesmon and are negative for S100, CD34, CD117, calretinin, AE1/3 and HMB45.” We also note the presence of clear cells and both this and hyalinisation have been reported in intravascular leiomyomatosis together with the suggestion that the appearances of intravascular leiomyomatosis differ somewhat from benign leiomyoma (Han et al., 1998, Yaguchi et al., 2010).Fig. 1A H&E stained section of resected tumour from the right ventricle at 10X magnification showing a large thick-walled blood vessel, spindle cells loosely packed in a myxoid stroma. No mitoses are seen.
Fig. 1B Part of the same section is shown at 20x magnification.
No prophylaxis was offered following surgery and the patient was lost to follow-up. She re-presented in 2009 with large pelvic and abdominal masses (Fig. 2a), lung nodules (Fig. 2b) and a suspicion of recurrence in the IVC indicating a diagnosis of intravascular leiomyomatosis. The following year in 2010 a cardiac MRI scan confirmed the presence of tumour in the IVC and right atrium. Treatment with a combination of goserelin and letrozole was commenced in August 2010 resulting in a rapid reduction in the size of pelvic and abdominal leiomyomas (Fig. 3A and B), a slight reduction in the size of pulmonary metastases was also seen together with regression of disease in the IVC on cardiac MRI.Fig. 2 Axial contrast enhanced CT abdomen & pelvis performed in 2009 demonstrates large uterine leiomyomata (A) and pulmonary nodules (arrow B).
Fig. 3 Coronal CT reformat from a contrast enhanced CT performed in July 2010 (A), September 2010 (B) and 2012 (C) shows shrinkage of the masses.
There was a further slight reduction in the volume of intra-abdominal disease (Fig. 3C) in 2011. However, the patient was increasingly distressed by the side effects of oestrogen suppression, particularly by insomnia and reduced libido and discontinued treatment to relieve these symptoms in 2012. A CT in March 2013 showed slight progression in both the pelvic and abdominal disease and lung metastases. In June 2013 a repeat CT showed a further increase in the size of the pelvic disease and a cardiac MRI and echocardiogram showed possible recurrent disease in the IVC. Ulipristal acetate was commenced in March 2013 but has since been discontinued. Letrozole and goserelin treatment was recommenced in October 2013 and continued until 2015.
At an out-patient visit in August 2015 she reported that during a trip to the Southern USA in February 2013 to visit a relative, during which she had much more exposure to sunlight than in the UK, she experienced a significant reduction in the size of the abdominal masses and the associated abdominal bloating and discomfort. She was also taking oral vitamin D3 supplements in the form of cod liver oil and vitamin D3. Following this experience, noting that her tumours were smaller in the Summer, during the year 2015 she started regularly using a sunbed twice a week, when access to strong sunshine was not possible. She continued to take cod liver oil and vitamin D3. This combined strategy proved successful and she was able to stop the letrozole and goserelin in 2015 without suffering a relapse. Vitamin D blood levels were not examined following this new information, because we had no baseline prior to the start of self-medicated vitamin D supplementation. Fig. 4 shows a comparison between a representative tumour in 2013 and the same tumour in 2015 showing a small reduction in tumour volume. The patient remains well to this day with stable disease by RECIST, although a more recent scan may show slight progression, and has not needed to recommence treatment with letrozole and goserelin in the last 5 years.Fig. 4 Axial T2W MRI in 2013 (A) and 2015 (B) showing a large soft tissue mass centred on the uterus (*). Maximum axial dimension in 2013 was 24.2 × 13.9 cm compared with 22.4 × 12.2 cm in 2015.
2 Discussion
Uterine leiomyomas (fibroids) are extremely common. It is estimated that by the age of 50, nearly 70% of white women and >80% of African-American women will have ultrasound evidence of uterine fibroids. A recent study demonstrated a link between low blood levels of 25-hydroxyvitamin D (<20 ng/ml) and an increased risk of leiomyomata (Han et al., 1998). A study in Italy reported similar findings, demonstrating that women with at least one uterine leiomyoma had a significantly lower blood level of 25-hydroxyvitamin D3. In this study 25-hydroxyvitamin D3 deficiency was defined as <10 ng/ml and this was associated with an odds ratio for leiomyoma of 2.4 (95% confidence interval 1.2–4.9, P-0.16) compared with controls (Yaguchi et al., 2010). An American nutrition survey African-American women were 10 times more likely to have low vitamin D levels than white women (Baird et al., 2013). The increased incidence of uterine leiomyomas in African–American women has been identified as a public health issue (Eltoukhi et al., 2014; Paffoni et al., 2013). It has been shown that 1–25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates the expression of oestrogen and progesterone receptors in uterine leiomyoma cells (Al-Hendy et al., 2015; Nesby-O'Dell et al., 2002). Treating these cells with 1,25(OH)2D3 reduced the expression of oestrogen receptor-α, progesterone receptor-A and B and members of the steroid receptor coactivator (SRC) family. In addition, 1,25(OH)2D3 also reduces TGFβ3- induced fibrosis-related gene expression, e.g. collagen and fibronectin genes, in uterine leiomyoma cells (Halder et al., 2011; Sharan et al., 2011). Vitamin D3 has also been shown to inhibit the proliferation of uterine leiomyoma cells via inhibition of catechol-o-methyltransferase (Al-Hendy et al., 2016) and to inhibit WNT/β-catenin and mTOR signalling pathways in uterine leiomyoma cells (Ciavattini et al., 2016). There is a strong case for considering vitamin D supplementation in women of reproductive age and hypovitaminosis D as a preventive measure and some evidence that this can prevent the progression of pre-existing uterine leiomyomas (Ordulu et al., 2016).
3 Conclusions
The role of vitamin D in the pathogenesis of leiomyomas is still not universally recognised by gynecologists. Hypovitaminosis D is a significant problem in women of darker skin ethnicity living in Northern climates, since they require greater sun exposure to generate sufficient vitamin D in the skin, sometimes compounded by cultural factors. This case highlights the potential value of sunlight and vitamin D supplementation in controlling leiomyomas. What is particularly unusual is the fact that this woman was diagnosed with the potentially life-threatening situation of intravascular leiomyomatosis with tumour extending up the IVC into the right atrium prior to successful treatment with combined oestrogen deprivation. This is now recognised to be a disease of intermediate grade malignancy as reported by Ordulu et al. (2016), with a gene expression profile similar to that of leiomyosarcoma, rather than leiomyoma or normal myometrium and the frequent finding of a translocation der[14]t[12;14](q14.3;q24) as shown by co-localization of probes for HMGA2 (12q14.3) and 14q24 by FISH. In contrast, this study also showed no evidence in the intravenous leiomyomatosis cases of loss of 7q22, frequently deleted in uterine leiomyomata. This case is by no means proof, but it seems likely that this condition is also influenced by the same hormonal factors as common leiomyomas and hence its growth is potentially enhanced by lack of vitamin D and impeded by repletion.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Authorship
Both authors contributed to the manuscript, IJ was mainly responsible for the case report and discussion and was the physician who initially cared for the patient. CM was responsible for the choice and presentation of the images. Both authors reviewed the final manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding acknowledgements
We wish to acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre, Clinical Research Facility in Imaging and the Cancer Research Network. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health. | GOSERELIN, LETROZOLE | DrugsGivenReaction | CC BY-NC-ND | 33364287 | 18,880,673 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coma'. | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | CYTARABINE, DAUNORUBICIN, HYDROCORTISONE, IDARUBICIN, METHOTREXATE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cranial nerve disorder'. | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | CYTARABINE, DAUNORUBICIN, HYDROCORTISONE, IDARUBICIN, METHOTREXATE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Encephalomyelitis'. | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | CYTARABINE, DAUNORUBICIN, HYDROCORTISONE, IDARUBICIN, METHOTREXATE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Incorrect route of product administration'. | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | CYTARABINE, DAUNORUBICIN, HYDROCORTISONE, IDARUBICIN, METHOTREXATE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mental impairment'. | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | CYTARABINE, DAUNORUBICIN, HYDROCORTISONE, IDARUBICIN, METHOTREXATE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelopathy'. | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | CYTARABINE, DAUNORUBICIN, HYDROCORTISONE, IDARUBICIN, METHOTREXATE, TRETINOIN | DrugsGivenReaction | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the administration route of drug 'HYDROCORTISONE'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the administration route of drug 'METHOTREXATE'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | Intrathecal | DrugAdministrationRoute | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the dosage of drug 'HYDROCORTISONE'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | RECEIVED HIS FIRST DOSE OF PROPHYLACTIC INTRATHECAL CHEMOTHERAPY WITH METHOTREXATE, CYTARABINE, A... | DrugDosageText | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the dosage of drug 'IDARUBICIN'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | THE PATIENT WAS SUBSEQUENTLY ADMITTED IN AUGUST 2010 FOR THE FIRST CYCLE OF CONSOLIDATION THERAPY... | DrugDosageText | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the dosage of drug 'METHOTREXATE'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | RECEIVED HIS FIRST DOSE OF PROPHYLACTIC INTRATHECAL CHEMOTHERAPY WITH METHOTREXATE, CYTARABINE, A... | DrugDosageText | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the outcome of reaction 'Coma'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the outcome of reaction 'Cranial nerve disorder'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | Fatal | ReactionOutcome | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the outcome of reaction 'Encephalomyelitis'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | Fatal | ReactionOutcome | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the outcome of reaction 'Mental impairment'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | Fatal | ReactionOutcome | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
What was the outcome of reaction 'Myelopathy'? | Inadvertent intrathecal administration of daunomycin resulting in fatality: Case report and therapeutic considerations.
Daunomycin is a chemotherapeutic agent of the anthracycline family that is administered intravenously, most commonly in combination therapy. The authors report the first known adult case of inadvertently administered daunomycin directly into the human central nervous system and the neurologic manifestations and therapeutic interventions that followed.
A 53-year-old male presenting to the hospital for his second cycle of consolidation therapy for acute promyelocytic leukemia t(15;17) was accidentally administered 93 mg of intrathecal (IT) daunomycin. Within several hours of injection, the patient subsequently developed bilateral lower extremity pain, ascending paresthesias, headache, and left cranial nerve (CN) III palsy. Immediately following these neurologic sequalae, a subarachnoid lumbar drain was placed at the L4-5 interspace for the initial irrigation and drainage of cerebrospinal fluid (CSF). By hospital day 2, the patient's mental status significantly declined requiring an external ventricular drain (EVD) for hydrocephalus. Despite therapeutic interventions, the patient developed an ascending radiculomyeloencephalopathy with deterioration in clinical status. Eighteen days after the inadvertent injection of IT daunomycin, the patient became comatose and lost all cranial nerve function.
Accidental IT injection of daunomycin is a neurosurgical emergency and warrants prompt intervention. Symptoms can mimic other medical conditions, making it imperative an accurate diagnosis is made so that appropriate therapies are implemented. At this time, therapies include rapid removal of the chemotherapeutic agent from the IT compartment by aspiration and irrigation; however, it is unclear if neuroprotective agents may provide added benefit.
1 Background and importance
Daunomycin (or daunorubicin) is a cytotoxic anthracycline antibiotic that is often used in combination therapy for treatment of acute myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), neuroblastoma, and rhabdomyosarcoma [1]. Discovered over 50 years ago, daunomycin is an produced naturally by Streptomyces peucetius, a species of actinobacteria [2]. Daunomycin imparts its effects by DNA intercalation through a thermodynamically favorable process. Daunomycin binds DNA with a preference for a triplet sequence containing an AT base-pair flanked by adjacent GC base-pairs, as this provides an arrangement of hydrogen bonds with an ideal stereochemical fit [3]. A potent inhibitor of topoisomerase II, daunomycin facilitates the formation of double strand breakages [3].
Daunomycin and other anthracycline derivatives such as doxorubicin are commonly associated with cardiotoxicity [4]. While the association with adverse cardiac events have been extensively documented, relatively little is known about the potential adverse effects of daunomycin on the central nervous system (CNS). Dose-dependent neurotoxic effects of doxorubicin have been demonstrated, however, and is thought to occur by impairment of long-term potentiation, induction of apoptosis, and increased superoxide production and lipid peroxidation [5,6]. While anthracycline administration is typically performed intravenously, doxorubicin is thought to accumulate within the CNS in cancer patients due to reduced blood-brain barrier integrity given an upregulation in pro-inflammatory cytokines [2,5].
Not uncommonly, inadvertent intrathecal (IT) injection is another means by which neurotoxic agents may be introduced to the CNS. For example, 35 cases of accidental IT administration of vincristine have been reported, with 28 case fatalities [7]. Direct aspiration and continuous irrigation of CSF has been proposed as a means of reducing the concentration of an inadvertently intrathecally administered toxic agent and preventing diffuse nervous system damage [8]. With respect to daunomycin, only a single case has been reported in a pediatric patient that led to progressive diffuse cerebral atrophy with fatal outcome despite aggressive measures [9]. Here, the authors report the first case of accidental IT administration of daunomycin in an adult patient and describe the clinical course, neurologic manifestations, and therapeutic interventions that followed.
2 Clinical presentation
2.1 History
A 53-year-old man with a past medical history of obstructive sleep apnea (OSA), Helicobacter gastritis, and prior myocardial infarction was admitted to Georgetown University Hospital for treatment of acute promyelocytic leukemia in September 2010. At the time of his acute myocardial infarction in June 2010, the patient was diagnosed with acute promyelocytic leukemia, t(15;17). He was transferred to Georgetown University Hospital and underwent induction therapy with All-Trans Retinoic Acid (ATRA), daunomycin, and cytarabine. His hospital course at that time was complicated by neutropenic fever and typhilitis. After induction treatment, a bone marrow biopsy in July 2010 revealed normocellular activity without residual blasts consistent with a complete morphologic remission.
The patient was subsequently admitted in August 2010 for the first cycle of consolidation therapy with ATRA, idarubicin, and cytarabine. The patient also received his first dose of prophylactic intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone. A bone marrow biopsy at that time showed no morphologic evidence of leukemia. The patient was admitted in September 2010 for his second cycle of consolidation therapy with daunomycin (128 mg) and high-dose cytarabine (4140 mg). He received his first dose of intravenous daunomycin and cytarabine without incident. The following day, the patient was brought down to the radiology suite for a fluoroscopic guided lumbar puncture with administration of intrathecal chemotherapy. Lumbar puncture (LP) was performed, revealing clear CSF, 2 RBCs, 1 WBCs, protein 58, and glucose 60. Over the next few hours, the patient began to complain of bilateral leg pain and paresthesias, increasing back pain, and headache. At that time, it was discovered that he had inadvertently received 93 mg of daunomycin intrathecally instead of triple therapy with methotrexate, cytarabine, and hydrocortisone. The neurosurgical service was consulted several hours after intrathecal administration, and the patient was transferred to the neurosurgical intensive care unit for further management.
2.2 Presentation and treatment
On admission to the neurosurgical intensive care unit, the patient complained of bilateral lower extremity pain, paresthesias, and headache. Immediately after assessing the patient, a subarachnoid lumbar drain (LD) was placed at the L4-5 interspace. Red-tinged CSF was noted to drain at the time of lumbar puncture. Prior to placement of lumbar drain, a CSF lavage was performed followed by continuous CSF drainage at a rate of 15 mL per hour. Laboratory analysis after LD placement revealed pink CSF, 100 RBCs, 40 WBCs, 2135 protein, and 118 glucose.
On hospital day 2, a right external ventricular drain (EVD) was placed after endotracheal intubation due to a decline in mental status and concern for hydrocephalus on radiological studies, including increased size of the third ventricle and temporal horns of the lateral ventricles. The intracranial pressure was 40 cm H2O at the time of insertion, and the EVD was opened to drain at 10 cm H2O. Elevated intracranial pressure and cerebral edema seen on serial computed tomography (CT) scans were managed using CSF drainage, hypertonic saline, and hyperventilation. An attempt to wean the EVD in the ensuing days was unsuccessful due to elevated intracranial pressures. On hospital day 14, the patient was taken to the operating room for the insertion of a ventriculo-peritoneal (VP) shunt. Postoperative head CT showed moderate improvement in the size of the lateral ventricles, however, a subsequent head CT on postoperative day 2 revealed dilated lateral ventricles and raised concern for proximal shunt failure. The patient was therefore taken emergently to the operating room for revision of the proximal shunt catheter.
2.3 Clinical course
Several hours after the incident, the patient was examined and noted to have a left CN III palsy. The patient experienced a decline in mental status requiring intubation and placement of an EVD on hospital day 2. During the subsequent days, the patient developed bilateral lower extremity paraparesis, which progressed in an ascending manner. An MRI of the patient's lumbosacral spine demonstrated thickening and perimedullar enhancement of the conus medullaris and cauda equina (Fig. 1). By hospital day 5, the patient was unable to move his lower extremities. He was areflexic in his lower extremities and hyperreflexic in his upper extremities. The patient intermittently followed commands in his upper extremities but was only able to move his thumbs. On hospital day 8, the EVD was raised to 15 cm H2O, but the patient was unable to tolerate as ICPs were sustained above 20 cm H2O. Therefore, a VP shunt was placed on hospital day 14. An MRI scan of the brain showed diffuse leptomeningeal enhancement of the skull base and anterior interhemispheric fissure (Fig. 2).Fig. 1 Parasagittal Gd-enhanced T1-weighted magnetic resonance images of the lumbosacral spinal cord obtained 13 days after inadvertent intrathecal daunomycin administration, showing thickening and abnormal enhancement of the conus medullaris and cauda equina.
Fig. 1Fig. 2 Axial Gd-enhanced T1-weighted magnetic resonance images of the brain 10 days after inadvertent intrathecal daunomycin administration, demonstrating diffuse abnormal leptomeningeal enhancement at the base of the skull, Sylvian fissures, and anterior interhemispheric fissure. There is also signal abnormality at the nuclei accumbens in the basal ganglia regions.
Fig. 2
Eighteen days after the incident, the patient's neurological state severely deteriorated. The patient was unable to follow commands and lost all cranial nerve function on examination. Cold caloric testing was performed on hospital day 19 and demonstrated an absent vestibulo-ocular reflex. Due to the patient's poor neurological examination, the family chose to withdraw care and allow natural death.
3 Discussion
Inadvertent injection of IT daunomycin been documented only once previously in the literature in a pediatric patient [9]. To our knowledge, this is the first reported case of inadvertent IT daunomycin injection in an adult patient, as well as the first in the neurosurgical literature. The prior case involved a 3½-year-old girl with pneumonia and otitis media who was diagnosed with ALL. A mislabeling error led to the inappropriate IT injection of daunorubicin as opposed to cytosine arabinoside, which was recognized one hour after injection. At this time, hydrocortisone was injected into the IT space, a 2-day course of intravenous methylprednisolone was started, and a LD was placed for continuous CSF drainage. CT head, neurological examination, and nerve conduction studies were all normal at this time, and the LD was removed on day 4.
Unlike our patient, it took nearly 1 week for symptom onset, with a presentation of meningeal signs being evident on day 6. CSF studies at this time demonstrated elevated protein (3200 mg/dL), glucose (109 mg/dl), and RBCs (208 cells/mm3), similar to the CSF profile of our patient. On day 10, CT head demonstrated cerebral atrophy, and profound neurologic deterioration occurred by day 17. Another difference from our case was that this patient remained relatively stable in this condition for at least another 7 weeks until electroencephalography at 9 weeks demonstrated no brain activity; ventilator support was discontinued at this time. A side-by-side comparison of these two cases is presented in Table 1.Table 1 A comparison of two cases of inadvertent intrathecal daunomycin injection.
Table 1 Patient 1 Patient 23
Age, sex 53, Male 3½, Female
Diagnosis APL ALL
Time to symptom onset 3–4 h 6 days
Initial presentation Headache, back pain, bilateral leg pain, paresthesias Headache, neck stiffness
Initial imaging studies Hydrocephalus, conus medullaris enhancement Normal
CSF profile at symptom Onset Red-tinged, 100 RBCs, 40 WBCs, 2135 protein, 118 glucose Red-tinged, 208 RBCs, 3200 protein, 109 glucose
Time to intervention 3–4 h 1 h
Interventions implemented CSF lavage, continuous CSF drainage, EVD (Day 2), VP shunt (Day 14) IT hydrocortisone injection, 2-days IV methylprednisolone, continuous CSF drainage.
Time of brain death Day 19 Day 63
The antitumor effects of anthracycline agents such as daunomycin are distinct from their intrinsic cytotoxic mechanisms. In neoplastic tissue, daunomycin induces double strand DNA breaks by the inhibition of topoisomerase II, a process that leads to tumor cell death [1]. In contrast, healthy tissues, including the heart, brain, and kidney, may be affected by a variety of dose-dependent mechanisms. Daunomycin is not traditionally considered neurotoxic such as vincristine; however, a number of different mechanisms may be at play including formation of reaction oxygen species, enhanced brain nictric oxid synthase formation, and persistent activation of microglia and increased acute phase reactents [[10], [11], [12], [13]].
Intrathecal injection of daunomycin acts by a dose-dependent mechanism to cause neuronal cytotoxicity in the CNS [9]. As the current case demonstrates, most damage is initially present near the site of injection (L4-L5 interspace), and progresses cranially to cause ascending paraparesis and other neurologic deficits. This phenomenon and transverse myelopathy has been reported in similar cases resulting from the inadvertent IT administration of other chemotherapeutic compounds. This includes methotrexate, cytarabine, and most commonly vincristine [7,[14], [15], [16], [17]]. Since the first reported IT injection of vincristine in 1968, 35 cases have been published; this is thought to be an underestimate, with many more cases going unreported and anecdotal accounts suggesting more than 100 cases [7,18]. Over the last two decades, discussion over the best preventative practices have taken place including dilution of vincristine concentrations or replacing syringes altogether with mini-bags [7,19]. Despite this, fatal cases of inadvertent IT injections continue to be reported, with one group mistakenly attributing symptoms to Guillain-Barre Syndrome [20,21].
Methods of limiting neurotoxicity after inadvertent injection include reducing drug availability within the CSF and preventing excessive caudo-cranial transport of the compound. Since drug cytotoxicity is dose-dependent, removal of drug by immediate CSF aspiration can theoretically limit diffusion and direct cytotoxic effects. However, studies have shown that CSF aspiration alone fails to retrieve substantial quantities of drug; in cases of intrathecal vincristine injection, no patient survived in which only aspiration of CSF was performed [14]. When irrigation of the intrathecal compartment was combined with aspiration, survival improved and damage was limited to sensorimotor deficits in the upper and lower extremities, but only when irrigation lasted more than 24 h and continuous drainage was maintained by lumbar drain and EVD [8,14]. Irrigation and drainage serves not only to remove substantial quantities of drug, but also to limit caudo-cranial diffusion, a process that may be further limited by maintaining the patient at a minimum 45° angle throughout treatment.
In cases of inadvertent IT vincristine injection, several compounds have been used as empiric antineurotoxic therapy, although the evidence for the use of these agents is weak [8,14]. Glutamic acid, folic acid, pyridoxine, and corticosteroids have traditionally been used, based on evidence acquired from animal studies [[22], [23], [24]]. Only glutamic acid has been proven to limit neurotoxicity in clinical trials but only when chemotherapy had been given at therapeutic, intravenous doses [25]. However, no patient survived in which antineurotoxic therapy had been used exclusively [8,14]. Only when paired with aspiration and irrigation may these compounds benefit the patient, although survival remains poor. As previously mentioned, similar studies have highlighted the use of compounds like dexrazoxane and epicatechin to limit cytotoxicity of daunomycin when the drug is given at conventional, intravenous doses [12,13]. Thus, in cases of inadvertent IT administration of daunomycin, these drugs may have similar benefit when paired with aggressive neurosurgical therapy.
4 Conclusion
To date, this is the second documented case of inadvertent intrathecal administration of daunomycin, and the first reported case in an adult patient. Our report describes the time course, neurologic manifestations, and radiographic findings associated with direct daunomycin neurotoxicity despite neurosurgical intervention. A few hours after receiving an accidental intrathecal injection of daunomycin, the patient experienced bilateral lower extremity pain and paresthesias, which progressed within days to bilateral lower extremity paralysis and the eventual loss of all cranial nerve function by hospital day 18. MRI of the patient's lumbosacral spine revealed progressive thickening and enhancement of the conus medullaris and cauda equina. MRI of the brain was characterized by diffuse, abnormal leptomeningeal enhancement of the skull base, Sylvian fissures, and anterior interhemispheric fissure.
Like many chemotherapeutic agents, daunomycin causes a dose-dependent cytotoxicity. As with previously reported cases, care was taken to rapidly remove the chemotherapeutic agent from the IT compartment by aspiration and irrigation and followed by continuous drainage by LD and EVD. However, even aggressive neurosurgical therapy did not prevent progressive neurological decline in our patient. In this case, the patient became symptomatic hours after accidental injection. It is therefore unknown whether earlier recognition, leading to more prompt initiation of therapy, would have improved the patient's outcome. In addition, it remains unclear whether administration of neuroprotective agents would have been effective in this case, although this remains something to explore in future instances.
Patient consent
Consent was not obtained as the patient expired and this report has been completely anonymized and does not include identifiable personal health information.
Funding
No funding was received for this case report.
Declaration of Competing Interest
The authors deny any conflict of interest. | Fatal | ReactionOutcome | CC BY-NC-ND | 33364452 | 18,941,912 | 2021-03 |
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