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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Embolism'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enterocolitis'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
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Grade B (Very good): B
Grade C (Good): C
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Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatotoxicity'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
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Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ileus'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
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Grade B (Very good): B
Grade C (Good): C
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Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palmar-plantar erythrodysaesthesia syndrome'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
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Grade B (Very good): B
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P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paraesthesia'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Perineal infection'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Stoma site infection'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
What was the administration route of drug 'FLUOROURACIL'? | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
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P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | Intravenous bolus | DrugAdministrationRoute | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
What was the administration route of drug 'LEUCOVORIN'? | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
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P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
What was the administration route of drug 'OXALIPLATIN'? | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
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Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Motor dysfunction'. | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC-ND | 33643649 | 19,042,858 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC-ND | 33643649 | 19,018,928 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC-ND | 33643649 | 18,997,351 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urinary tract infection'. | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC-ND | 33643649 | 18,997,351 | 2021-03 |
What was the outcome of reaction 'Motor dysfunction'? | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | Recovered | ReactionOutcome | CC BY-NC-ND | 33643649 | 19,042,858 | 2021-03 |
What was the outcome of reaction 'Off label use'? | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | Recovered | ReactionOutcome | CC BY-NC-ND | 33643649 | 19,018,928 | 2021-03 |
What was the outcome of reaction 'Pneumonia'? | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | Recovered | ReactionOutcome | CC BY-NC-ND | 33643649 | 18,997,351 | 2021-03 |
What was the outcome of reaction 'Posterior reversible encephalopathy syndrome'? | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | Recovered | ReactionOutcome | CC BY-NC-ND | 33643649 | 19,018,928 | 2021-03 |
What was the outcome of reaction 'Status epilepticus'? | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | Recovered | ReactionOutcome | CC BY-NC-ND | 33643649 | 19,018,928 | 2021-03 |
What was the outcome of reaction 'Urinary tract infection'? | Posterior reversible encephalopathy syndrome presenting as refractory status epilepticus in a patient taking Mycophenolate mofetil for IgA nephropathy: A case report.
•Posterior reversible encephalopathy syndrome is one of the numerous causes of status epilepticus and it should be kept in mind while encountering such clinical scenario.•Mycophenolate mofetil can be contributory cause of PRES.•Prompt recognition and timely intervention is a key to full recovery without any residual neurological deficits after refractory status epilepticus.
1 Introduction
Status epilepticus is a neurological emergency which is defined as a continuous seizure lasting for more than 5 minutes or two or more seizures without full regain of consciousness between any of them [1]. One-third of people with status epilepticus will eventually develop refractory status epilepticus in which there is persistent seizures despite treatment with benzodiazepines and one antiepileptic drug [2]. Posterior reversible encephalopathy syndrome is a clinico-radiological syndrome which presents with rapid onset of symptoms including headache, seizures, altered consciousness, and visual disturbance. PRES is one among the numerous causes of status epilepticus. Therefore, it is vital to detect it early for better neurological outcome. PRES is strongly associated with conditions like renal disease, hypertension, vascular and autoimmune diseases, exposure to immunosuppressive drugs, and organ transplantation.[3]We hereby report a case of a patient receiving Mycophenolate mofetil for IgA nephropathy who presented with refractory status epilepticus as a manifestation of PRES.
2 Case report
A 28 year old female was referred to our center with history of generalized tonic clonic seizures 5 days prior to the presentation to our hospital. There was no history of fever, neck rigidity, vomiting, and photophobia. There was no history of similar illness in the family and no history of drug allergy. During the stay in the previous hospital, the patient developed two more episodes of generalized tonic clonic seizure and multiple episodes of focal seizure due to which patient was intubated in view of refractory seizure. At arrival in our center, the patient had GCS of E1VETM1 and bilateral pupils were sluggishly reactive to light. Her vital signs and systemic examination were unremarkable. She was diagnosed with IgA nephropathy 5 months earlier and was currently taking Mycophenolate mofetil.
Initial laboratory investigations showed no abnormal results except the finding of erythrocytes in urine examination. Lumbar puncture was done by the team of Intensivists but CSF analysis showed no abnormal findings. An initial CT scan of head showed no acute abnormal changes. Investigations to rule out autoimmune encephalitis were sent which were negative.
After admission in our intensive care unit, the patient was kept on anticonvulsant therapy (Levetiracetam, Oxcarbazepine and Sodium Valproate). Despite these measures, she continued to have seizure activity and was then started on infusion of propofol. EEG was done which showed epileptic spike when propofol infusion was stopped and it subsided when propofol infusion was restarted. On 2nd day of admission, she was also started on benzodiazepines (Clobazam). Ketamine infusion was also started as she continued to have seizure activity. This was able to control her seizures and was continued for one more day. Her propofol infusion was continued until the 4th day of admission.
For IgA Nephropathy, Mycophenolate mofetil was discontinued from the time of admission and steroid was started. An MRI scan of the brain was done which showed Cortical/Subcortical T2 flair hyperintensity involving the left posterior parietal region with no diffusion restriction or susceptibility change characteristic of PRES as shown in Fig. 1. During the stay in the hospital, the patient developed Urinary tract infection and Hospital Acquired pneumonia which were treated with appropriate antibiotics. She also underwent tracheostomy due to prolonged mechanical ventilation. The patient was finally discharged with oral antiepiletics (Levetiracetam, Clobazam and Oxcarbazepine) after successful decannulation of tracheostomy tube. At the time of discharge, the patient had residual neurological deficit in terms of motor weakness of bilateral upper and lower limbs, which improved completely with continuous physiotherapy and rehabilitation. At the three month period of follow up in the hospital she was completely asymptomatic.Fig. 1 MRI examination-hyperintense lesions in the left posterior parietal region.
Fig. 1
3 Discussion
Posterior reversible encephalopathy syndrome is a serious neurological condition triggered by various clinical conditions. Typical PRES presentation includes headache, visual disturbances, stupor and seizures. Seizures are usually generalized and they occur in the acute stage of the disease, that commonly resolve within days. Refractory status epilepticus is a rare occurrence in PRES [4,5]. The treatment of PRES is aimed to identify underlying causes of the syndrome, and to control hypertension and seizures. In our case, refractory status epilepticus was aggressively managed with intravenous infusion of propofol and ketamine in addition to other antiepileptic drugs.
The proposed pathogenic mechanism for PRES involved hypertension as an inducer of loss of cerebral autoregulation, brain hyperperfusion and endothelial injury leading to the vasogenic edema [6,7]. Association of PRES with Mycophenolate mofetil has been reported in the literature [8,9]. The precise pathogenesis of PRES with Mycophenolate mofetil is not understood. But, it is found that Mycophenolate mofetil inhibits the expression of VCAM-1 and ICAM-1, disrupting the remodeling of the vessel wall leading to impairment of smooth muscle cell proliferation [10].
Not much is known about the incidence of PRES in kidney diseases like IgA Nephropathy. This may be the first reported case of PRES in IgA Nephropathy. Other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis should be considered as differential diagnosis during evaluation of PRES. There is limited history and broad differential diagnosis, and early neuroimaging is crucial for the diagnosis of PRES.[11]Typical radiological findings in PRES includes increased signal on T2 and fluid-attenuated inversion recovery (FLAIR) imaging of subcortical white matter with vasogenic edema predominantly involving the parieto-occipital and posterior temporal lobes of both hemispheres of the brain [12].
4 Conclusion
Several cases of PRES are being reported frequently in association with different clinical scenario. Our case showed the rare association of refractory status epilepticus as presenting feature of PRES in patient taking Mycophenolate mofetil for IgA Nephropathy. Complete recovery is possible even after life threatening prolonged refractory status epilepticus with prompt recognition and treatment.
Sources of funding
This study has not received any funding.
Ethical approval
This case report was conducted in compliance with ethical standards.
Consent
Informed written consent has been obtained.
Author contribution
I. Kripa KC took relevant history, clinical examination, collected relevant investigations of the patient and wrote the report. And she was directly involved in patient's care.
II. Supriya Lamichhane also wrote the report with relevant history and investigations. And she was directly involved in patient's care.
III. Sarita Kathayat also wrote the report and revised it with relevant information.
IV. Rohit Kumar Chaudhary reviewed and edited the case report. And he was directly involved in patient's care.
V. Sushil Khanal worked for literature review and revision of the case report into its final version.
VI. Subhash Prasad Acharya provided support and mentorship for development, writing and revision of this case report.
Research registration
NA.
Guarantor
Sushil Khanal.
Provenance and peer review
Not commissioned, externally peer reviewed.
Declaration of competing interest
There is no any conflict of interest.
Appendix A Supplementary data
The following is the supplementary data to this article:Multimedia component 1
Multimedia component 1
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.amsu.2021.01.095. | Recovered | ReactionOutcome | CC BY-NC-ND | 33643649 | 18,997,351 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease complication'. | Carfilzomib-induced pulmonary hypertension with associated right ventricular dysfunction: A case report.
Carfilzomib, a selective proteasome inhibitor, is approved for use in relapsed and refractory multiple myeloma. Its link to left ventricular dysfunction is well established but little is known about its effects on the right ventricle. One of its rare complications is pulmonary hypertension, which at its extreme may result in right ventricular dysfunction. Here, we present a case of an elderly male veteran with multiple myeloma status post various failed therapies who developed acute dyspnea after four cycles of carfilzomib and subsequently found to have severe pulmonary hypertension with resultant acute right ventricular failure, which recovered after cessation of carfilzomib. This case highlights the need for careful cardiovascular surveillance while on carfilzomib and the importance of knowing even its rarest complications as these cardiotoxicities are reversible with discontinuation of the drug.
Introduction
Carfilzomib is a selective and irreversible proteasome inhibitor (PI) approved for treatment of relapsed and refractory multiple myeloma.1 Aggregated safety results from four phase II trials,2 including a majority of patients with underlying cardiac disease, subsequently found 7.2% of them developed cardiac failure but there were no significant differences in overall mortality between those with and without pre-existing cardiac disorders.2 Similarly, a small case series from a single center of 67 patients treated with carfilzomib found that most patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib also had a history of the specific cardiovascular (CV) event they exhibited, reflecting experience in a real-world patient population.3 The ASPIRE trial compared carfilzomib plus standard therapy (lenalidomide and dexamethasone) to standard therapy alone and showed carfilzomib group to have higher any-grade dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), heart failure (6.4% vs 4.1%) and ischemic heart disease (5.9% vs 4.6%).4 There is little debate regarding the increased CV events associated with carfilzomib, in particular, when it relates to left ventricular function. However, there is scant data on carfilzomib-induced pulmonary hypertension (PH) in the real-world myeloma population and the risks for developing right ventricular (RV) dysfunction. It is imperative for clinicians to be aware and, therefore, be able to identify these complications as these CV sequalae may be reversible with cessation of the medication. Our aim is to report our experience with an interesting real-world case of carfilzomib-induced acute PH with associated RV failure and highlight the need for routine surveillance with echocardiography for early detection of these CV complications.
Case presentation
A 71-year-old veteran male with IgG lambda multiple myeloma, status post failed autologous stem cell transplant with melphalan as well as numerous lines of chemotherapy including bortezomib, presented with acute dyspnea 2 months after he was started on carfilzomib/bendamustine/dexamethasone combination therapy. His other comorbid conditions included systemic hypertension that is treated with carvedilol and amlodipine, remote history of pulmonary embolism now on apixaban, obstructive sleep apnea while compliant with continuous positive airway pressure use and obesity. He had normal pulmonary function test 2 years prior to this index episode. The patient also had a baseline transthoracic echocardiogram (TTE) just before starting carfilzomib revealing normal biventricular and valvular function without evidence of PH, but there was trace circumferential pericardial effusion that’s been chronic for at least 2 years prior. On starting carfilzomib, the patient started noticing worsening dyspnea on exertion until 2 months later when he suddenly developed shortness of breath while ambulating immediately after completing cycle 4 of carfilzomib infusion. He was transferred urgently to the emergency room at which time the vitals were within normal limits except for exertional oxygen saturation of 88% while on room air. The exam was significant for an obese male with mild respiratory distress and mild bilateral lower extremity edema. Cardiac troponins were within normal limits, but brain natriuretic peptide was mildly elevated (148 μg/dL). Electrocardiogram revealed new T-wave inversions in leads V2–V3 (Figure 1). Computed tomography pulmonary angiogram study with contrast demonstrated normal lung parenchyma without evidence of pulmonary embolism or infiltrates. Repeat TTE, however, showed newly dilated RV with significantly reduced RV systolic function (Figure 2) with tricuspid annular plane systolic excursion (TAPSE) of 1.3 cm and an estimated pulmonary arterial systolic pressure (PASP) of 56–61 mmHg (Figure 3).
Figure 1. Electrocardiogram: new nonspecific T-wave changes in V2–V3 when patient became acutely dyspneic after carfilzomib infusion.
Figure 2. RV focused view during chemotherapy: newly dilated RV with reduced systolic function (TAPSE was 1.3 cm) and lateral wall akinesis. Chronic trace pericardial effusion is also present. LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Figure 3. Continuous-wave Doppler during chemotherapy: pulmonary arterial systolic pressure is newly elevated as demonstrated by increased tricuspid regurgitation peak velocity of 3.47 m/s.
Having systematically excluded all major cardiopulmonary disorders (to include pulmonary embolism, acute coronary syndrome, pneumonia, acute anemia) and given the temporal relationship of treatment with carfilzomib to patient’s presentation, decision was made to stop carfilzomib. The patient did not receive any further medical interventions because he was clinically stable once admitted. No diuretics were given. No arterial blood gas was obtained. The patient was discharged after 2 days of monitoring. Right heart catheterization 2 weeks later revealed right atrial pressure of 7 mmHg, pulmonary arterial mean pressure of 28 mmHg, pulmonary capillary wedge pressure of 12 mmHg, normal cardiac output and pulmonary vascular resistance of 2.1 woods unit. Given restoration of near normal pulmonary pressures with discontinuation of the drug, carfilzomib-induced PH was confirmed as the diagnosis. A follow-up TTE one and a half months later (Figure 4) demonstrated normalization of RV size and systolic function (TAPSE was 2.3 cm). The patient’s symptoms and functional capacity also returned to baseline. Unfortunately, given multiple failed treatments for multiple myeloma, patient finally succumbed to complications of the disease 5 months later.
Figure 4. TTE after cessation of carfilzomib: apical four-chamber view demonstrating recovered RV size and systolic function (TASPE was 2.3 cm). LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Discussion
Carfilzomib-induced PH as documented in the package insert occurs in up to 2% of patients, though ⩾ grade 3 PH adverse event as defined by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) is seen in < 1%.1 This definition is different from standards set by the 6th World Symposium on Pulmonary Hypertension Task Force,5 which defines PH as mean pulmonary arterial pressure (PAP) > 20 mmHg. Although our patient did not have direct mean PAP measured, he did have severely elevated PASP during his index episode. With this finding, we presume that his mean PAP was also over 20 mmHg. There is little literature on the association of carfilzomib with acute PH and RV dysfunction. There is one similar case report of carfilzomib-induced PH in a 77-year-old female patient, who developed PH following seven cycles of carfilzomib/pomalidomide/dexamethasone therapy, although she was asymptomatic. A routine screening TTE showed pulmonary systolic pressure of 65–70 mmHg with mild RV enlargement, flattening of interventricular septum but preserved RV systolic function.6 In contrast, our patient was a male who after only four cycles of therapy developed symptoms with evidence of profound RV systolic dysfunction on TTE. In both cases, PH resolved with discontinuation of carfilzomib and, in our case, RV dysfunction resolved as well.
Carfilzomib’s exact mechanism of action on the CV system remains largely undefined. One theory is PI may lead to intracellular accumulation of misfolded proteins and ultimately abnormal protein homeostasis contributing to apoptosis of cardiomyocytes.7 Another proposed mechanism is endothelial and oxidative stress leading to vascular dysfunction, increased vascular tone and hypertension.6 Interestingly, carfilzomib has been shown in the literature to reverse pulmonary arterial hypertension in rat models8 but not in humans. This discrepancy is not fully understood. Differences between bortezomib and carfilzomib are also not entirely clear but may depend on carfilzomib’s irreversible and highly potent proteasome inhibition activity.7 Risk factors for cardiotoxicity include prior PI and doxorubicin exposure as well as pre-existing CV conditions such as heart failure and hypertension9 although these cardiotoxic effects do not appear to be cumulative or dose-related.10 Combination therapy with carfilzomib and dexamethasone may elevate risks for heart failure. Steroids can induce secondary hypertension and fluid retention, both of which can be exacerbated by routine intravenous fluids administered with this regimen. Bottomline, overall attributable risks and natural history of carfilzomib-related cardiotoxicity are still evolving and incompletely characterized.
There may be several reasons for RV dysfunction found in our case. First, the rise in PAP is likely very rapid in our patient. RV is a low-pressure chamber and when its afterload is acutely elevated, systolic dysfunction may ensue especially when compensatory hypertrophy has not taken place. Second, our veteran is obese. Obesity is an independent risk factor for RV dysfunction. One small study evaluating 35 otherwise healthy obese patients found that isolated obesity had evidence of subclinical abnormalities in RV structure and function by echocardiographic parameters.11 Finally, our patient had pre-existing CV conditions, such as hypertension and history of pulmonary embolism, which could have contributed to RV abnormalities.
According to a consensus document on management of carfilzomib from European Myeloma Network, a baseline assessment using the SCORE (Systemic Coronary Risk Evaluation) model as a formal and objective way of estimating CV risk is recommended. Echocardiogram is recommended as an initial screening and surveillance tool if concerns for any new CV symptoms or signs arise.12 Early detection for carfilzomib-induced cardiotoxicity is imperative as these complications are typically reversible with cessation of the medication. This reversal, which was observed in our patient (Figure 4), can be as early as weeks to months.6
Conclusion
Carfilzomib-induced CV effects are usually attributed to left-sided heart failure, but RV dysfunction can occur especially when acute PH occurs. PH is a known, albeit, rare complication of carfilzomib. It is important to be cognizant of PH as a likely cause for patients with acute dyspnea while on the PI. Routine screening echocardiograms should be considered prior to and during therapy particularly in those with pre-existing CV conditions as these cardiotoxicities are typically reversible with cessation of the drug.
The authors thank Bradley McGregor, MD, from Dana Farber Cancer Institute for his expertise and mentorship during editing portion of this paper.
Author contributions: P.-C.M. drafted, conceptualized and revised the manuscript. J.A. and V.B. both made substantial contributions to conception and manuscript revisions. All authors have read and approved the manuscript. All have agreed to be personally accountable for their own contributions.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Our institution does not require Institutional Review Board approval for reporting individual cases or case series.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the research department of the Veterans Affairs Boston Healthcare System.
ORCID iD: Pei-Chun McGregor
https://orcid.org/0000-0003-1346-689X
Informed consent: Written informed consent was obtained from a legally authorized representative for anonymized patient information and images to be published in this article. | AMLODIPINE BESYLATE, APIXABAN, BENDAMUSTINE, CARFILZOMIB, CARVEDILOL, DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33643656 | 19,031,624 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Carfilzomib-induced pulmonary hypertension with associated right ventricular dysfunction: A case report.
Carfilzomib, a selective proteasome inhibitor, is approved for use in relapsed and refractory multiple myeloma. Its link to left ventricular dysfunction is well established but little is known about its effects on the right ventricle. One of its rare complications is pulmonary hypertension, which at its extreme may result in right ventricular dysfunction. Here, we present a case of an elderly male veteran with multiple myeloma status post various failed therapies who developed acute dyspnea after four cycles of carfilzomib and subsequently found to have severe pulmonary hypertension with resultant acute right ventricular failure, which recovered after cessation of carfilzomib. This case highlights the need for careful cardiovascular surveillance while on carfilzomib and the importance of knowing even its rarest complications as these cardiotoxicities are reversible with discontinuation of the drug.
Introduction
Carfilzomib is a selective and irreversible proteasome inhibitor (PI) approved for treatment of relapsed and refractory multiple myeloma.1 Aggregated safety results from four phase II trials,2 including a majority of patients with underlying cardiac disease, subsequently found 7.2% of them developed cardiac failure but there were no significant differences in overall mortality between those with and without pre-existing cardiac disorders.2 Similarly, a small case series from a single center of 67 patients treated with carfilzomib found that most patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib also had a history of the specific cardiovascular (CV) event they exhibited, reflecting experience in a real-world patient population.3 The ASPIRE trial compared carfilzomib plus standard therapy (lenalidomide and dexamethasone) to standard therapy alone and showed carfilzomib group to have higher any-grade dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), heart failure (6.4% vs 4.1%) and ischemic heart disease (5.9% vs 4.6%).4 There is little debate regarding the increased CV events associated with carfilzomib, in particular, when it relates to left ventricular function. However, there is scant data on carfilzomib-induced pulmonary hypertension (PH) in the real-world myeloma population and the risks for developing right ventricular (RV) dysfunction. It is imperative for clinicians to be aware and, therefore, be able to identify these complications as these CV sequalae may be reversible with cessation of the medication. Our aim is to report our experience with an interesting real-world case of carfilzomib-induced acute PH with associated RV failure and highlight the need for routine surveillance with echocardiography for early detection of these CV complications.
Case presentation
A 71-year-old veteran male with IgG lambda multiple myeloma, status post failed autologous stem cell transplant with melphalan as well as numerous lines of chemotherapy including bortezomib, presented with acute dyspnea 2 months after he was started on carfilzomib/bendamustine/dexamethasone combination therapy. His other comorbid conditions included systemic hypertension that is treated with carvedilol and amlodipine, remote history of pulmonary embolism now on apixaban, obstructive sleep apnea while compliant with continuous positive airway pressure use and obesity. He had normal pulmonary function test 2 years prior to this index episode. The patient also had a baseline transthoracic echocardiogram (TTE) just before starting carfilzomib revealing normal biventricular and valvular function without evidence of PH, but there was trace circumferential pericardial effusion that’s been chronic for at least 2 years prior. On starting carfilzomib, the patient started noticing worsening dyspnea on exertion until 2 months later when he suddenly developed shortness of breath while ambulating immediately after completing cycle 4 of carfilzomib infusion. He was transferred urgently to the emergency room at which time the vitals were within normal limits except for exertional oxygen saturation of 88% while on room air. The exam was significant for an obese male with mild respiratory distress and mild bilateral lower extremity edema. Cardiac troponins were within normal limits, but brain natriuretic peptide was mildly elevated (148 μg/dL). Electrocardiogram revealed new T-wave inversions in leads V2–V3 (Figure 1). Computed tomography pulmonary angiogram study with contrast demonstrated normal lung parenchyma without evidence of pulmonary embolism or infiltrates. Repeat TTE, however, showed newly dilated RV with significantly reduced RV systolic function (Figure 2) with tricuspid annular plane systolic excursion (TAPSE) of 1.3 cm and an estimated pulmonary arterial systolic pressure (PASP) of 56–61 mmHg (Figure 3).
Figure 1. Electrocardiogram: new nonspecific T-wave changes in V2–V3 when patient became acutely dyspneic after carfilzomib infusion.
Figure 2. RV focused view during chemotherapy: newly dilated RV with reduced systolic function (TAPSE was 1.3 cm) and lateral wall akinesis. Chronic trace pericardial effusion is also present. LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Figure 3. Continuous-wave Doppler during chemotherapy: pulmonary arterial systolic pressure is newly elevated as demonstrated by increased tricuspid regurgitation peak velocity of 3.47 m/s.
Having systematically excluded all major cardiopulmonary disorders (to include pulmonary embolism, acute coronary syndrome, pneumonia, acute anemia) and given the temporal relationship of treatment with carfilzomib to patient’s presentation, decision was made to stop carfilzomib. The patient did not receive any further medical interventions because he was clinically stable once admitted. No diuretics were given. No arterial blood gas was obtained. The patient was discharged after 2 days of monitoring. Right heart catheterization 2 weeks later revealed right atrial pressure of 7 mmHg, pulmonary arterial mean pressure of 28 mmHg, pulmonary capillary wedge pressure of 12 mmHg, normal cardiac output and pulmonary vascular resistance of 2.1 woods unit. Given restoration of near normal pulmonary pressures with discontinuation of the drug, carfilzomib-induced PH was confirmed as the diagnosis. A follow-up TTE one and a half months later (Figure 4) demonstrated normalization of RV size and systolic function (TAPSE was 2.3 cm). The patient’s symptoms and functional capacity also returned to baseline. Unfortunately, given multiple failed treatments for multiple myeloma, patient finally succumbed to complications of the disease 5 months later.
Figure 4. TTE after cessation of carfilzomib: apical four-chamber view demonstrating recovered RV size and systolic function (TASPE was 2.3 cm). LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Discussion
Carfilzomib-induced PH as documented in the package insert occurs in up to 2% of patients, though ⩾ grade 3 PH adverse event as defined by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) is seen in < 1%.1 This definition is different from standards set by the 6th World Symposium on Pulmonary Hypertension Task Force,5 which defines PH as mean pulmonary arterial pressure (PAP) > 20 mmHg. Although our patient did not have direct mean PAP measured, he did have severely elevated PASP during his index episode. With this finding, we presume that his mean PAP was also over 20 mmHg. There is little literature on the association of carfilzomib with acute PH and RV dysfunction. There is one similar case report of carfilzomib-induced PH in a 77-year-old female patient, who developed PH following seven cycles of carfilzomib/pomalidomide/dexamethasone therapy, although she was asymptomatic. A routine screening TTE showed pulmonary systolic pressure of 65–70 mmHg with mild RV enlargement, flattening of interventricular septum but preserved RV systolic function.6 In contrast, our patient was a male who after only four cycles of therapy developed symptoms with evidence of profound RV systolic dysfunction on TTE. In both cases, PH resolved with discontinuation of carfilzomib and, in our case, RV dysfunction resolved as well.
Carfilzomib’s exact mechanism of action on the CV system remains largely undefined. One theory is PI may lead to intracellular accumulation of misfolded proteins and ultimately abnormal protein homeostasis contributing to apoptosis of cardiomyocytes.7 Another proposed mechanism is endothelial and oxidative stress leading to vascular dysfunction, increased vascular tone and hypertension.6 Interestingly, carfilzomib has been shown in the literature to reverse pulmonary arterial hypertension in rat models8 but not in humans. This discrepancy is not fully understood. Differences between bortezomib and carfilzomib are also not entirely clear but may depend on carfilzomib’s irreversible and highly potent proteasome inhibition activity.7 Risk factors for cardiotoxicity include prior PI and doxorubicin exposure as well as pre-existing CV conditions such as heart failure and hypertension9 although these cardiotoxic effects do not appear to be cumulative or dose-related.10 Combination therapy with carfilzomib and dexamethasone may elevate risks for heart failure. Steroids can induce secondary hypertension and fluid retention, both of which can be exacerbated by routine intravenous fluids administered with this regimen. Bottomline, overall attributable risks and natural history of carfilzomib-related cardiotoxicity are still evolving and incompletely characterized.
There may be several reasons for RV dysfunction found in our case. First, the rise in PAP is likely very rapid in our patient. RV is a low-pressure chamber and when its afterload is acutely elevated, systolic dysfunction may ensue especially when compensatory hypertrophy has not taken place. Second, our veteran is obese. Obesity is an independent risk factor for RV dysfunction. One small study evaluating 35 otherwise healthy obese patients found that isolated obesity had evidence of subclinical abnormalities in RV structure and function by echocardiographic parameters.11 Finally, our patient had pre-existing CV conditions, such as hypertension and history of pulmonary embolism, which could have contributed to RV abnormalities.
According to a consensus document on management of carfilzomib from European Myeloma Network, a baseline assessment using the SCORE (Systemic Coronary Risk Evaluation) model as a formal and objective way of estimating CV risk is recommended. Echocardiogram is recommended as an initial screening and surveillance tool if concerns for any new CV symptoms or signs arise.12 Early detection for carfilzomib-induced cardiotoxicity is imperative as these complications are typically reversible with cessation of the medication. This reversal, which was observed in our patient (Figure 4), can be as early as weeks to months.6
Conclusion
Carfilzomib-induced CV effects are usually attributed to left-sided heart failure, but RV dysfunction can occur especially when acute PH occurs. PH is a known, albeit, rare complication of carfilzomib. It is important to be cognizant of PH as a likely cause for patients with acute dyspnea while on the PI. Routine screening echocardiograms should be considered prior to and during therapy particularly in those with pre-existing CV conditions as these cardiotoxicities are typically reversible with cessation of the drug.
The authors thank Bradley McGregor, MD, from Dana Farber Cancer Institute for his expertise and mentorship during editing portion of this paper.
Author contributions: P.-C.M. drafted, conceptualized and revised the manuscript. J.A. and V.B. both made substantial contributions to conception and manuscript revisions. All authors have read and approved the manuscript. All have agreed to be personally accountable for their own contributions.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Our institution does not require Institutional Review Board approval for reporting individual cases or case series.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the research department of the Veterans Affairs Boston Healthcare System.
ORCID iD: Pei-Chun McGregor
https://orcid.org/0000-0003-1346-689X
Informed consent: Written informed consent was obtained from a legally authorized representative for anonymized patient information and images to be published in this article. | AMLODIPINE BESYLATE, APIXABAN, BENDAMUSTINE, CARFILZOMIB, CARVEDILOL, DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33643656 | 19,031,624 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Carfilzomib-induced pulmonary hypertension with associated right ventricular dysfunction: A case report.
Carfilzomib, a selective proteasome inhibitor, is approved for use in relapsed and refractory multiple myeloma. Its link to left ventricular dysfunction is well established but little is known about its effects on the right ventricle. One of its rare complications is pulmonary hypertension, which at its extreme may result in right ventricular dysfunction. Here, we present a case of an elderly male veteran with multiple myeloma status post various failed therapies who developed acute dyspnea after four cycles of carfilzomib and subsequently found to have severe pulmonary hypertension with resultant acute right ventricular failure, which recovered after cessation of carfilzomib. This case highlights the need for careful cardiovascular surveillance while on carfilzomib and the importance of knowing even its rarest complications as these cardiotoxicities are reversible with discontinuation of the drug.
Introduction
Carfilzomib is a selective and irreversible proteasome inhibitor (PI) approved for treatment of relapsed and refractory multiple myeloma.1 Aggregated safety results from four phase II trials,2 including a majority of patients with underlying cardiac disease, subsequently found 7.2% of them developed cardiac failure but there were no significant differences in overall mortality between those with and without pre-existing cardiac disorders.2 Similarly, a small case series from a single center of 67 patients treated with carfilzomib found that most patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib also had a history of the specific cardiovascular (CV) event they exhibited, reflecting experience in a real-world patient population.3 The ASPIRE trial compared carfilzomib plus standard therapy (lenalidomide and dexamethasone) to standard therapy alone and showed carfilzomib group to have higher any-grade dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), heart failure (6.4% vs 4.1%) and ischemic heart disease (5.9% vs 4.6%).4 There is little debate regarding the increased CV events associated with carfilzomib, in particular, when it relates to left ventricular function. However, there is scant data on carfilzomib-induced pulmonary hypertension (PH) in the real-world myeloma population and the risks for developing right ventricular (RV) dysfunction. It is imperative for clinicians to be aware and, therefore, be able to identify these complications as these CV sequalae may be reversible with cessation of the medication. Our aim is to report our experience with an interesting real-world case of carfilzomib-induced acute PH with associated RV failure and highlight the need for routine surveillance with echocardiography for early detection of these CV complications.
Case presentation
A 71-year-old veteran male with IgG lambda multiple myeloma, status post failed autologous stem cell transplant with melphalan as well as numerous lines of chemotherapy including bortezomib, presented with acute dyspnea 2 months after he was started on carfilzomib/bendamustine/dexamethasone combination therapy. His other comorbid conditions included systemic hypertension that is treated with carvedilol and amlodipine, remote history of pulmonary embolism now on apixaban, obstructive sleep apnea while compliant with continuous positive airway pressure use and obesity. He had normal pulmonary function test 2 years prior to this index episode. The patient also had a baseline transthoracic echocardiogram (TTE) just before starting carfilzomib revealing normal biventricular and valvular function without evidence of PH, but there was trace circumferential pericardial effusion that’s been chronic for at least 2 years prior. On starting carfilzomib, the patient started noticing worsening dyspnea on exertion until 2 months later when he suddenly developed shortness of breath while ambulating immediately after completing cycle 4 of carfilzomib infusion. He was transferred urgently to the emergency room at which time the vitals were within normal limits except for exertional oxygen saturation of 88% while on room air. The exam was significant for an obese male with mild respiratory distress and mild bilateral lower extremity edema. Cardiac troponins were within normal limits, but brain natriuretic peptide was mildly elevated (148 μg/dL). Electrocardiogram revealed new T-wave inversions in leads V2–V3 (Figure 1). Computed tomography pulmonary angiogram study with contrast demonstrated normal lung parenchyma without evidence of pulmonary embolism or infiltrates. Repeat TTE, however, showed newly dilated RV with significantly reduced RV systolic function (Figure 2) with tricuspid annular plane systolic excursion (TAPSE) of 1.3 cm and an estimated pulmonary arterial systolic pressure (PASP) of 56–61 mmHg (Figure 3).
Figure 1. Electrocardiogram: new nonspecific T-wave changes in V2–V3 when patient became acutely dyspneic after carfilzomib infusion.
Figure 2. RV focused view during chemotherapy: newly dilated RV with reduced systolic function (TAPSE was 1.3 cm) and lateral wall akinesis. Chronic trace pericardial effusion is also present. LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Figure 3. Continuous-wave Doppler during chemotherapy: pulmonary arterial systolic pressure is newly elevated as demonstrated by increased tricuspid regurgitation peak velocity of 3.47 m/s.
Having systematically excluded all major cardiopulmonary disorders (to include pulmonary embolism, acute coronary syndrome, pneumonia, acute anemia) and given the temporal relationship of treatment with carfilzomib to patient’s presentation, decision was made to stop carfilzomib. The patient did not receive any further medical interventions because he was clinically stable once admitted. No diuretics were given. No arterial blood gas was obtained. The patient was discharged after 2 days of monitoring. Right heart catheterization 2 weeks later revealed right atrial pressure of 7 mmHg, pulmonary arterial mean pressure of 28 mmHg, pulmonary capillary wedge pressure of 12 mmHg, normal cardiac output and pulmonary vascular resistance of 2.1 woods unit. Given restoration of near normal pulmonary pressures with discontinuation of the drug, carfilzomib-induced PH was confirmed as the diagnosis. A follow-up TTE one and a half months later (Figure 4) demonstrated normalization of RV size and systolic function (TAPSE was 2.3 cm). The patient’s symptoms and functional capacity also returned to baseline. Unfortunately, given multiple failed treatments for multiple myeloma, patient finally succumbed to complications of the disease 5 months later.
Figure 4. TTE after cessation of carfilzomib: apical four-chamber view demonstrating recovered RV size and systolic function (TASPE was 2.3 cm). LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Discussion
Carfilzomib-induced PH as documented in the package insert occurs in up to 2% of patients, though ⩾ grade 3 PH adverse event as defined by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) is seen in < 1%.1 This definition is different from standards set by the 6th World Symposium on Pulmonary Hypertension Task Force,5 which defines PH as mean pulmonary arterial pressure (PAP) > 20 mmHg. Although our patient did not have direct mean PAP measured, he did have severely elevated PASP during his index episode. With this finding, we presume that his mean PAP was also over 20 mmHg. There is little literature on the association of carfilzomib with acute PH and RV dysfunction. There is one similar case report of carfilzomib-induced PH in a 77-year-old female patient, who developed PH following seven cycles of carfilzomib/pomalidomide/dexamethasone therapy, although she was asymptomatic. A routine screening TTE showed pulmonary systolic pressure of 65–70 mmHg with mild RV enlargement, flattening of interventricular septum but preserved RV systolic function.6 In contrast, our patient was a male who after only four cycles of therapy developed symptoms with evidence of profound RV systolic dysfunction on TTE. In both cases, PH resolved with discontinuation of carfilzomib and, in our case, RV dysfunction resolved as well.
Carfilzomib’s exact mechanism of action on the CV system remains largely undefined. One theory is PI may lead to intracellular accumulation of misfolded proteins and ultimately abnormal protein homeostasis contributing to apoptosis of cardiomyocytes.7 Another proposed mechanism is endothelial and oxidative stress leading to vascular dysfunction, increased vascular tone and hypertension.6 Interestingly, carfilzomib has been shown in the literature to reverse pulmonary arterial hypertension in rat models8 but not in humans. This discrepancy is not fully understood. Differences between bortezomib and carfilzomib are also not entirely clear but may depend on carfilzomib’s irreversible and highly potent proteasome inhibition activity.7 Risk factors for cardiotoxicity include prior PI and doxorubicin exposure as well as pre-existing CV conditions such as heart failure and hypertension9 although these cardiotoxic effects do not appear to be cumulative or dose-related.10 Combination therapy with carfilzomib and dexamethasone may elevate risks for heart failure. Steroids can induce secondary hypertension and fluid retention, both of which can be exacerbated by routine intravenous fluids administered with this regimen. Bottomline, overall attributable risks and natural history of carfilzomib-related cardiotoxicity are still evolving and incompletely characterized.
There may be several reasons for RV dysfunction found in our case. First, the rise in PAP is likely very rapid in our patient. RV is a low-pressure chamber and when its afterload is acutely elevated, systolic dysfunction may ensue especially when compensatory hypertrophy has not taken place. Second, our veteran is obese. Obesity is an independent risk factor for RV dysfunction. One small study evaluating 35 otherwise healthy obese patients found that isolated obesity had evidence of subclinical abnormalities in RV structure and function by echocardiographic parameters.11 Finally, our patient had pre-existing CV conditions, such as hypertension and history of pulmonary embolism, which could have contributed to RV abnormalities.
According to a consensus document on management of carfilzomib from European Myeloma Network, a baseline assessment using the SCORE (Systemic Coronary Risk Evaluation) model as a formal and objective way of estimating CV risk is recommended. Echocardiogram is recommended as an initial screening and surveillance tool if concerns for any new CV symptoms or signs arise.12 Early detection for carfilzomib-induced cardiotoxicity is imperative as these complications are typically reversible with cessation of the medication. This reversal, which was observed in our patient (Figure 4), can be as early as weeks to months.6
Conclusion
Carfilzomib-induced CV effects are usually attributed to left-sided heart failure, but RV dysfunction can occur especially when acute PH occurs. PH is a known, albeit, rare complication of carfilzomib. It is important to be cognizant of PH as a likely cause for patients with acute dyspnea while on the PI. Routine screening echocardiograms should be considered prior to and during therapy particularly in those with pre-existing CV conditions as these cardiotoxicities are typically reversible with cessation of the drug.
The authors thank Bradley McGregor, MD, from Dana Farber Cancer Institute for his expertise and mentorship during editing portion of this paper.
Author contributions: P.-C.M. drafted, conceptualized and revised the manuscript. J.A. and V.B. both made substantial contributions to conception and manuscript revisions. All authors have read and approved the manuscript. All have agreed to be personally accountable for their own contributions.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Our institution does not require Institutional Review Board approval for reporting individual cases or case series.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the research department of the Veterans Affairs Boston Healthcare System.
ORCID iD: Pei-Chun McGregor
https://orcid.org/0000-0003-1346-689X
Informed consent: Written informed consent was obtained from a legally authorized representative for anonymized patient information and images to be published in this article. | AMLODIPINE BESYLATE, APIXABAN, BENDAMUSTINE, CARFILZOMIB, CARVEDILOL, DEXAMETHASONE | DrugsGivenReaction | CC BY-NC | 33643656 | 19,031,624 | 2021 |
What was the outcome of reaction 'Disease complication'? | Carfilzomib-induced pulmonary hypertension with associated right ventricular dysfunction: A case report.
Carfilzomib, a selective proteasome inhibitor, is approved for use in relapsed and refractory multiple myeloma. Its link to left ventricular dysfunction is well established but little is known about its effects on the right ventricle. One of its rare complications is pulmonary hypertension, which at its extreme may result in right ventricular dysfunction. Here, we present a case of an elderly male veteran with multiple myeloma status post various failed therapies who developed acute dyspnea after four cycles of carfilzomib and subsequently found to have severe pulmonary hypertension with resultant acute right ventricular failure, which recovered after cessation of carfilzomib. This case highlights the need for careful cardiovascular surveillance while on carfilzomib and the importance of knowing even its rarest complications as these cardiotoxicities are reversible with discontinuation of the drug.
Introduction
Carfilzomib is a selective and irreversible proteasome inhibitor (PI) approved for treatment of relapsed and refractory multiple myeloma.1 Aggregated safety results from four phase II trials,2 including a majority of patients with underlying cardiac disease, subsequently found 7.2% of them developed cardiac failure but there were no significant differences in overall mortality between those with and without pre-existing cardiac disorders.2 Similarly, a small case series from a single center of 67 patients treated with carfilzomib found that most patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib also had a history of the specific cardiovascular (CV) event they exhibited, reflecting experience in a real-world patient population.3 The ASPIRE trial compared carfilzomib plus standard therapy (lenalidomide and dexamethasone) to standard therapy alone and showed carfilzomib group to have higher any-grade dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), heart failure (6.4% vs 4.1%) and ischemic heart disease (5.9% vs 4.6%).4 There is little debate regarding the increased CV events associated with carfilzomib, in particular, when it relates to left ventricular function. However, there is scant data on carfilzomib-induced pulmonary hypertension (PH) in the real-world myeloma population and the risks for developing right ventricular (RV) dysfunction. It is imperative for clinicians to be aware and, therefore, be able to identify these complications as these CV sequalae may be reversible with cessation of the medication. Our aim is to report our experience with an interesting real-world case of carfilzomib-induced acute PH with associated RV failure and highlight the need for routine surveillance with echocardiography for early detection of these CV complications.
Case presentation
A 71-year-old veteran male with IgG lambda multiple myeloma, status post failed autologous stem cell transplant with melphalan as well as numerous lines of chemotherapy including bortezomib, presented with acute dyspnea 2 months after he was started on carfilzomib/bendamustine/dexamethasone combination therapy. His other comorbid conditions included systemic hypertension that is treated with carvedilol and amlodipine, remote history of pulmonary embolism now on apixaban, obstructive sleep apnea while compliant with continuous positive airway pressure use and obesity. He had normal pulmonary function test 2 years prior to this index episode. The patient also had a baseline transthoracic echocardiogram (TTE) just before starting carfilzomib revealing normal biventricular and valvular function without evidence of PH, but there was trace circumferential pericardial effusion that’s been chronic for at least 2 years prior. On starting carfilzomib, the patient started noticing worsening dyspnea on exertion until 2 months later when he suddenly developed shortness of breath while ambulating immediately after completing cycle 4 of carfilzomib infusion. He was transferred urgently to the emergency room at which time the vitals were within normal limits except for exertional oxygen saturation of 88% while on room air. The exam was significant for an obese male with mild respiratory distress and mild bilateral lower extremity edema. Cardiac troponins were within normal limits, but brain natriuretic peptide was mildly elevated (148 μg/dL). Electrocardiogram revealed new T-wave inversions in leads V2–V3 (Figure 1). Computed tomography pulmonary angiogram study with contrast demonstrated normal lung parenchyma without evidence of pulmonary embolism or infiltrates. Repeat TTE, however, showed newly dilated RV with significantly reduced RV systolic function (Figure 2) with tricuspid annular plane systolic excursion (TAPSE) of 1.3 cm and an estimated pulmonary arterial systolic pressure (PASP) of 56–61 mmHg (Figure 3).
Figure 1. Electrocardiogram: new nonspecific T-wave changes in V2–V3 when patient became acutely dyspneic after carfilzomib infusion.
Figure 2. RV focused view during chemotherapy: newly dilated RV with reduced systolic function (TAPSE was 1.3 cm) and lateral wall akinesis. Chronic trace pericardial effusion is also present. LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Figure 3. Continuous-wave Doppler during chemotherapy: pulmonary arterial systolic pressure is newly elevated as demonstrated by increased tricuspid regurgitation peak velocity of 3.47 m/s.
Having systematically excluded all major cardiopulmonary disorders (to include pulmonary embolism, acute coronary syndrome, pneumonia, acute anemia) and given the temporal relationship of treatment with carfilzomib to patient’s presentation, decision was made to stop carfilzomib. The patient did not receive any further medical interventions because he was clinically stable once admitted. No diuretics were given. No arterial blood gas was obtained. The patient was discharged after 2 days of monitoring. Right heart catheterization 2 weeks later revealed right atrial pressure of 7 mmHg, pulmonary arterial mean pressure of 28 mmHg, pulmonary capillary wedge pressure of 12 mmHg, normal cardiac output and pulmonary vascular resistance of 2.1 woods unit. Given restoration of near normal pulmonary pressures with discontinuation of the drug, carfilzomib-induced PH was confirmed as the diagnosis. A follow-up TTE one and a half months later (Figure 4) demonstrated normalization of RV size and systolic function (TAPSE was 2.3 cm). The patient’s symptoms and functional capacity also returned to baseline. Unfortunately, given multiple failed treatments for multiple myeloma, patient finally succumbed to complications of the disease 5 months later.
Figure 4. TTE after cessation of carfilzomib: apical four-chamber view demonstrating recovered RV size and systolic function (TASPE was 2.3 cm). LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Discussion
Carfilzomib-induced PH as documented in the package insert occurs in up to 2% of patients, though ⩾ grade 3 PH adverse event as defined by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) is seen in < 1%.1 This definition is different from standards set by the 6th World Symposium on Pulmonary Hypertension Task Force,5 which defines PH as mean pulmonary arterial pressure (PAP) > 20 mmHg. Although our patient did not have direct mean PAP measured, he did have severely elevated PASP during his index episode. With this finding, we presume that his mean PAP was also over 20 mmHg. There is little literature on the association of carfilzomib with acute PH and RV dysfunction. There is one similar case report of carfilzomib-induced PH in a 77-year-old female patient, who developed PH following seven cycles of carfilzomib/pomalidomide/dexamethasone therapy, although she was asymptomatic. A routine screening TTE showed pulmonary systolic pressure of 65–70 mmHg with mild RV enlargement, flattening of interventricular septum but preserved RV systolic function.6 In contrast, our patient was a male who after only four cycles of therapy developed symptoms with evidence of profound RV systolic dysfunction on TTE. In both cases, PH resolved with discontinuation of carfilzomib and, in our case, RV dysfunction resolved as well.
Carfilzomib’s exact mechanism of action on the CV system remains largely undefined. One theory is PI may lead to intracellular accumulation of misfolded proteins and ultimately abnormal protein homeostasis contributing to apoptosis of cardiomyocytes.7 Another proposed mechanism is endothelial and oxidative stress leading to vascular dysfunction, increased vascular tone and hypertension.6 Interestingly, carfilzomib has been shown in the literature to reverse pulmonary arterial hypertension in rat models8 but not in humans. This discrepancy is not fully understood. Differences between bortezomib and carfilzomib are also not entirely clear but may depend on carfilzomib’s irreversible and highly potent proteasome inhibition activity.7 Risk factors for cardiotoxicity include prior PI and doxorubicin exposure as well as pre-existing CV conditions such as heart failure and hypertension9 although these cardiotoxic effects do not appear to be cumulative or dose-related.10 Combination therapy with carfilzomib and dexamethasone may elevate risks for heart failure. Steroids can induce secondary hypertension and fluid retention, both of which can be exacerbated by routine intravenous fluids administered with this regimen. Bottomline, overall attributable risks and natural history of carfilzomib-related cardiotoxicity are still evolving and incompletely characterized.
There may be several reasons for RV dysfunction found in our case. First, the rise in PAP is likely very rapid in our patient. RV is a low-pressure chamber and when its afterload is acutely elevated, systolic dysfunction may ensue especially when compensatory hypertrophy has not taken place. Second, our veteran is obese. Obesity is an independent risk factor for RV dysfunction. One small study evaluating 35 otherwise healthy obese patients found that isolated obesity had evidence of subclinical abnormalities in RV structure and function by echocardiographic parameters.11 Finally, our patient had pre-existing CV conditions, such as hypertension and history of pulmonary embolism, which could have contributed to RV abnormalities.
According to a consensus document on management of carfilzomib from European Myeloma Network, a baseline assessment using the SCORE (Systemic Coronary Risk Evaluation) model as a formal and objective way of estimating CV risk is recommended. Echocardiogram is recommended as an initial screening and surveillance tool if concerns for any new CV symptoms or signs arise.12 Early detection for carfilzomib-induced cardiotoxicity is imperative as these complications are typically reversible with cessation of the medication. This reversal, which was observed in our patient (Figure 4), can be as early as weeks to months.6
Conclusion
Carfilzomib-induced CV effects are usually attributed to left-sided heart failure, but RV dysfunction can occur especially when acute PH occurs. PH is a known, albeit, rare complication of carfilzomib. It is important to be cognizant of PH as a likely cause for patients with acute dyspnea while on the PI. Routine screening echocardiograms should be considered prior to and during therapy particularly in those with pre-existing CV conditions as these cardiotoxicities are typically reversible with cessation of the drug.
The authors thank Bradley McGregor, MD, from Dana Farber Cancer Institute for his expertise and mentorship during editing portion of this paper.
Author contributions: P.-C.M. drafted, conceptualized and revised the manuscript. J.A. and V.B. both made substantial contributions to conception and manuscript revisions. All authors have read and approved the manuscript. All have agreed to be personally accountable for their own contributions.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Our institution does not require Institutional Review Board approval for reporting individual cases or case series.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the research department of the Veterans Affairs Boston Healthcare System.
ORCID iD: Pei-Chun McGregor
https://orcid.org/0000-0003-1346-689X
Informed consent: Written informed consent was obtained from a legally authorized representative for anonymized patient information and images to be published in this article. | Fatal | ReactionOutcome | CC BY-NC | 33643656 | 19,031,624 | 2021 |
What was the outcome of reaction 'Pulmonary hypertension'? | Carfilzomib-induced pulmonary hypertension with associated right ventricular dysfunction: A case report.
Carfilzomib, a selective proteasome inhibitor, is approved for use in relapsed and refractory multiple myeloma. Its link to left ventricular dysfunction is well established but little is known about its effects on the right ventricle. One of its rare complications is pulmonary hypertension, which at its extreme may result in right ventricular dysfunction. Here, we present a case of an elderly male veteran with multiple myeloma status post various failed therapies who developed acute dyspnea after four cycles of carfilzomib and subsequently found to have severe pulmonary hypertension with resultant acute right ventricular failure, which recovered after cessation of carfilzomib. This case highlights the need for careful cardiovascular surveillance while on carfilzomib and the importance of knowing even its rarest complications as these cardiotoxicities are reversible with discontinuation of the drug.
Introduction
Carfilzomib is a selective and irreversible proteasome inhibitor (PI) approved for treatment of relapsed and refractory multiple myeloma.1 Aggregated safety results from four phase II trials,2 including a majority of patients with underlying cardiac disease, subsequently found 7.2% of them developed cardiac failure but there were no significant differences in overall mortality between those with and without pre-existing cardiac disorders.2 Similarly, a small case series from a single center of 67 patients treated with carfilzomib found that most patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib also had a history of the specific cardiovascular (CV) event they exhibited, reflecting experience in a real-world patient population.3 The ASPIRE trial compared carfilzomib plus standard therapy (lenalidomide and dexamethasone) to standard therapy alone and showed carfilzomib group to have higher any-grade dyspnea (19.4% vs 14.9%), hypertension (14.3% vs 6.9%), heart failure (6.4% vs 4.1%) and ischemic heart disease (5.9% vs 4.6%).4 There is little debate regarding the increased CV events associated with carfilzomib, in particular, when it relates to left ventricular function. However, there is scant data on carfilzomib-induced pulmonary hypertension (PH) in the real-world myeloma population and the risks for developing right ventricular (RV) dysfunction. It is imperative for clinicians to be aware and, therefore, be able to identify these complications as these CV sequalae may be reversible with cessation of the medication. Our aim is to report our experience with an interesting real-world case of carfilzomib-induced acute PH with associated RV failure and highlight the need for routine surveillance with echocardiography for early detection of these CV complications.
Case presentation
A 71-year-old veteran male with IgG lambda multiple myeloma, status post failed autologous stem cell transplant with melphalan as well as numerous lines of chemotherapy including bortezomib, presented with acute dyspnea 2 months after he was started on carfilzomib/bendamustine/dexamethasone combination therapy. His other comorbid conditions included systemic hypertension that is treated with carvedilol and amlodipine, remote history of pulmonary embolism now on apixaban, obstructive sleep apnea while compliant with continuous positive airway pressure use and obesity. He had normal pulmonary function test 2 years prior to this index episode. The patient also had a baseline transthoracic echocardiogram (TTE) just before starting carfilzomib revealing normal biventricular and valvular function without evidence of PH, but there was trace circumferential pericardial effusion that’s been chronic for at least 2 years prior. On starting carfilzomib, the patient started noticing worsening dyspnea on exertion until 2 months later when he suddenly developed shortness of breath while ambulating immediately after completing cycle 4 of carfilzomib infusion. He was transferred urgently to the emergency room at which time the vitals were within normal limits except for exertional oxygen saturation of 88% while on room air. The exam was significant for an obese male with mild respiratory distress and mild bilateral lower extremity edema. Cardiac troponins were within normal limits, but brain natriuretic peptide was mildly elevated (148 μg/dL). Electrocardiogram revealed new T-wave inversions in leads V2–V3 (Figure 1). Computed tomography pulmonary angiogram study with contrast demonstrated normal lung parenchyma without evidence of pulmonary embolism or infiltrates. Repeat TTE, however, showed newly dilated RV with significantly reduced RV systolic function (Figure 2) with tricuspid annular plane systolic excursion (TAPSE) of 1.3 cm and an estimated pulmonary arterial systolic pressure (PASP) of 56–61 mmHg (Figure 3).
Figure 1. Electrocardiogram: new nonspecific T-wave changes in V2–V3 when patient became acutely dyspneic after carfilzomib infusion.
Figure 2. RV focused view during chemotherapy: newly dilated RV with reduced systolic function (TAPSE was 1.3 cm) and lateral wall akinesis. Chronic trace pericardial effusion is also present. LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Figure 3. Continuous-wave Doppler during chemotherapy: pulmonary arterial systolic pressure is newly elevated as demonstrated by increased tricuspid regurgitation peak velocity of 3.47 m/s.
Having systematically excluded all major cardiopulmonary disorders (to include pulmonary embolism, acute coronary syndrome, pneumonia, acute anemia) and given the temporal relationship of treatment with carfilzomib to patient’s presentation, decision was made to stop carfilzomib. The patient did not receive any further medical interventions because he was clinically stable once admitted. No diuretics were given. No arterial blood gas was obtained. The patient was discharged after 2 days of monitoring. Right heart catheterization 2 weeks later revealed right atrial pressure of 7 mmHg, pulmonary arterial mean pressure of 28 mmHg, pulmonary capillary wedge pressure of 12 mmHg, normal cardiac output and pulmonary vascular resistance of 2.1 woods unit. Given restoration of near normal pulmonary pressures with discontinuation of the drug, carfilzomib-induced PH was confirmed as the diagnosis. A follow-up TTE one and a half months later (Figure 4) demonstrated normalization of RV size and systolic function (TAPSE was 2.3 cm). The patient’s symptoms and functional capacity also returned to baseline. Unfortunately, given multiple failed treatments for multiple myeloma, patient finally succumbed to complications of the disease 5 months later.
Figure 4. TTE after cessation of carfilzomib: apical four-chamber view demonstrating recovered RV size and systolic function (TASPE was 2.3 cm). LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle; TAPSE: tricuspid annular plane systolic excursion.
Discussion
Carfilzomib-induced PH as documented in the package insert occurs in up to 2% of patients, though ⩾ grade 3 PH adverse event as defined by NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) is seen in < 1%.1 This definition is different from standards set by the 6th World Symposium on Pulmonary Hypertension Task Force,5 which defines PH as mean pulmonary arterial pressure (PAP) > 20 mmHg. Although our patient did not have direct mean PAP measured, he did have severely elevated PASP during his index episode. With this finding, we presume that his mean PAP was also over 20 mmHg. There is little literature on the association of carfilzomib with acute PH and RV dysfunction. There is one similar case report of carfilzomib-induced PH in a 77-year-old female patient, who developed PH following seven cycles of carfilzomib/pomalidomide/dexamethasone therapy, although she was asymptomatic. A routine screening TTE showed pulmonary systolic pressure of 65–70 mmHg with mild RV enlargement, flattening of interventricular septum but preserved RV systolic function.6 In contrast, our patient was a male who after only four cycles of therapy developed symptoms with evidence of profound RV systolic dysfunction on TTE. In both cases, PH resolved with discontinuation of carfilzomib and, in our case, RV dysfunction resolved as well.
Carfilzomib’s exact mechanism of action on the CV system remains largely undefined. One theory is PI may lead to intracellular accumulation of misfolded proteins and ultimately abnormal protein homeostasis contributing to apoptosis of cardiomyocytes.7 Another proposed mechanism is endothelial and oxidative stress leading to vascular dysfunction, increased vascular tone and hypertension.6 Interestingly, carfilzomib has been shown in the literature to reverse pulmonary arterial hypertension in rat models8 but not in humans. This discrepancy is not fully understood. Differences between bortezomib and carfilzomib are also not entirely clear but may depend on carfilzomib’s irreversible and highly potent proteasome inhibition activity.7 Risk factors for cardiotoxicity include prior PI and doxorubicin exposure as well as pre-existing CV conditions such as heart failure and hypertension9 although these cardiotoxic effects do not appear to be cumulative or dose-related.10 Combination therapy with carfilzomib and dexamethasone may elevate risks for heart failure. Steroids can induce secondary hypertension and fluid retention, both of which can be exacerbated by routine intravenous fluids administered with this regimen. Bottomline, overall attributable risks and natural history of carfilzomib-related cardiotoxicity are still evolving and incompletely characterized.
There may be several reasons for RV dysfunction found in our case. First, the rise in PAP is likely very rapid in our patient. RV is a low-pressure chamber and when its afterload is acutely elevated, systolic dysfunction may ensue especially when compensatory hypertrophy has not taken place. Second, our veteran is obese. Obesity is an independent risk factor for RV dysfunction. One small study evaluating 35 otherwise healthy obese patients found that isolated obesity had evidence of subclinical abnormalities in RV structure and function by echocardiographic parameters.11 Finally, our patient had pre-existing CV conditions, such as hypertension and history of pulmonary embolism, which could have contributed to RV abnormalities.
According to a consensus document on management of carfilzomib from European Myeloma Network, a baseline assessment using the SCORE (Systemic Coronary Risk Evaluation) model as a formal and objective way of estimating CV risk is recommended. Echocardiogram is recommended as an initial screening and surveillance tool if concerns for any new CV symptoms or signs arise.12 Early detection for carfilzomib-induced cardiotoxicity is imperative as these complications are typically reversible with cessation of the medication. This reversal, which was observed in our patient (Figure 4), can be as early as weeks to months.6
Conclusion
Carfilzomib-induced CV effects are usually attributed to left-sided heart failure, but RV dysfunction can occur especially when acute PH occurs. PH is a known, albeit, rare complication of carfilzomib. It is important to be cognizant of PH as a likely cause for patients with acute dyspnea while on the PI. Routine screening echocardiograms should be considered prior to and during therapy particularly in those with pre-existing CV conditions as these cardiotoxicities are typically reversible with cessation of the drug.
The authors thank Bradley McGregor, MD, from Dana Farber Cancer Institute for his expertise and mentorship during editing portion of this paper.
Author contributions: P.-C.M. drafted, conceptualized and revised the manuscript. J.A. and V.B. both made substantial contributions to conception and manuscript revisions. All authors have read and approved the manuscript. All have agreed to be personally accountable for their own contributions.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval: Our institution does not require Institutional Review Board approval for reporting individual cases or case series.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the research department of the Veterans Affairs Boston Healthcare System.
ORCID iD: Pei-Chun McGregor
https://orcid.org/0000-0003-1346-689X
Informed consent: Written informed consent was obtained from a legally authorized representative for anonymized patient information and images to be published in this article. | Recovered | ReactionOutcome | CC BY-NC | 33643656 | 19,031,624 | 2021 |
What was the administration route of drug 'NOREPINEPHRINE'? | Jarisch-Herxheimer Reaction After Cephalosporin Administration in Syphilis.
The Jarisch-Herxheimer reaction (JHR) is a well-described entity most commonly occurring after the treatment of syphilis with penicillin. Patients often experience flu-like symptoms, in addition to worsening of cutaneous manifestations of syphilis. Severe reactions are uncommon but may include signs of exaggerated systemic inflammatory response. We report a case of a 33-year-old male with secondary syphilis who was treated with ceftriaxone and subsequently developed fluid-refractory hypotension requiring vasopressor administration and intensive care unit admission. To our knowledge, this is the first report of severe hypotension as a result of JHR in a patient with syphilis who was treated with cephalosporin antibiotics.
Introduction
The Jarisch-Herxheimer reaction (JHR) is a well-reported phenomenon most commonly occurring after the treatment of syphilis with penicillin. Patients often experience flu-like symptoms, which include but are not limited to fevers, chills, and myalgias, in addition to worsening of skin rash and other cutaneous manifestations of the disease. The reaction typically occurs within the first four to 12 hours after antibiotic administration and self-resolves within 24 hours. The mechanism of the JHR remains unknown, but cytokine release in response to treponemal lipoproteins is thought to be implicated in its pathogenesis. Severe reactions are uncommon but may include signs of an exaggerated systemic inflammatory response, including hemodynamic instability and thermoregulatory dysfunction. Herein, we report a case of secondary syphilis treated with ceftriaxone who subsequently developed fluid-refractory hypotension requiring vasopressor administration. This article was previously presented as a poster at the 2018 Kentucky American College of Physicians meeting on October 3, 2018.
Case presentation
A 33-year-old male with human immunodeficiency virus (HIV), not on highly active antiretroviral therapy (HAART) for the last two years, presented to an outside emergency department with a three-week history of subjective fever, arthralgias, myalgias, and a diffuse painful papular upper body rash. The rash had progressed from his trunk to involve his face, arms, and upper legs. He reported painless genital lesions preceding the diffuse rash, as well as two unprotected sexual encounters approximately one month prior. The patient took no home medications and had no known medication allergies. In the emergency department, he was found to have a temperature of 100.9°F, a heart rate of 130 beats per minute, and a respiratory rate of 22 breaths per minute. Urinalysis was not suggestive of infection, and chest radiograph demonstrated no infiltrate. Blood and urine cultures were obtained. He was given 1 L bolus of intravenous fluids and 1 g of ceftriaxone intravenously for presumed sepsis. He was subsequently transferred to our institution for further workup and management.
Upon arrival to our emergency department six hours later, the patient was febrile to 102.8°F with a heart rate of 161 beats per minute and systolic blood pressure initially 89 mmHg. Physical exam was remarkable for normal mentation, tachycardia but no murmurs, and clear lung fields bilaterally. There were erythematous scaly papular and plaque-like lesions over the face, back, chest, arms, abdomen, and upper legs (Figures 1, 2). The rash spared the palms and soles. He also had an erythematous papule on the mucosa of the lower lip. The patient remained hypotensive, with a blood pressure of 82/53 mmHg, despite 3 L of normal saline. A central venous catheter was placed, and a norepinephrine drip was started. The patient also received empiric antibiotic treatment with vancomycin and cefepime for presumed septic shock. The patient was admitted to the medical intensive care unit, where he required less than 24 hours of vasopressor administration with norepinephrine to maintain adequate blood pressure.
Figure 1 Scaly, erythematous papular lesions located diffusely over the patient's back.
Figure 2 A closer view of the papulosquamous lesions over the patient's posterolateral arm and upper back.
Blood and urine cultures obtained at the outside hospital prior to the first antibiotic dose were negative for bacterial growth. Broad-spectrum antibiotics were discontinued once cultures showed no growth for over 48 hours and the patient remained clinically stable. Blood cultures, fungal cultures, acid-fast bacilli smear and cultures, cerebrospinal fluid (CSF) cultures, cryptococcal serum and CSF antigens, Histoplasma galactomannan urine antigen, Neisseria gonorrhea polymerase chain reaction (PCR), and Chlamydia trachomatis PCR obtained at our facility were all negative. CSF studies demonstrated no red blood cells, no white blood cells, glucose 53 mg/dL (reference range 40-70 mg/dL), and protein 49.5 mg/dL (reference range 10-45 mg/dL), which was not thought to be consistent with aseptic meningitis. Rapid plasma reagin (RPR) was positive, and syphilis serum titer was 1:256 dL. CSF RPR was negative, and CSF Treponema pallidum IgG by immunofluorescence assay was nonreactive. The patient was also noted to have a CD4 T-cell count of 162/mm3 (reference range 338 to 1448 per mm3) and HIV-1 ribonucleic acid (RNA) of 456,000 copies/mL. Dermatology was consulted and deferred skin biopsy as exam findings were clinically consistent with secondary syphilis. The patient was treated with 2.4 million units of intramuscular benzathine penicillin. The remainder of his hospital course was uncomplicated, and he was discharged home after three days with close follow-up with Infectious Diseases with plans to resume HAART as an outpatient.
Discussion
Since 2001, the incidence of primary and secondary syphilis in the United States has increased dramatically. In 2018, the rate of primary and secondary syphilis was 10.8 cases per 100,000 population, which marked a 14.9% increase from 2017 and a 71.4% increase from 2014 [1]. Syphilis is caused by the spirochete Treponema pallidum, and the infection’s manifestations depend upon the stage of the disease. Primary syphilis classically presents as a non-tender genital chancre. The chancre may go unnoticed if not in a highly visible location, and thus treatment often is delayed until further progression of the disease. Secondary syphilis typically occurs two to eight weeks after the initial infection, with a characteristic rash, often involving the trunk, face, and extremities. Classically, the lesions may involve the palms and soles, although lack of involvement does exclude the diagnosis. Moist, heaped-up intertriginous lesions known as condyloma lata may be present. Skin lesions are highly infectious, and biopsy of these lesions examined under dark-field microscopy will reveal treponemes. In addition to classic dermatologic manifestations, secondary syphilis may also present with aseptic meningitis, patchy alopecia, and other mucocutaneous involvement. If untreated, the infection may enter a latent phase in which there are no signs or symptoms of the disease, but serological tests remain positive. Endarteritis is the characteristic presentation of tertiary syphilis and may manifest with neurologic involvement, cardiovascular involvement, or gummatous syphilis. Neurologic sequelae include focal ischemia due to meningovascular involvement and general paresis. Tabes dorsalis, for instance, is defined by syphilitic involvement of the posterior columns of the spinal cord, which leads to sensory ataxia of the lower extremities. Cardiovascular involvement may lead to aortitis and aortic aneurysm. Gummatous disease presents as destructive lesions of the skin, soft tissue, and bony structures. Syphilis may also be transmitted from mother to fetus, and congenital syphilis has varied manifestations but will not be discussed in detail in this report.
The diagnosis of syphilis often begins with nontreponemal screening tests, including RPR and venereal disease research laboratory (VDRL). Patients with positive screening tests should be tested for specific treponemal markers, such as fluorescent treponemal absorption assay, treponemal particle agglutination, enzyme immunoassays, and chemiluminescence immunoassays. CSF analysis should be performed if there are any neurologic or ophthalmic symptoms at any stage of the disease.
The treatment of choice for all stages of syphilis is penicillin G. Primary, secondary, and early latent disease may be treated with a single injection of 2.4 million units of penicillin G benzathine. Tertiary syphilis and late latent disease require treatment duration of three weeks with daily benzathine penicillin injections. Neurosyphilis should be treated with 3 to 4 million units of intravenous crystalline benzathine penicillin every four hours for three weeks [2].
One of the most common complications of treatment is the Jarisch-Herxheimer reaction (JHR). Classically described with penicillin administration in patients with syphilis, the JHR is also known to occur in other spirochetal diseases, including leptospirosis and Borrelia infection. One prospective observational study reported a higher incidence of JHR in patients with HIV who were treated for syphilis compared to non-HIV infected patients (34.6% vs. 25.2%, respectively), although this difference was not statistically significant [3]. Symptoms of JHR include fevers, chills, headache, myalgia, and worsening of skin manifestations. The reaction typically occurs within the first four to six hours after induction of therapy, with peak symptoms occurring around six to eight hours and resolution of symptoms by 16 to 24 hours [4].
The exact mechanism of JHR remains unclear. The most widely accepted theory is that lipopolysaccharides, a constituent of bacterial cell membranes, are released during exposure to certain antibiotics and may cause a systemic inflammatory response [4,5]. It is postulated that treponemal lipoproteins, once released, undergo phagocytosis by macrophages, which then secrete tumor necrosis factor alpha. Other cytokines, including interleukins IL-6 and IL-8, are also implicated in the inflammatory response to these lipoproteins. In the early phases of the reaction, patients may exhibit vasoconstriction and elevated blood pressure. Later, there is often vasodilation and decreased peripheral resistance, leading to hypotension. There have been few reports of severe reactions requiring vasopressors for hypotension in patients with JHR after treatment of leptospirosis [6,7]. However, most patients recover spontaneously and require minimal supportive care.
The patient described here had a profound reaction to cephalosporin administration with fluid-refractory hypotension but had subsequent clinical improvement and no further complications during the remainder of his hospital stay. A comprehensive evaluation for other infectious etiologies of his symptoms was unrevealing. He had no known allergies and tolerated further cephalosporin administration; thus, anaphylaxis was not likely implicated as the etiology of his symptoms. Given the timing of his symptoms in relation to antibiotic administration and diagnosis of secondary syphilis, his clinical presentation was thought to be most consistent with JHR.
Conclusions
We report a case of a patient who required admission to the intensive care unit and vasopressor support in the setting of presumed JHR. To our knowledge, this is the first report of a patient with syphilis who experienced severe hypotension from presumed JHR requiring vasopressor administration after administration of a cephalosporin antibiotic. Providers must be aware that JHR may occur in patients who are treated for syphilis, and, although rare, severe reactions may occur.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Intravenous drip | DrugAdministrationRoute | CC BY | 33643725 | 19,002,110 | 2021-01-17 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Jarisch-Herxheimer Reaction After Cephalosporin Administration in Syphilis.
The Jarisch-Herxheimer reaction (JHR) is a well-described entity most commonly occurring after the treatment of syphilis with penicillin. Patients often experience flu-like symptoms, in addition to worsening of cutaneous manifestations of syphilis. Severe reactions are uncommon but may include signs of exaggerated systemic inflammatory response. We report a case of a 33-year-old male with secondary syphilis who was treated with ceftriaxone and subsequently developed fluid-refractory hypotension requiring vasopressor administration and intensive care unit admission. To our knowledge, this is the first report of severe hypotension as a result of JHR in a patient with syphilis who was treated with cephalosporin antibiotics.
Introduction
The Jarisch-Herxheimer reaction (JHR) is a well-reported phenomenon most commonly occurring after the treatment of syphilis with penicillin. Patients often experience flu-like symptoms, which include but are not limited to fevers, chills, and myalgias, in addition to worsening of skin rash and other cutaneous manifestations of the disease. The reaction typically occurs within the first four to 12 hours after antibiotic administration and self-resolves within 24 hours. The mechanism of the JHR remains unknown, but cytokine release in response to treponemal lipoproteins is thought to be implicated in its pathogenesis. Severe reactions are uncommon but may include signs of an exaggerated systemic inflammatory response, including hemodynamic instability and thermoregulatory dysfunction. Herein, we report a case of secondary syphilis treated with ceftriaxone who subsequently developed fluid-refractory hypotension requiring vasopressor administration. This article was previously presented as a poster at the 2018 Kentucky American College of Physicians meeting on October 3, 2018.
Case presentation
A 33-year-old male with human immunodeficiency virus (HIV), not on highly active antiretroviral therapy (HAART) for the last two years, presented to an outside emergency department with a three-week history of subjective fever, arthralgias, myalgias, and a diffuse painful papular upper body rash. The rash had progressed from his trunk to involve his face, arms, and upper legs. He reported painless genital lesions preceding the diffuse rash, as well as two unprotected sexual encounters approximately one month prior. The patient took no home medications and had no known medication allergies. In the emergency department, he was found to have a temperature of 100.9°F, a heart rate of 130 beats per minute, and a respiratory rate of 22 breaths per minute. Urinalysis was not suggestive of infection, and chest radiograph demonstrated no infiltrate. Blood and urine cultures were obtained. He was given 1 L bolus of intravenous fluids and 1 g of ceftriaxone intravenously for presumed sepsis. He was subsequently transferred to our institution for further workup and management.
Upon arrival to our emergency department six hours later, the patient was febrile to 102.8°F with a heart rate of 161 beats per minute and systolic blood pressure initially 89 mmHg. Physical exam was remarkable for normal mentation, tachycardia but no murmurs, and clear lung fields bilaterally. There were erythematous scaly papular and plaque-like lesions over the face, back, chest, arms, abdomen, and upper legs (Figures 1, 2). The rash spared the palms and soles. He also had an erythematous papule on the mucosa of the lower lip. The patient remained hypotensive, with a blood pressure of 82/53 mmHg, despite 3 L of normal saline. A central venous catheter was placed, and a norepinephrine drip was started. The patient also received empiric antibiotic treatment with vancomycin and cefepime for presumed septic shock. The patient was admitted to the medical intensive care unit, where he required less than 24 hours of vasopressor administration with norepinephrine to maintain adequate blood pressure.
Figure 1 Scaly, erythematous papular lesions located diffusely over the patient's back.
Figure 2 A closer view of the papulosquamous lesions over the patient's posterolateral arm and upper back.
Blood and urine cultures obtained at the outside hospital prior to the first antibiotic dose were negative for bacterial growth. Broad-spectrum antibiotics were discontinued once cultures showed no growth for over 48 hours and the patient remained clinically stable. Blood cultures, fungal cultures, acid-fast bacilli smear and cultures, cerebrospinal fluid (CSF) cultures, cryptococcal serum and CSF antigens, Histoplasma galactomannan urine antigen, Neisseria gonorrhea polymerase chain reaction (PCR), and Chlamydia trachomatis PCR obtained at our facility were all negative. CSF studies demonstrated no red blood cells, no white blood cells, glucose 53 mg/dL (reference range 40-70 mg/dL), and protein 49.5 mg/dL (reference range 10-45 mg/dL), which was not thought to be consistent with aseptic meningitis. Rapid plasma reagin (RPR) was positive, and syphilis serum titer was 1:256 dL. CSF RPR was negative, and CSF Treponema pallidum IgG by immunofluorescence assay was nonreactive. The patient was also noted to have a CD4 T-cell count of 162/mm3 (reference range 338 to 1448 per mm3) and HIV-1 ribonucleic acid (RNA) of 456,000 copies/mL. Dermatology was consulted and deferred skin biopsy as exam findings were clinically consistent with secondary syphilis. The patient was treated with 2.4 million units of intramuscular benzathine penicillin. The remainder of his hospital course was uncomplicated, and he was discharged home after three days with close follow-up with Infectious Diseases with plans to resume HAART as an outpatient.
Discussion
Since 2001, the incidence of primary and secondary syphilis in the United States has increased dramatically. In 2018, the rate of primary and secondary syphilis was 10.8 cases per 100,000 population, which marked a 14.9% increase from 2017 and a 71.4% increase from 2014 [1]. Syphilis is caused by the spirochete Treponema pallidum, and the infection’s manifestations depend upon the stage of the disease. Primary syphilis classically presents as a non-tender genital chancre. The chancre may go unnoticed if not in a highly visible location, and thus treatment often is delayed until further progression of the disease. Secondary syphilis typically occurs two to eight weeks after the initial infection, with a characteristic rash, often involving the trunk, face, and extremities. Classically, the lesions may involve the palms and soles, although lack of involvement does exclude the diagnosis. Moist, heaped-up intertriginous lesions known as condyloma lata may be present. Skin lesions are highly infectious, and biopsy of these lesions examined under dark-field microscopy will reveal treponemes. In addition to classic dermatologic manifestations, secondary syphilis may also present with aseptic meningitis, patchy alopecia, and other mucocutaneous involvement. If untreated, the infection may enter a latent phase in which there are no signs or symptoms of the disease, but serological tests remain positive. Endarteritis is the characteristic presentation of tertiary syphilis and may manifest with neurologic involvement, cardiovascular involvement, or gummatous syphilis. Neurologic sequelae include focal ischemia due to meningovascular involvement and general paresis. Tabes dorsalis, for instance, is defined by syphilitic involvement of the posterior columns of the spinal cord, which leads to sensory ataxia of the lower extremities. Cardiovascular involvement may lead to aortitis and aortic aneurysm. Gummatous disease presents as destructive lesions of the skin, soft tissue, and bony structures. Syphilis may also be transmitted from mother to fetus, and congenital syphilis has varied manifestations but will not be discussed in detail in this report.
The diagnosis of syphilis often begins with nontreponemal screening tests, including RPR and venereal disease research laboratory (VDRL). Patients with positive screening tests should be tested for specific treponemal markers, such as fluorescent treponemal absorption assay, treponemal particle agglutination, enzyme immunoassays, and chemiluminescence immunoassays. CSF analysis should be performed if there are any neurologic or ophthalmic symptoms at any stage of the disease.
The treatment of choice for all stages of syphilis is penicillin G. Primary, secondary, and early latent disease may be treated with a single injection of 2.4 million units of penicillin G benzathine. Tertiary syphilis and late latent disease require treatment duration of three weeks with daily benzathine penicillin injections. Neurosyphilis should be treated with 3 to 4 million units of intravenous crystalline benzathine penicillin every four hours for three weeks [2].
One of the most common complications of treatment is the Jarisch-Herxheimer reaction (JHR). Classically described with penicillin administration in patients with syphilis, the JHR is also known to occur in other spirochetal diseases, including leptospirosis and Borrelia infection. One prospective observational study reported a higher incidence of JHR in patients with HIV who were treated for syphilis compared to non-HIV infected patients (34.6% vs. 25.2%, respectively), although this difference was not statistically significant [3]. Symptoms of JHR include fevers, chills, headache, myalgia, and worsening of skin manifestations. The reaction typically occurs within the first four to six hours after induction of therapy, with peak symptoms occurring around six to eight hours and resolution of symptoms by 16 to 24 hours [4].
The exact mechanism of JHR remains unclear. The most widely accepted theory is that lipopolysaccharides, a constituent of bacterial cell membranes, are released during exposure to certain antibiotics and may cause a systemic inflammatory response [4,5]. It is postulated that treponemal lipoproteins, once released, undergo phagocytosis by macrophages, which then secrete tumor necrosis factor alpha. Other cytokines, including interleukins IL-6 and IL-8, are also implicated in the inflammatory response to these lipoproteins. In the early phases of the reaction, patients may exhibit vasoconstriction and elevated blood pressure. Later, there is often vasodilation and decreased peripheral resistance, leading to hypotension. There have been few reports of severe reactions requiring vasopressors for hypotension in patients with JHR after treatment of leptospirosis [6,7]. However, most patients recover spontaneously and require minimal supportive care.
The patient described here had a profound reaction to cephalosporin administration with fluid-refractory hypotension but had subsequent clinical improvement and no further complications during the remainder of his hospital stay. A comprehensive evaluation for other infectious etiologies of his symptoms was unrevealing. He had no known allergies and tolerated further cephalosporin administration; thus, anaphylaxis was not likely implicated as the etiology of his symptoms. Given the timing of his symptoms in relation to antibiotic administration and diagnosis of secondary syphilis, his clinical presentation was thought to be most consistent with JHR.
Conclusions
We report a case of a patient who required admission to the intensive care unit and vasopressor support in the setting of presumed JHR. To our knowledge, this is the first report of a patient with syphilis who experienced severe hypotension from presumed JHR requiring vasopressor administration after administration of a cephalosporin antibiotic. Providers must be aware that JHR may occur in patients who are treated for syphilis, and, although rare, severe reactions may occur.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | 3 LITER | DrugDosageText | CC BY | 33643725 | 19,002,110 | 2021-01-17 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Influenza'. | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | AMLODIPINE BESYLATE, CHONDROITIN SULFATE (BOVINE), CODEINE PHOSPHATE, DEXTROMETHORPHAN HYDROBROMIDE, HYDROCORTISONE BUTYRATE, IPRAGLIFLOZIN L-PROLINE, PEMBROLIZUMAB, SENNOSIDES | DrugsGivenReaction | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Interstitial lung disease'. | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | AMLODIPINE BESYLATE, CHONDROITIN SULFATE (BOVINE), CODEINE PHOSPHATE, DEXTROMETHORPHAN HYDROBROMIDE, HYDROCORTISONE BUTYRATE, IPRAGLIFLOZIN L-PROLINE, PEMBROLIZUMAB, SENNOSIDES | DrugsGivenReaction | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What is the weight of the patient? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | 68 kg. | Weight | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'AMLODIPINE BESYLATE'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'CHONDROITIN SULFATE (BOVINE)'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Parenteral | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'CODEINE PHOSPHATE'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'DEXTROMETHORPHAN HYDROBROMIDE'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'HYDROCORTISONE BUTYRATE'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Parenteral | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'IPRAGLIFLOZIN L-PROLINE'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'PEMBROLIZUMAB'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the administration route of drug 'SENNOSIDES'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the outcome of reaction 'Influenza'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Recovering | ReactionOutcome | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
What was the outcome of reaction 'Interstitial lung disease'? | Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.
A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.
Abbreviations
irAEan immune-related adverse event
ICIimmune checkpoint inhibitor
CAEcarcinoembryonic antigen
KL-6krebs von den Lungen-6
CTcomputed tomography
PD-1programmed cell death-1
PD-L1programmed death-ligand 1
PD-L2programmed death-ligand 2
1 Introduction
In Japan, the use of immune checkpoint inhibitor (ICI) for the treatment of lung cancer was approved in December 2015. Then, ICI has become a key chemotherapeutic drug for lung cancer. However, it may cause immune-related adverse events (irAEs), which are often challenging to treat. Herein, we present a patient with interstitial lung disease treated with pembrolizumab who acquired influenza.
2 Case presentation
A 67-year-old man with diabetes mellitus who presented with atelectasis in the right lung was admitted to our hospital. The patient had a smoking history of 10 pack-years. Based on previous examination results, the patient was diagnosed with cT2aN3M1c stage IV B lung adenocarcinoma of the right upper lung. Right malignant pleural effusion was present, for which drainage was performed. The tumor proportion score was 100%, and there were no driver mutations. Therefore, pembrolizumab was used as the first-line treatment.
On the day of the second cycle of pembrolizumab, the patient was admitted to the hospital due to fever and hypoxemia.
Before treatment with pembrolizumab, the patient's carcinoembryonic antigen (CEA) level was 1574.3 ng/mL. However, it decreased to 860.5 ng/mL upon admission. The therapeutic effect of chemotherapy showed stable disease by computed tomography (CT) (Fig. 1). The Krebs von den Lungen-6 (KL-6) level was slightly elevated at 647 U/mL, and the pulmonary surfactant protein D level was normal (17.2 ng/mL). Chest radiography revealed a mass in the right upper lung and consolidation in the left lung (Fig. 2a). CT scan showed ground-glass opacity in the left lung (Fig. 2b). The influenza virus antigen test result was positive for influenza virus type A antigen.Fig. 1 Computed tomography. a: before treatment of immune checkpoint inhibitor, b: on admission.
Fig. 1Fig. 2 Chest imaging on admission. a: Chest radiography. b: computed tomography.
Fig. 2
The patient was then treated with peramivir as his pneumonia was caused by the influenza virus. To manage respiratory failure, oxygen administration was initiated at a flow rate of 3 L/min using a face mask and methylprednisolone was administered at a dose of 40 mg/day. On the 2nd day of hospitalization, his body temperature decreased. However, the oxygen flow rate was maintained at 3 L/min as the patient's respiratory status did not improve. Methylprednisolone was discontinued on the 3rd day of hospitalization, and treatment was switched to prednisolone at a dose of 30 mg/day on the 4th day of hospitalization. However, on the 8th day of hospitalization, the oxygen flow rate was increased to 4 L/min. Then, chest CT scan was performed on the 9th day of hospitalization, and results showed enlargement of ground-glass opacity in the left lung (Fig. 3). Therefore, treatment with methylprednisolone at a dose of 1000 mg was started. On the 10th day, the oxygen flow rate was further increased to 5 L/min. Pleural effusion was drained considering that the respiratory failure resulted from the pleural effusion. However, despite this, the patient's respiratory condition did not improve. On the 11th day of hospitalization, despite treatment with methylprednisolone, respiratory failure progressed rapidly and morphine administration was initiated for the management of dyspnea. The patient eventually died on the 12th day of hospitalization.Fig. 3 Computed tomography on the 9th day of hospitalization.
Fig. 3
3 Discussion
In this case report, the patient died due to influenza while on treatment with pembrolizumab. Whether the cause of death was lung injury, which is an irAE associated with influenza, or severe influenza virus pneumonia was challenging to confirm. Moreover, there are only few reports on influenza in a patient receiving ICI treatment. Hence, this case is considered valuable.
Recent studies have shown that ICI is effective for the treatment of various cancers, including lung tumors. In the management of lung cancer, ICI is used as not only a single agent but also in combination with other chemotherapeutic drugs. In addition, this drug plays a central role in the treatment of lung cancer, and it can be used as first-line treatment, second-line treatment, and maintenance therapy after chemoradiation therapy.
Although ICI is effective, some studies have shown the occurrence of irAE associated with this drug. In patients with non-small cell lung cancer treated with pembrolizumab, the incidence rates of interstitial lung disease are 4.1%–7.0% in those with all grade and 2.1%–3.0% in those with grade 3 or higher. The median onset time is 65.5 (range: 5–816) days [[1], [2], [3]]. Additionally, there are various types of irAE; for example, Chopra A et al. reported a drug-induced sarcoidosis-like reaction [4]. Therefore, in the treatment of ICI, one must be cautious regarding the occurrence of irAE during the course of treatment.
Pembrolizumab is an antibody against programmed cell death-1 (PD-1), which is associated with immune responses. PD-1 is expressed on activated T and B cells. Moreover, it has two ligands: programmed death-ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells, and programmed death-ligand 2 (PD-L2), which is restricted to macrophages and dendritic cells. Both ligands play an important role in maintaining immune tolerance [5].
Some studies have reported an association between viral infection and PD-1. In chronic virus infections, PD-1 expression increased on the surface of regulatory T cells [6], and it contributed to immune tolerance in CD8+ T cells [7]. Even in acute virus infection, including influenza, PD-1 expression on CD8+ T cells is elevated [8]. Therefore, PD-1-mediated immune tolerance might occur in both chronic and acute infections. John A et al. revealed that the use of anti-PD-1 antibody enhances T cell function and improves viral clearance in severe influenza [9]. This result indicated that anti-PD-1 antibody might be effective for the treatment of virus infection. In addition, activated CD8+ T cells produced cytokines and eliminated virus-infected cells [10]. Therefore, if there is excessive immune response, lung injury may occur. However, overproduction of cytokines can cause systemic disorders such as lung injury [11]. Therefore, it is considered that viral infection during ICI treatment may increase cytokine production compared to infection without ICI treatment, which may result in lung injury.
On one hand, in cancer patients with or without ICI treatment, serious complications from influenza can occur. Cooksley et al. reported that about 9% of cancer patients who were hospitalized due to influenza die. Therefore, influenza vaccination is recommended for this group of patients [12]. However, the efficacy and safety of influenza vaccination during ICI treatment has not yet been validated. In the study of Heinz et al., the vaccination groups had a higher number of adverse events than the control group [13]. Nevertheless, Dirk et al. reported that in patients with cancer treated with nivolumab, there was no significant difference in the incidence of irAEs or severe adverse events between the influenza vaccination group and non-vaccination group (irAEs: 26% vs 22%, severe adverse events: 7% vs 4%) [14]. Similarly, Curtis R et al. showed that the incidence of adverse events did not increase in 370 vaccinated patients with cancer treated with ICI [15].
In our case, the patient did not receive influenza vaccination. Whether the patient died of pneumonia associated with the influenza virus or of lung injury, which is a severe irAE, was challenging to confirm. CT features of influenza pneumonia and lung injury associated with irAE have been reported. The predominant CT findings in influenza pneumonia were bilateral, peripheral, ground-glass opacities and/or bilateral areas of consolidation [16]. On the other hand, the CT findings in lung injury associated with irAE were ground-glass opacities, consolidation, bronchiectasis, interlobular septal thickening and intralobular lines. These findings were present in both diffuse lung involvement or localized lung involvement [17]. However, as the CT findings of both the conditions are similar, it is not possible to distinguish them clearly. In our case, the CT findings were ground-glass opacities confined to the left lung, and it was difficult to determine which condition was more likely. Therefore, we considered the clinical course of the patient for determining the most likely condition. In cases of death due to influenza pneumonia, Takayanagi et al. reported that five out of eight cases died within four days after admission [18]. In lung injury as associated with irAE, Jarushka N et al. reported five cases of death [19]. Although the number of days since the onset of irAE was not stated, one patient died due to recurrent pneumonitis during corticosteroid administration was tapered and three patients died as a result of infection due to immunosuppression performed to treat pneumonitis. Two of the three patients had been treated with long-term corticosteroids and immunosuppressants for lung injury. In addition, Sawai et al. reported a case [20] that died 21 days after the onset of lung injury, and Oda et al. reported a case [21] that died 23 days after the onset of lung injury. Therefore, lung injury associated with irAE does not always result in death within a few days after onset. In this case, patient died on the 12th day after the onset of lung injury. The degree of respiratory failure in the patient remained unchanged for 7 days after admission, and despite treatment with anti-influenza drugs, it rapidly deteriorated on the 8th day. Therefore, we considered that the lung injury was associated with irAE. In viral infection, PD-1 expression on CD8+ T cells was enhanced to suppress excessive immune response. Therefore, it is considered that, even in our case, there was a mechanism that worked to prevent an excessive immune response after influenza infection, but an excessive immune response occurred because the immune tolerance mediated by PD-1 was inhibited by ICI treatment, which ultimately resulted in lung injury. Reports on the development of irAEs caused by viral infection during ICI treatment are limited, and the incidence of irAEs has not been validated. As in our case, patients may die due to infection. Hence, more studies about the association between ICI and viral infection or the efficacy of influenza vaccination should be conducted in the future.
4 Conclusion
Viral infection during ICI treatment may be a risk factor of irAEs. Therefore, caution should be taken to prevent transmission of viral infection, and one must be knowledgeable on not only the symptoms of influenza but also the development of irAEs in cancer patients. | Fatal | ReactionOutcome | CC BY-NC-ND | 33643837 | 15,867,611 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Oxygen therapy via a noninvasive helmet: A COVID-19 novelty with potential post-pandemic uses.
COVID-19 has placed a significant strain upon healthcare resources at a global level and refractory hypoxemia is the leading cause of death among COVID-19 patients. The management of limited resources such as mechanical ventilators has remained a contentious issue both at an individual and institutional level since the beginning of the pandemic. As a result, the COVID-19 pandemic has presented challenges to critical care practitioners to find innovative ways to provide supplemental oxygen therapy to their patients. We present a single-center experience: a case series of five COVID-19 infected patients managed with a novel approach to provide supplemental oxygen and positive end-expiration pressure (PEEP) via the helmet. Three of the five patients responded to therapy, did not require intubation, and survived to discharge. The other two patients continued to deteriorate clinically, required endotracheal intubation, and subsequently expired during their hospitalization. We extrapolated our accumulated experience with non-invasive oxygen support by helmet in COVID-19 patients to a non-COVID-19 postoperative patient who underwent sinus surgery and developed hypoxemic respiratory failure also resulting in avoidance of endotracheal intubation. We conclude that oxygen therapy via a helmet is a safe, cost-effective technique to prevent intubation in carefully selected patients with infectious and non-infectious causes of hypoxic respiratory failure. Our positive experience with the system warrants further large-scale study and possible technique refinement.
1 Introduction
The severe acute respiratory syndrome coronavirus (SARS-CoV-2), commonly referred to as COVID-19, was first reported in Wuhan, China in late 2019 [1], and has since caused a global pandemic [2,3]. The virus primarily affects the lungs and, in serious cases, can lead to acute severe respiratory failure requiring admission to the intensive care unit (ICU) and endotracheal intubation. Mortality predominantly occurs as a result of refractory hypoxemia and the associated sequelae including multi-organ dysfunction and failure [5]. Globally, the volume of patients and the severity of illness overwhelmed the medical resources of hospitals [2] and, in the United States, the Society of Critical Care Medicine projected that our resources were at risk of being insufficient to meet the anticipated needs [6].
Resource management for items such as ICU beds, ventilators, and key health care personnel has been debated through out the ongoing pandemic [5,9,10]. In order to address the appropriate utilization of sparse resources and the possibility to reduce morbidity and increased mortality related to endotracheal intubation, we began to explore novel methods for providing respiratory support to critically ill COVID-19 patients.
European practitioners of hyperbaric oxygen therapy have reported their experience in treating hypoxic patients with a soft, clear, vinyl helmet system that could be used to provide oxygen therapy with high FiO2 and a modest amount of positive end-expiratory pressure (PEEP) outside of a hyperbaric environment [15]. Traditionally, these devices are used to provide intermittent periods of oxygen therapy (FiO2 1.0) while exposed to a hyperbaric environment in a hyperbaric chamber. This technique had been employed in Italy with negligible leakage of exhaled air around viral filters and associated aerosolized droplets [16] thereby decreasing the risk of exposure to aerosolized droplets of infectious material amongst healthcare personnel. These helmets can also create a high FiO2 environment outside of a hyperbaric chamber and thus, we designed a treatment algorithm whereby we would use these helmets in our ICU to potentially prevent the need for intubation and thereby maintain an adequate supply of available ventilators and supplies. This case series describes our experience with using the oxygen helmet in a subset of critically ill COVID-19 patients.
2 Methods
The three models of the helmet (PN 580, PN5200, and PN5202; Sea-Long Medical Systems LLCX, Texas) have a clear plastic hood that covers the patient's head. The helmet is connected to a plastic ring that is supported by a soft, rubber collar that is tailored to each patient by measuring the neck circumference. The rubber collar forms a tight seal against the skin of the patient and permits a modest amount of PEEP within the helmet. The helmet has two connection ports to which expiratory and inspiratory tubing are attached. The inspiratory tubing can be connected to high-flow nasal cannula or NIPPV device, while a viral filter is connected to the expiratory tubing. The helmet is secured to the patient by armpit braces with padding to prevent skin breakdown See Fig. 1.Fig. 1 High-flow (a) and NIPPV (b) via helmet demonstrated in Mayo Clinic physicians.
Fig. 1
At our institution, HFNC was provided in conjunction with the helmet. Additionally, a PEEP valve and a viral filter were added to the circuit. All patients received high-flow nasal cannula with PEEP ranging from 5 to 10 cmH2O, the minimum flow delivered was 50 L of oxygen, and FiO2 was titrated according to the patient's arterial blood gas. A training session was provided to all clinicians and respiratory therapists using this modality in COVID-19 patients.
A systematic approach was used for the management of refractory hypoxemia in COVID-19 patients at our institution. Accordingly, patients with increasing oxygen requirements on the nasal cannula or oxygen mask were placed on a reservoir nasal cannula or non-rebreather mask and encouraged to self-prone as much as tolerated. If they continue to experience desaturations and/or further increases in their work of breathing (tachypnea, retractions, shallow respirations, or subjective fatigue), they were designated to a trial of high-flow oxygen therapy via the helmet. Initial FiO2 and flow rate settings were selected and titrated based on patient need and response to therapy. If the patient was not already on FiO2 1.0, the FiO2 was titrated by at least 0.1 at the initiation of helmet therapy. Respiratory rate, work of breathing, and arterial blood gases were frequently assessed for patients using high-flow via helmet. Patients who did not tolerate the helmet as defined by continued increased work of breathing, continued desaturation (SpO2 <88%) or continued worsening PaO2 (<60) or those who had further clinical decompensation while on high-flow via helmet were intubated endotracheally. There were no objective cutoffs defining non-tolerance to helmet therapy as this was a clinical decision based on the above-mentioned criteria. During this time period, the ICU staffing model included at least one provider, senior nurse, and respiratory therapist who had been trained to monitor patients receiving oxygen therapy via the helmet technique.
Additional COVID-19 therapies were given to patients according to our treatment algorithm (Fig. 2). Patients were assigned to receive different therapies such as dexamethasone, remdesivir, tocilizumab, lenzilumab, or convalescent plasma according to their oxygen requirements and inflammatory markers. The guidelines with respect to pharmacological treatment and standard of care for patients with COVID-19 have represented a dynamic state; the different treatment regimens provide were consistent with the standard of care at the time of the patient's hospitalization. All patients received either prophylactic or therapeutic anticoagulation according to our anticoagulation algorithm. All patients signed a research release at the time of their admission and this retrospective analysis was deemed exempt from IRB review.Fig. 2 Mayo Clinic Florida inpatient treatment algorithm for COVID-19 infection.
Fig. 2
3 Case descriptions
3.1 Case #1
A 70-year-old male with a past medical history of morbid obesity (BMI = 42.0 kg/m2), hypertension, diabetes mellitus type 2, and depression presented to the emergency department with acute respiratory failure in the setting of COVID-19 pneumonia. The patient presented with oxygen saturations <70% (measured by pulse oximetry) with adequate waveforms. His respiratory rate was >40 breaths per minute and was placed on NIPPV with initial settings of inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) of 10/5 cmH2O with FiO2 1.0. He was admitted directly to the ICU but did not tolerate NIPPV support due to agitation. The patient was provided with a trial of therapy with HFNC via helmet along with nitric oxide (40 ppm), but because of persistent hypoxemia and worsening encephalopathy, he was endotracheally intubated for mechanical ventilatory support within 8hrs of admission. His COVID-19 treatment regimen included remdesivir, tocilizumab, and dexamethasone. His 22-day ICU course was complicated by renal failure requiring dialysis, bacteremia, thrombocytopenia, and intracerebral hemorrhages. Life support measures were withdrawn after goals of care discussion as per the patient and family wishes.
3.2 Case #2
A 74-year-old male with a past medical history of obstructive sleep apnea (OSA) and obesity presented with acute hypoxic respiratory failure in the setting of COVID-19 pneumonia. On admission day 3, the patient had increasing oxygen requirements with HFNC (flow 50L, FiO2 1.0) with additional oxygen supplementation via a non-rebreather mask (flow 15L). Having failed to tolerate a brief trial (<15min) of bi-level NIPPV (10/5 cmH2O, FiO2 1.0), he was then transitioned to HFNC (Flow 45L/min, FiO2 1.0) via helmet in combination with inhaled nitric oxide (40 ppm). He received convalescent plasma, remdesivir, dexamethasone, and lenzilumab as part of his COVID-19 treatment. On admission day 6, the patient was transitioned back to the floor and was progressively weaned off helmet ventilation to the nasal cannula. He was subsequently discharged home.
3.3 Case #3
A 68-year-old male with a past medical history of hypertension, gastroesophageal reflux disease, and hyperlipidemia presented with a 4-day history of cough, fever, chest tightness, and weakness after returning from a trip from New Zealand. On admission day 3, his oxygen requirements increased as his dyspnea worsened and work of breathing intensified. He engaged in a self-proning posture with supplemental oxygen provided via a non-rebreather mask (flow 15L/min), and experienced an improvement in his hypoxia (oxygen saturations increased from 92% to 98%) and associated dyspnea. He was then transferred to the ICU for closer monitoring and placed on non-invasive helmet ventilation with HFNC (Flow 80L/min, FiO2 0.8) and inhaled nitric oxide (20 ppm). He received hydroxychloroquine, lenzilumab, and tocilizumab as part of his COVID-19 treatment. After 8 days on noninvasive ventilation via helmet, his condition continued to improve and he was transitioned to an oxygen mask and eventually nasal cannula. He was then discharged home with supplemental oxygen provided via nasal cannula (NC) (2L/min).
3.4 Case #4
A 73-year-old female with a history of hypothyroidism, gastroesophageal reflux disease, hyperlipidemia, and chronic kidney disease presented to the emergency department with nausea, fatigue, and non-productive cough in the setting of COVID-19 pneumonia. Her hospital course was complicated by hypoxemic respiratory failure with a progressively increasing need for O2 via nasal cannula to non-rebreather mask at 15L/min. Her hypoxia continued to worsen and she required HFNC (Flow 80L/min, FiO2 0.8) via helmet therapy. She received lopinavir/ritonavir, remdesivir, ribavirin, tocilizumab, and hydroxychloroquine as part of her COVID-19 treatment. After three days of helmet therapy with HFNC, she was transferred to the floor on 6L NC and was eventually discharged home on 2L NC.
3.5 Case # 5
A 76-year-old male with a past medical history of chronic obstructive pulmonary disease (COPD) and small-cell lung cancer status post-chemotherapy and radiation (>5yrs prior to presentation, in remission) presented with acute hypoxic respiratory failure due to COVID-19 pneumonia. He was initially admitted to the general medical wards; but, due to escalating oxygen requirements, he was transferred to the ICU on the third day of hospitalization. There he was placed on HFNC (Flow 70L/min, FiO2 1.0) via the helmet along with inhaled nitric oxide (40 ppm). He received remdesivir, tocilizumab, and dexamethasone as part of his COVID-19 treatment. Unfortunately, he continued to deteriorate, and due to increasing hypoxia and work of breathing, he required endotracheal intubation on day 8 of hospitalization. His clinical condition deteriorated further and, after goals of care discussion with family, the patient was transitioned to hospice care and expired.
3.6 Scope for the future - helmet therapy for non-covid-19 patients
A 66-year-old male patient with a past medical history of congestive heart failure, associated with a reduced ejection fraction, underwent maxillary sinus repair surgery. His COVID-19 negative status was confirmed pre-operatively. He was extubated postoperatively but developed hypoxia due to flash pulmonary edema while recovering in PACU on a non-rebreather. His surgical procedure presented a contra-indication for NIPPV therapy and the ICU service was consulted for the need for possible reintubation. The patient was instead managed with HFNC (Flow 70L/min, FiO2 1.0) via helmet and intravenous furosemide. He had symptomatic improvements within 24 hours and was subsequently transferred to the general ward. The remainder of his hospitalization was uneventful from a respiratory perspective and he was eventually discharged home.
4 Discussion
We used noninvasive oxygenation via the helmet in carefully selected patients to decrease dispersion of the COVID-19 virus and to reduce the need for endotracheal intubation and mechanical ventilation. We went a step further and use this modality in a COVID-negative patient with hypoxic respiratory failure as an innovative way to explore the potential of this therapy.
Our report demonstrates favorable outcomes in a majority of the patients. Those of our patients who survived their acute hypoxic illness demonstrated increased tissue oxygenation after the application of the oxygen helmet. The patients who died during hospitalization demonstrated many risk factors known for increased mortality associated with COVID-19 and include male sex, obesity, pulmonary disease including COPD and lung cancer, diabetes, hypertension, and thrombocytopenia [[24], [25], [26]]. Table 1 summarizes the main characteristics and the outcomes for the patients included in this case series.Table 1 Patient characteristics and outcomes.
Table 1 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Age 70 74 68 73 76
Sex M M M F M
Duration of hospitalization before helmet treatment 2 days 1 day 3 days 7 days 3 days
Time elapsed between symptom onset and helmet therapy 9 days 6 days 8 days 14 days 13 days
P/F Ratio (Prior to initiation of oxygen helmet) <200 <200 <300 <300 <100
CRP 235.3 168.5 79 229.7 82.8
IL-6 >400 314 30.9 16.2 16.1
d-dimer >42000 678 751 1516 1058
SOFA score (Day of admission) 5 3 3 2 3
Helmet settings
Flow rate (L/min) 60 30 50 80 50
FiO2 1.0 0.8 0.8 0.8 1.0
PEEP (cmH2O) 8 7 5 5 7
Average respiratory rate 24 32 30 22 24
Duration of helmet therapy 1 day 1 day 7 days 5 days 4 days
Duration of NO 16 days 6 days 1 day No 12 days
Intubation (yes/no) Yes No No No Yes
Duration of hospital stay 22 days 9 days 13 days 17 days 14 days
Outcome Deceased Alive Alive Alive Deceased
The patient population who would benefit from this treatment modality should be carefully selected. The most important selection criterion to be considered is the respiratory function of the patient. The helmet is dependent on the patient's ability to generate tidal volume and minute ventilation sufficient to meet their needs. Patients who are unable to tolerate the mask associated with NIPPV due to facial anatomy, facial hair, skin breakdown from prolonged use of mask, or risk of aspiration, can also benefit from this practice. The factors which helped us in selecting the patients include claustrophobia, mask intolerance, degree of CO2 retention, degree of hypoxia, risk of vomiting/aspiration, and patient/family preference.
The usage of oxygen hood in the current COVID-19 pandemic showcased several advantages. The cost of each hood is measured in hundreds of dollars as opposed to the thousands of dollars range when compared with mechanical ventilation. Furthermore, this therapy decreases overall hospital costs associated with the prolonged ICU admission mechanical ventilation entails [17]. While the rubberneck gaskets are used for single patients due to the customized sizing procedure required, the hoods can be sterilized and reused on multiple patients. The hoods are also compatible with adjunct therapy such as nitric oxide (NO) therapy, an approach that has been used with success in COVID-19 patients [[19], [20], [21]]. Oxygen supplementation with the oxygen helmet also provides the patient with the ability to drink fluids through a straw, wear glasses under the helmet, and engage in verbal communication with greater ease. More importantly, the neck seal and the viral filter reduces the risk of aerosol generation and nosocomial infection for healthcare workers and other patients. Thus, not only helmet oxygenation a cost-effective alternative, but it also has the potential to prevent intubation and preserve ventilators in the current pandemic. Table 2 provides a visual reference for relative comparison of multiple modalities of providing supplemental oxygen.Table 2 Relative Comparison of multiple modalities of providing supplemental oxygen.
Table 2 Oxygen helmet HFNC BiPAP MEchanical Ventilation
COST $$ $$ $$$ $$$
RISK OF AEROSOLIZATION Low High High Low
INDICATIONS FOR USE:
-HYPOXIC FAILURE + + + +
-HYPERCARBIC FAILURE – – + +
PATIENT COMFORT Medium Medium Low Low
USE OF INHALED NO ALONG WITH DEVICE + + – +
There is a potential to expand the application of this method of oxygen therapy to other patients for whom traditional NIPPV or intubation is either contraindicated or sought to be avoided. We demonstrated this by preventing intubation in a COVID-negative patient, who underwent maxillary sinus surgery when NIPPV was contraindicated. Preventing intubation has many benefits including preventing ventilator-induced lung injury (VILI), ICU associated delirium, infection, and longer ICU stay & hospitalization. This practice can possibly be applied in surgical patients such as gastric bypass patients with fresh anastomoses, immunocompromised patients at risk of developing ventilator-associated pneumonia, or hypoxic patients with advanced directives precluding intubation (i.e. Do Not Intubate (DNI) orders). Thus, more trials of this innovative type of ventilation with either high-flow or NIPPV in different patient populations are necessary to fully demonstrate its potential.
While there are numerous benefits to the helmet, there are limitations that need to be considered. This includes the inability to titrate PEEP to higher levels as well as the inability to adjust the tidal volume. Furthermore, there is a risk of nitrogen dioxide (NO2) development—a pulmonary irritant with lethal potential [22]. This highlights the need for continuous patient monitoring with a trained team of critical care providers. Though the helmet was used in Europe previously [16], this practice is not widely recognized in North America and thus, its availability is low. Patient mobility was not assessed in our case series due to clinical condition. The patients with COVID-19 were prone to significant desaturation episodes with even minimal movement at the nadir of their course and this correlated with the timing of treatment with the oxygen helmet. Any periods of patient mobility that did occur were limited to repositioning in bed or moving to the bedside chair. Furthermore, while some PEEP is provided, our case series documents the use of helmet therapy to provide increased oxygen support rather than ventilatory support and it is not clear to what degree the helmet therapy may assist in a patient with profound hypercapnia.
The regimen of pharmacotherapy provided to the patients in our series may represent a confounding variable. The standards of care during the pandemic, particularly during the early phases, represented a dynamic set of guidelines supported by varying levels of evidence. The differing treatments provided to our patients reflect this state of flux but were appropriate with respect to the guidelines at the time of the individual patient's hospitalization. We recognize that certain medications and treatment regimens have subsequently fallen out of favor as the medical community's COVID-19 knowledge-base has grown.
In conclusion, further studies are required to investigate the impact of these limitations. Although a previous randomized control trial with ARDS patients demonstrated its utility in reducing intubation rates and consequently reducing the 90-day mortality, new trials are necessary to replicate our outcomes on a larger scale [11].
5 Conclusion
Supplemental oxygen therapy via the hyperbaric helmet is an innovative modality with the potential for widespread utilization in critical care practice. This cost-effective approach is well-tolerated in appropriately selected patients with escalating supplemental oxygen requirements, highlighting the benefits provided by the helmet over other modalities. However, oxygen therapy with the helmet does warrant further study to confirm its efficacy on a larger scale.
Declaration of competing interest
This manuscript has not been presented in whole or in part. No funding was provided and the authors do not have any conflicts of interest to declare.
Acknowledgements
The authors wish to acknowledge the hard work of every team member in our critical care units including the physicians, advance practice providers, nurses, respiratory therapists, patient care assistants, physical therapists, occupational therapists, without whom we could not provide the highest-quality and innovative patient care. | HYDROXYCHLOROQUINE, LOPINAVIR\RITONAVIR, OXYGEN, REMDESIVIR, RIBAVIRIN, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33643838 | 19,721,017 | 2021 |
What was the administration route of drug 'OXYGEN'? | Oxygen therapy via a noninvasive helmet: A COVID-19 novelty with potential post-pandemic uses.
COVID-19 has placed a significant strain upon healthcare resources at a global level and refractory hypoxemia is the leading cause of death among COVID-19 patients. The management of limited resources such as mechanical ventilators has remained a contentious issue both at an individual and institutional level since the beginning of the pandemic. As a result, the COVID-19 pandemic has presented challenges to critical care practitioners to find innovative ways to provide supplemental oxygen therapy to their patients. We present a single-center experience: a case series of five COVID-19 infected patients managed with a novel approach to provide supplemental oxygen and positive end-expiration pressure (PEEP) via the helmet. Three of the five patients responded to therapy, did not require intubation, and survived to discharge. The other two patients continued to deteriorate clinically, required endotracheal intubation, and subsequently expired during their hospitalization. We extrapolated our accumulated experience with non-invasive oxygen support by helmet in COVID-19 patients to a non-COVID-19 postoperative patient who underwent sinus surgery and developed hypoxemic respiratory failure also resulting in avoidance of endotracheal intubation. We conclude that oxygen therapy via a helmet is a safe, cost-effective technique to prevent intubation in carefully selected patients with infectious and non-infectious causes of hypoxic respiratory failure. Our positive experience with the system warrants further large-scale study and possible technique refinement.
1 Introduction
The severe acute respiratory syndrome coronavirus (SARS-CoV-2), commonly referred to as COVID-19, was first reported in Wuhan, China in late 2019 [1], and has since caused a global pandemic [2,3]. The virus primarily affects the lungs and, in serious cases, can lead to acute severe respiratory failure requiring admission to the intensive care unit (ICU) and endotracheal intubation. Mortality predominantly occurs as a result of refractory hypoxemia and the associated sequelae including multi-organ dysfunction and failure [5]. Globally, the volume of patients and the severity of illness overwhelmed the medical resources of hospitals [2] and, in the United States, the Society of Critical Care Medicine projected that our resources were at risk of being insufficient to meet the anticipated needs [6].
Resource management for items such as ICU beds, ventilators, and key health care personnel has been debated through out the ongoing pandemic [5,9,10]. In order to address the appropriate utilization of sparse resources and the possibility to reduce morbidity and increased mortality related to endotracheal intubation, we began to explore novel methods for providing respiratory support to critically ill COVID-19 patients.
European practitioners of hyperbaric oxygen therapy have reported their experience in treating hypoxic patients with a soft, clear, vinyl helmet system that could be used to provide oxygen therapy with high FiO2 and a modest amount of positive end-expiratory pressure (PEEP) outside of a hyperbaric environment [15]. Traditionally, these devices are used to provide intermittent periods of oxygen therapy (FiO2 1.0) while exposed to a hyperbaric environment in a hyperbaric chamber. This technique had been employed in Italy with negligible leakage of exhaled air around viral filters and associated aerosolized droplets [16] thereby decreasing the risk of exposure to aerosolized droplets of infectious material amongst healthcare personnel. These helmets can also create a high FiO2 environment outside of a hyperbaric chamber and thus, we designed a treatment algorithm whereby we would use these helmets in our ICU to potentially prevent the need for intubation and thereby maintain an adequate supply of available ventilators and supplies. This case series describes our experience with using the oxygen helmet in a subset of critically ill COVID-19 patients.
2 Methods
The three models of the helmet (PN 580, PN5200, and PN5202; Sea-Long Medical Systems LLCX, Texas) have a clear plastic hood that covers the patient's head. The helmet is connected to a plastic ring that is supported by a soft, rubber collar that is tailored to each patient by measuring the neck circumference. The rubber collar forms a tight seal against the skin of the patient and permits a modest amount of PEEP within the helmet. The helmet has two connection ports to which expiratory and inspiratory tubing are attached. The inspiratory tubing can be connected to high-flow nasal cannula or NIPPV device, while a viral filter is connected to the expiratory tubing. The helmet is secured to the patient by armpit braces with padding to prevent skin breakdown See Fig. 1.Fig. 1 High-flow (a) and NIPPV (b) via helmet demonstrated in Mayo Clinic physicians.
Fig. 1
At our institution, HFNC was provided in conjunction with the helmet. Additionally, a PEEP valve and a viral filter were added to the circuit. All patients received high-flow nasal cannula with PEEP ranging from 5 to 10 cmH2O, the minimum flow delivered was 50 L of oxygen, and FiO2 was titrated according to the patient's arterial blood gas. A training session was provided to all clinicians and respiratory therapists using this modality in COVID-19 patients.
A systematic approach was used for the management of refractory hypoxemia in COVID-19 patients at our institution. Accordingly, patients with increasing oxygen requirements on the nasal cannula or oxygen mask were placed on a reservoir nasal cannula or non-rebreather mask and encouraged to self-prone as much as tolerated. If they continue to experience desaturations and/or further increases in their work of breathing (tachypnea, retractions, shallow respirations, or subjective fatigue), they were designated to a trial of high-flow oxygen therapy via the helmet. Initial FiO2 and flow rate settings were selected and titrated based on patient need and response to therapy. If the patient was not already on FiO2 1.0, the FiO2 was titrated by at least 0.1 at the initiation of helmet therapy. Respiratory rate, work of breathing, and arterial blood gases were frequently assessed for patients using high-flow via helmet. Patients who did not tolerate the helmet as defined by continued increased work of breathing, continued desaturation (SpO2 <88%) or continued worsening PaO2 (<60) or those who had further clinical decompensation while on high-flow via helmet were intubated endotracheally. There were no objective cutoffs defining non-tolerance to helmet therapy as this was a clinical decision based on the above-mentioned criteria. During this time period, the ICU staffing model included at least one provider, senior nurse, and respiratory therapist who had been trained to monitor patients receiving oxygen therapy via the helmet technique.
Additional COVID-19 therapies were given to patients according to our treatment algorithm (Fig. 2). Patients were assigned to receive different therapies such as dexamethasone, remdesivir, tocilizumab, lenzilumab, or convalescent plasma according to their oxygen requirements and inflammatory markers. The guidelines with respect to pharmacological treatment and standard of care for patients with COVID-19 have represented a dynamic state; the different treatment regimens provide were consistent with the standard of care at the time of the patient's hospitalization. All patients received either prophylactic or therapeutic anticoagulation according to our anticoagulation algorithm. All patients signed a research release at the time of their admission and this retrospective analysis was deemed exempt from IRB review.Fig. 2 Mayo Clinic Florida inpatient treatment algorithm for COVID-19 infection.
Fig. 2
3 Case descriptions
3.1 Case #1
A 70-year-old male with a past medical history of morbid obesity (BMI = 42.0 kg/m2), hypertension, diabetes mellitus type 2, and depression presented to the emergency department with acute respiratory failure in the setting of COVID-19 pneumonia. The patient presented with oxygen saturations <70% (measured by pulse oximetry) with adequate waveforms. His respiratory rate was >40 breaths per minute and was placed on NIPPV with initial settings of inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) of 10/5 cmH2O with FiO2 1.0. He was admitted directly to the ICU but did not tolerate NIPPV support due to agitation. The patient was provided with a trial of therapy with HFNC via helmet along with nitric oxide (40 ppm), but because of persistent hypoxemia and worsening encephalopathy, he was endotracheally intubated for mechanical ventilatory support within 8hrs of admission. His COVID-19 treatment regimen included remdesivir, tocilizumab, and dexamethasone. His 22-day ICU course was complicated by renal failure requiring dialysis, bacteremia, thrombocytopenia, and intracerebral hemorrhages. Life support measures were withdrawn after goals of care discussion as per the patient and family wishes.
3.2 Case #2
A 74-year-old male with a past medical history of obstructive sleep apnea (OSA) and obesity presented with acute hypoxic respiratory failure in the setting of COVID-19 pneumonia. On admission day 3, the patient had increasing oxygen requirements with HFNC (flow 50L, FiO2 1.0) with additional oxygen supplementation via a non-rebreather mask (flow 15L). Having failed to tolerate a brief trial (<15min) of bi-level NIPPV (10/5 cmH2O, FiO2 1.0), he was then transitioned to HFNC (Flow 45L/min, FiO2 1.0) via helmet in combination with inhaled nitric oxide (40 ppm). He received convalescent plasma, remdesivir, dexamethasone, and lenzilumab as part of his COVID-19 treatment. On admission day 6, the patient was transitioned back to the floor and was progressively weaned off helmet ventilation to the nasal cannula. He was subsequently discharged home.
3.3 Case #3
A 68-year-old male with a past medical history of hypertension, gastroesophageal reflux disease, and hyperlipidemia presented with a 4-day history of cough, fever, chest tightness, and weakness after returning from a trip from New Zealand. On admission day 3, his oxygen requirements increased as his dyspnea worsened and work of breathing intensified. He engaged in a self-proning posture with supplemental oxygen provided via a non-rebreather mask (flow 15L/min), and experienced an improvement in his hypoxia (oxygen saturations increased from 92% to 98%) and associated dyspnea. He was then transferred to the ICU for closer monitoring and placed on non-invasive helmet ventilation with HFNC (Flow 80L/min, FiO2 0.8) and inhaled nitric oxide (20 ppm). He received hydroxychloroquine, lenzilumab, and tocilizumab as part of his COVID-19 treatment. After 8 days on noninvasive ventilation via helmet, his condition continued to improve and he was transitioned to an oxygen mask and eventually nasal cannula. He was then discharged home with supplemental oxygen provided via nasal cannula (NC) (2L/min).
3.4 Case #4
A 73-year-old female with a history of hypothyroidism, gastroesophageal reflux disease, hyperlipidemia, and chronic kidney disease presented to the emergency department with nausea, fatigue, and non-productive cough in the setting of COVID-19 pneumonia. Her hospital course was complicated by hypoxemic respiratory failure with a progressively increasing need for O2 via nasal cannula to non-rebreather mask at 15L/min. Her hypoxia continued to worsen and she required HFNC (Flow 80L/min, FiO2 0.8) via helmet therapy. She received lopinavir/ritonavir, remdesivir, ribavirin, tocilizumab, and hydroxychloroquine as part of her COVID-19 treatment. After three days of helmet therapy with HFNC, she was transferred to the floor on 6L NC and was eventually discharged home on 2L NC.
3.5 Case # 5
A 76-year-old male with a past medical history of chronic obstructive pulmonary disease (COPD) and small-cell lung cancer status post-chemotherapy and radiation (>5yrs prior to presentation, in remission) presented with acute hypoxic respiratory failure due to COVID-19 pneumonia. He was initially admitted to the general medical wards; but, due to escalating oxygen requirements, he was transferred to the ICU on the third day of hospitalization. There he was placed on HFNC (Flow 70L/min, FiO2 1.0) via the helmet along with inhaled nitric oxide (40 ppm). He received remdesivir, tocilizumab, and dexamethasone as part of his COVID-19 treatment. Unfortunately, he continued to deteriorate, and due to increasing hypoxia and work of breathing, he required endotracheal intubation on day 8 of hospitalization. His clinical condition deteriorated further and, after goals of care discussion with family, the patient was transitioned to hospice care and expired.
3.6 Scope for the future - helmet therapy for non-covid-19 patients
A 66-year-old male patient with a past medical history of congestive heart failure, associated with a reduced ejection fraction, underwent maxillary sinus repair surgery. His COVID-19 negative status was confirmed pre-operatively. He was extubated postoperatively but developed hypoxia due to flash pulmonary edema while recovering in PACU on a non-rebreather. His surgical procedure presented a contra-indication for NIPPV therapy and the ICU service was consulted for the need for possible reintubation. The patient was instead managed with HFNC (Flow 70L/min, FiO2 1.0) via helmet and intravenous furosemide. He had symptomatic improvements within 24 hours and was subsequently transferred to the general ward. The remainder of his hospitalization was uneventful from a respiratory perspective and he was eventually discharged home.
4 Discussion
We used noninvasive oxygenation via the helmet in carefully selected patients to decrease dispersion of the COVID-19 virus and to reduce the need for endotracheal intubation and mechanical ventilation. We went a step further and use this modality in a COVID-negative patient with hypoxic respiratory failure as an innovative way to explore the potential of this therapy.
Our report demonstrates favorable outcomes in a majority of the patients. Those of our patients who survived their acute hypoxic illness demonstrated increased tissue oxygenation after the application of the oxygen helmet. The patients who died during hospitalization demonstrated many risk factors known for increased mortality associated with COVID-19 and include male sex, obesity, pulmonary disease including COPD and lung cancer, diabetes, hypertension, and thrombocytopenia [[24], [25], [26]]. Table 1 summarizes the main characteristics and the outcomes for the patients included in this case series.Table 1 Patient characteristics and outcomes.
Table 1 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Age 70 74 68 73 76
Sex M M M F M
Duration of hospitalization before helmet treatment 2 days 1 day 3 days 7 days 3 days
Time elapsed between symptom onset and helmet therapy 9 days 6 days 8 days 14 days 13 days
P/F Ratio (Prior to initiation of oxygen helmet) <200 <200 <300 <300 <100
CRP 235.3 168.5 79 229.7 82.8
IL-6 >400 314 30.9 16.2 16.1
d-dimer >42000 678 751 1516 1058
SOFA score (Day of admission) 5 3 3 2 3
Helmet settings
Flow rate (L/min) 60 30 50 80 50
FiO2 1.0 0.8 0.8 0.8 1.0
PEEP (cmH2O) 8 7 5 5 7
Average respiratory rate 24 32 30 22 24
Duration of helmet therapy 1 day 1 day 7 days 5 days 4 days
Duration of NO 16 days 6 days 1 day No 12 days
Intubation (yes/no) Yes No No No Yes
Duration of hospital stay 22 days 9 days 13 days 17 days 14 days
Outcome Deceased Alive Alive Alive Deceased
The patient population who would benefit from this treatment modality should be carefully selected. The most important selection criterion to be considered is the respiratory function of the patient. The helmet is dependent on the patient's ability to generate tidal volume and minute ventilation sufficient to meet their needs. Patients who are unable to tolerate the mask associated with NIPPV due to facial anatomy, facial hair, skin breakdown from prolonged use of mask, or risk of aspiration, can also benefit from this practice. The factors which helped us in selecting the patients include claustrophobia, mask intolerance, degree of CO2 retention, degree of hypoxia, risk of vomiting/aspiration, and patient/family preference.
The usage of oxygen hood in the current COVID-19 pandemic showcased several advantages. The cost of each hood is measured in hundreds of dollars as opposed to the thousands of dollars range when compared with mechanical ventilation. Furthermore, this therapy decreases overall hospital costs associated with the prolonged ICU admission mechanical ventilation entails [17]. While the rubberneck gaskets are used for single patients due to the customized sizing procedure required, the hoods can be sterilized and reused on multiple patients. The hoods are also compatible with adjunct therapy such as nitric oxide (NO) therapy, an approach that has been used with success in COVID-19 patients [[19], [20], [21]]. Oxygen supplementation with the oxygen helmet also provides the patient with the ability to drink fluids through a straw, wear glasses under the helmet, and engage in verbal communication with greater ease. More importantly, the neck seal and the viral filter reduces the risk of aerosol generation and nosocomial infection for healthcare workers and other patients. Thus, not only helmet oxygenation a cost-effective alternative, but it also has the potential to prevent intubation and preserve ventilators in the current pandemic. Table 2 provides a visual reference for relative comparison of multiple modalities of providing supplemental oxygen.Table 2 Relative Comparison of multiple modalities of providing supplemental oxygen.
Table 2 Oxygen helmet HFNC BiPAP MEchanical Ventilation
COST $$ $$ $$$ $$$
RISK OF AEROSOLIZATION Low High High Low
INDICATIONS FOR USE:
-HYPOXIC FAILURE + + + +
-HYPERCARBIC FAILURE – – + +
PATIENT COMFORT Medium Medium Low Low
USE OF INHALED NO ALONG WITH DEVICE + + – +
There is a potential to expand the application of this method of oxygen therapy to other patients for whom traditional NIPPV or intubation is either contraindicated or sought to be avoided. We demonstrated this by preventing intubation in a COVID-negative patient, who underwent maxillary sinus surgery when NIPPV was contraindicated. Preventing intubation has many benefits including preventing ventilator-induced lung injury (VILI), ICU associated delirium, infection, and longer ICU stay & hospitalization. This practice can possibly be applied in surgical patients such as gastric bypass patients with fresh anastomoses, immunocompromised patients at risk of developing ventilator-associated pneumonia, or hypoxic patients with advanced directives precluding intubation (i.e. Do Not Intubate (DNI) orders). Thus, more trials of this innovative type of ventilation with either high-flow or NIPPV in different patient populations are necessary to fully demonstrate its potential.
While there are numerous benefits to the helmet, there are limitations that need to be considered. This includes the inability to titrate PEEP to higher levels as well as the inability to adjust the tidal volume. Furthermore, there is a risk of nitrogen dioxide (NO2) development—a pulmonary irritant with lethal potential [22]. This highlights the need for continuous patient monitoring with a trained team of critical care providers. Though the helmet was used in Europe previously [16], this practice is not widely recognized in North America and thus, its availability is low. Patient mobility was not assessed in our case series due to clinical condition. The patients with COVID-19 were prone to significant desaturation episodes with even minimal movement at the nadir of their course and this correlated with the timing of treatment with the oxygen helmet. Any periods of patient mobility that did occur were limited to repositioning in bed or moving to the bedside chair. Furthermore, while some PEEP is provided, our case series documents the use of helmet therapy to provide increased oxygen support rather than ventilatory support and it is not clear to what degree the helmet therapy may assist in a patient with profound hypercapnia.
The regimen of pharmacotherapy provided to the patients in our series may represent a confounding variable. The standards of care during the pandemic, particularly during the early phases, represented a dynamic set of guidelines supported by varying levels of evidence. The differing treatments provided to our patients reflect this state of flux but were appropriate with respect to the guidelines at the time of the individual patient's hospitalization. We recognize that certain medications and treatment regimens have subsequently fallen out of favor as the medical community's COVID-19 knowledge-base has grown.
In conclusion, further studies are required to investigate the impact of these limitations. Although a previous randomized control trial with ARDS patients demonstrated its utility in reducing intubation rates and consequently reducing the 90-day mortality, new trials are necessary to replicate our outcomes on a larger scale [11].
5 Conclusion
Supplemental oxygen therapy via the hyperbaric helmet is an innovative modality with the potential for widespread utilization in critical care practice. This cost-effective approach is well-tolerated in appropriately selected patients with escalating supplemental oxygen requirements, highlighting the benefits provided by the helmet over other modalities. However, oxygen therapy with the helmet does warrant further study to confirm its efficacy on a larger scale.
Declaration of competing interest
This manuscript has not been presented in whole or in part. No funding was provided and the authors do not have any conflicts of interest to declare.
Acknowledgements
The authors wish to acknowledge the hard work of every team member in our critical care units including the physicians, advance practice providers, nurses, respiratory therapists, patient care assistants, physical therapists, occupational therapists, without whom we could not provide the highest-quality and innovative patient care. | Nasal | DrugAdministrationRoute | CC BY-NC-ND | 33643838 | 19,721,017 | 2021 |
What was the administration route of drug 'RIBAVIRIN'? | Oxygen therapy via a noninvasive helmet: A COVID-19 novelty with potential post-pandemic uses.
COVID-19 has placed a significant strain upon healthcare resources at a global level and refractory hypoxemia is the leading cause of death among COVID-19 patients. The management of limited resources such as mechanical ventilators has remained a contentious issue both at an individual and institutional level since the beginning of the pandemic. As a result, the COVID-19 pandemic has presented challenges to critical care practitioners to find innovative ways to provide supplemental oxygen therapy to their patients. We present a single-center experience: a case series of five COVID-19 infected patients managed with a novel approach to provide supplemental oxygen and positive end-expiration pressure (PEEP) via the helmet. Three of the five patients responded to therapy, did not require intubation, and survived to discharge. The other two patients continued to deteriorate clinically, required endotracheal intubation, and subsequently expired during their hospitalization. We extrapolated our accumulated experience with non-invasive oxygen support by helmet in COVID-19 patients to a non-COVID-19 postoperative patient who underwent sinus surgery and developed hypoxemic respiratory failure also resulting in avoidance of endotracheal intubation. We conclude that oxygen therapy via a helmet is a safe, cost-effective technique to prevent intubation in carefully selected patients with infectious and non-infectious causes of hypoxic respiratory failure. Our positive experience with the system warrants further large-scale study and possible technique refinement.
1 Introduction
The severe acute respiratory syndrome coronavirus (SARS-CoV-2), commonly referred to as COVID-19, was first reported in Wuhan, China in late 2019 [1], and has since caused a global pandemic [2,3]. The virus primarily affects the lungs and, in serious cases, can lead to acute severe respiratory failure requiring admission to the intensive care unit (ICU) and endotracheal intubation. Mortality predominantly occurs as a result of refractory hypoxemia and the associated sequelae including multi-organ dysfunction and failure [5]. Globally, the volume of patients and the severity of illness overwhelmed the medical resources of hospitals [2] and, in the United States, the Society of Critical Care Medicine projected that our resources were at risk of being insufficient to meet the anticipated needs [6].
Resource management for items such as ICU beds, ventilators, and key health care personnel has been debated through out the ongoing pandemic [5,9,10]. In order to address the appropriate utilization of sparse resources and the possibility to reduce morbidity and increased mortality related to endotracheal intubation, we began to explore novel methods for providing respiratory support to critically ill COVID-19 patients.
European practitioners of hyperbaric oxygen therapy have reported their experience in treating hypoxic patients with a soft, clear, vinyl helmet system that could be used to provide oxygen therapy with high FiO2 and a modest amount of positive end-expiratory pressure (PEEP) outside of a hyperbaric environment [15]. Traditionally, these devices are used to provide intermittent periods of oxygen therapy (FiO2 1.0) while exposed to a hyperbaric environment in a hyperbaric chamber. This technique had been employed in Italy with negligible leakage of exhaled air around viral filters and associated aerosolized droplets [16] thereby decreasing the risk of exposure to aerosolized droplets of infectious material amongst healthcare personnel. These helmets can also create a high FiO2 environment outside of a hyperbaric chamber and thus, we designed a treatment algorithm whereby we would use these helmets in our ICU to potentially prevent the need for intubation and thereby maintain an adequate supply of available ventilators and supplies. This case series describes our experience with using the oxygen helmet in a subset of critically ill COVID-19 patients.
2 Methods
The three models of the helmet (PN 580, PN5200, and PN5202; Sea-Long Medical Systems LLCX, Texas) have a clear plastic hood that covers the patient's head. The helmet is connected to a plastic ring that is supported by a soft, rubber collar that is tailored to each patient by measuring the neck circumference. The rubber collar forms a tight seal against the skin of the patient and permits a modest amount of PEEP within the helmet. The helmet has two connection ports to which expiratory and inspiratory tubing are attached. The inspiratory tubing can be connected to high-flow nasal cannula or NIPPV device, while a viral filter is connected to the expiratory tubing. The helmet is secured to the patient by armpit braces with padding to prevent skin breakdown See Fig. 1.Fig. 1 High-flow (a) and NIPPV (b) via helmet demonstrated in Mayo Clinic physicians.
Fig. 1
At our institution, HFNC was provided in conjunction with the helmet. Additionally, a PEEP valve and a viral filter were added to the circuit. All patients received high-flow nasal cannula with PEEP ranging from 5 to 10 cmH2O, the minimum flow delivered was 50 L of oxygen, and FiO2 was titrated according to the patient's arterial blood gas. A training session was provided to all clinicians and respiratory therapists using this modality in COVID-19 patients.
A systematic approach was used for the management of refractory hypoxemia in COVID-19 patients at our institution. Accordingly, patients with increasing oxygen requirements on the nasal cannula or oxygen mask were placed on a reservoir nasal cannula or non-rebreather mask and encouraged to self-prone as much as tolerated. If they continue to experience desaturations and/or further increases in their work of breathing (tachypnea, retractions, shallow respirations, or subjective fatigue), they were designated to a trial of high-flow oxygen therapy via the helmet. Initial FiO2 and flow rate settings were selected and titrated based on patient need and response to therapy. If the patient was not already on FiO2 1.0, the FiO2 was titrated by at least 0.1 at the initiation of helmet therapy. Respiratory rate, work of breathing, and arterial blood gases were frequently assessed for patients using high-flow via helmet. Patients who did not tolerate the helmet as defined by continued increased work of breathing, continued desaturation (SpO2 <88%) or continued worsening PaO2 (<60) or those who had further clinical decompensation while on high-flow via helmet were intubated endotracheally. There were no objective cutoffs defining non-tolerance to helmet therapy as this was a clinical decision based on the above-mentioned criteria. During this time period, the ICU staffing model included at least one provider, senior nurse, and respiratory therapist who had been trained to monitor patients receiving oxygen therapy via the helmet technique.
Additional COVID-19 therapies were given to patients according to our treatment algorithm (Fig. 2). Patients were assigned to receive different therapies such as dexamethasone, remdesivir, tocilizumab, lenzilumab, or convalescent plasma according to their oxygen requirements and inflammatory markers. The guidelines with respect to pharmacological treatment and standard of care for patients with COVID-19 have represented a dynamic state; the different treatment regimens provide were consistent with the standard of care at the time of the patient's hospitalization. All patients received either prophylactic or therapeutic anticoagulation according to our anticoagulation algorithm. All patients signed a research release at the time of their admission and this retrospective analysis was deemed exempt from IRB review.Fig. 2 Mayo Clinic Florida inpatient treatment algorithm for COVID-19 infection.
Fig. 2
3 Case descriptions
3.1 Case #1
A 70-year-old male with a past medical history of morbid obesity (BMI = 42.0 kg/m2), hypertension, diabetes mellitus type 2, and depression presented to the emergency department with acute respiratory failure in the setting of COVID-19 pneumonia. The patient presented with oxygen saturations <70% (measured by pulse oximetry) with adequate waveforms. His respiratory rate was >40 breaths per minute and was placed on NIPPV with initial settings of inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) of 10/5 cmH2O with FiO2 1.0. He was admitted directly to the ICU but did not tolerate NIPPV support due to agitation. The patient was provided with a trial of therapy with HFNC via helmet along with nitric oxide (40 ppm), but because of persistent hypoxemia and worsening encephalopathy, he was endotracheally intubated for mechanical ventilatory support within 8hrs of admission. His COVID-19 treatment regimen included remdesivir, tocilizumab, and dexamethasone. His 22-day ICU course was complicated by renal failure requiring dialysis, bacteremia, thrombocytopenia, and intracerebral hemorrhages. Life support measures were withdrawn after goals of care discussion as per the patient and family wishes.
3.2 Case #2
A 74-year-old male with a past medical history of obstructive sleep apnea (OSA) and obesity presented with acute hypoxic respiratory failure in the setting of COVID-19 pneumonia. On admission day 3, the patient had increasing oxygen requirements with HFNC (flow 50L, FiO2 1.0) with additional oxygen supplementation via a non-rebreather mask (flow 15L). Having failed to tolerate a brief trial (<15min) of bi-level NIPPV (10/5 cmH2O, FiO2 1.0), he was then transitioned to HFNC (Flow 45L/min, FiO2 1.0) via helmet in combination with inhaled nitric oxide (40 ppm). He received convalescent plasma, remdesivir, dexamethasone, and lenzilumab as part of his COVID-19 treatment. On admission day 6, the patient was transitioned back to the floor and was progressively weaned off helmet ventilation to the nasal cannula. He was subsequently discharged home.
3.3 Case #3
A 68-year-old male with a past medical history of hypertension, gastroesophageal reflux disease, and hyperlipidemia presented with a 4-day history of cough, fever, chest tightness, and weakness after returning from a trip from New Zealand. On admission day 3, his oxygen requirements increased as his dyspnea worsened and work of breathing intensified. He engaged in a self-proning posture with supplemental oxygen provided via a non-rebreather mask (flow 15L/min), and experienced an improvement in his hypoxia (oxygen saturations increased from 92% to 98%) and associated dyspnea. He was then transferred to the ICU for closer monitoring and placed on non-invasive helmet ventilation with HFNC (Flow 80L/min, FiO2 0.8) and inhaled nitric oxide (20 ppm). He received hydroxychloroquine, lenzilumab, and tocilizumab as part of his COVID-19 treatment. After 8 days on noninvasive ventilation via helmet, his condition continued to improve and he was transitioned to an oxygen mask and eventually nasal cannula. He was then discharged home with supplemental oxygen provided via nasal cannula (NC) (2L/min).
3.4 Case #4
A 73-year-old female with a history of hypothyroidism, gastroesophageal reflux disease, hyperlipidemia, and chronic kidney disease presented to the emergency department with nausea, fatigue, and non-productive cough in the setting of COVID-19 pneumonia. Her hospital course was complicated by hypoxemic respiratory failure with a progressively increasing need for O2 via nasal cannula to non-rebreather mask at 15L/min. Her hypoxia continued to worsen and she required HFNC (Flow 80L/min, FiO2 0.8) via helmet therapy. She received lopinavir/ritonavir, remdesivir, ribavirin, tocilizumab, and hydroxychloroquine as part of her COVID-19 treatment. After three days of helmet therapy with HFNC, she was transferred to the floor on 6L NC and was eventually discharged home on 2L NC.
3.5 Case # 5
A 76-year-old male with a past medical history of chronic obstructive pulmonary disease (COPD) and small-cell lung cancer status post-chemotherapy and radiation (>5yrs prior to presentation, in remission) presented with acute hypoxic respiratory failure due to COVID-19 pneumonia. He was initially admitted to the general medical wards; but, due to escalating oxygen requirements, he was transferred to the ICU on the third day of hospitalization. There he was placed on HFNC (Flow 70L/min, FiO2 1.0) via the helmet along with inhaled nitric oxide (40 ppm). He received remdesivir, tocilizumab, and dexamethasone as part of his COVID-19 treatment. Unfortunately, he continued to deteriorate, and due to increasing hypoxia and work of breathing, he required endotracheal intubation on day 8 of hospitalization. His clinical condition deteriorated further and, after goals of care discussion with family, the patient was transitioned to hospice care and expired.
3.6 Scope for the future - helmet therapy for non-covid-19 patients
A 66-year-old male patient with a past medical history of congestive heart failure, associated with a reduced ejection fraction, underwent maxillary sinus repair surgery. His COVID-19 negative status was confirmed pre-operatively. He was extubated postoperatively but developed hypoxia due to flash pulmonary edema while recovering in PACU on a non-rebreather. His surgical procedure presented a contra-indication for NIPPV therapy and the ICU service was consulted for the need for possible reintubation. The patient was instead managed with HFNC (Flow 70L/min, FiO2 1.0) via helmet and intravenous furosemide. He had symptomatic improvements within 24 hours and was subsequently transferred to the general ward. The remainder of his hospitalization was uneventful from a respiratory perspective and he was eventually discharged home.
4 Discussion
We used noninvasive oxygenation via the helmet in carefully selected patients to decrease dispersion of the COVID-19 virus and to reduce the need for endotracheal intubation and mechanical ventilation. We went a step further and use this modality in a COVID-negative patient with hypoxic respiratory failure as an innovative way to explore the potential of this therapy.
Our report demonstrates favorable outcomes in a majority of the patients. Those of our patients who survived their acute hypoxic illness demonstrated increased tissue oxygenation after the application of the oxygen helmet. The patients who died during hospitalization demonstrated many risk factors known for increased mortality associated with COVID-19 and include male sex, obesity, pulmonary disease including COPD and lung cancer, diabetes, hypertension, and thrombocytopenia [[24], [25], [26]]. Table 1 summarizes the main characteristics and the outcomes for the patients included in this case series.Table 1 Patient characteristics and outcomes.
Table 1 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Age 70 74 68 73 76
Sex M M M F M
Duration of hospitalization before helmet treatment 2 days 1 day 3 days 7 days 3 days
Time elapsed between symptom onset and helmet therapy 9 days 6 days 8 days 14 days 13 days
P/F Ratio (Prior to initiation of oxygen helmet) <200 <200 <300 <300 <100
CRP 235.3 168.5 79 229.7 82.8
IL-6 >400 314 30.9 16.2 16.1
d-dimer >42000 678 751 1516 1058
SOFA score (Day of admission) 5 3 3 2 3
Helmet settings
Flow rate (L/min) 60 30 50 80 50
FiO2 1.0 0.8 0.8 0.8 1.0
PEEP (cmH2O) 8 7 5 5 7
Average respiratory rate 24 32 30 22 24
Duration of helmet therapy 1 day 1 day 7 days 5 days 4 days
Duration of NO 16 days 6 days 1 day No 12 days
Intubation (yes/no) Yes No No No Yes
Duration of hospital stay 22 days 9 days 13 days 17 days 14 days
Outcome Deceased Alive Alive Alive Deceased
The patient population who would benefit from this treatment modality should be carefully selected. The most important selection criterion to be considered is the respiratory function of the patient. The helmet is dependent on the patient's ability to generate tidal volume and minute ventilation sufficient to meet their needs. Patients who are unable to tolerate the mask associated with NIPPV due to facial anatomy, facial hair, skin breakdown from prolonged use of mask, or risk of aspiration, can also benefit from this practice. The factors which helped us in selecting the patients include claustrophobia, mask intolerance, degree of CO2 retention, degree of hypoxia, risk of vomiting/aspiration, and patient/family preference.
The usage of oxygen hood in the current COVID-19 pandemic showcased several advantages. The cost of each hood is measured in hundreds of dollars as opposed to the thousands of dollars range when compared with mechanical ventilation. Furthermore, this therapy decreases overall hospital costs associated with the prolonged ICU admission mechanical ventilation entails [17]. While the rubberneck gaskets are used for single patients due to the customized sizing procedure required, the hoods can be sterilized and reused on multiple patients. The hoods are also compatible with adjunct therapy such as nitric oxide (NO) therapy, an approach that has been used with success in COVID-19 patients [[19], [20], [21]]. Oxygen supplementation with the oxygen helmet also provides the patient with the ability to drink fluids through a straw, wear glasses under the helmet, and engage in verbal communication with greater ease. More importantly, the neck seal and the viral filter reduces the risk of aerosol generation and nosocomial infection for healthcare workers and other patients. Thus, not only helmet oxygenation a cost-effective alternative, but it also has the potential to prevent intubation and preserve ventilators in the current pandemic. Table 2 provides a visual reference for relative comparison of multiple modalities of providing supplemental oxygen.Table 2 Relative Comparison of multiple modalities of providing supplemental oxygen.
Table 2 Oxygen helmet HFNC BiPAP MEchanical Ventilation
COST $$ $$ $$$ $$$
RISK OF AEROSOLIZATION Low High High Low
INDICATIONS FOR USE:
-HYPOXIC FAILURE + + + +
-HYPERCARBIC FAILURE – – + +
PATIENT COMFORT Medium Medium Low Low
USE OF INHALED NO ALONG WITH DEVICE + + – +
There is a potential to expand the application of this method of oxygen therapy to other patients for whom traditional NIPPV or intubation is either contraindicated or sought to be avoided. We demonstrated this by preventing intubation in a COVID-negative patient, who underwent maxillary sinus surgery when NIPPV was contraindicated. Preventing intubation has many benefits including preventing ventilator-induced lung injury (VILI), ICU associated delirium, infection, and longer ICU stay & hospitalization. This practice can possibly be applied in surgical patients such as gastric bypass patients with fresh anastomoses, immunocompromised patients at risk of developing ventilator-associated pneumonia, or hypoxic patients with advanced directives precluding intubation (i.e. Do Not Intubate (DNI) orders). Thus, more trials of this innovative type of ventilation with either high-flow or NIPPV in different patient populations are necessary to fully demonstrate its potential.
While there are numerous benefits to the helmet, there are limitations that need to be considered. This includes the inability to titrate PEEP to higher levels as well as the inability to adjust the tidal volume. Furthermore, there is a risk of nitrogen dioxide (NO2) development—a pulmonary irritant with lethal potential [22]. This highlights the need for continuous patient monitoring with a trained team of critical care providers. Though the helmet was used in Europe previously [16], this practice is not widely recognized in North America and thus, its availability is low. Patient mobility was not assessed in our case series due to clinical condition. The patients with COVID-19 were prone to significant desaturation episodes with even minimal movement at the nadir of their course and this correlated with the timing of treatment with the oxygen helmet. Any periods of patient mobility that did occur were limited to repositioning in bed or moving to the bedside chair. Furthermore, while some PEEP is provided, our case series documents the use of helmet therapy to provide increased oxygen support rather than ventilatory support and it is not clear to what degree the helmet therapy may assist in a patient with profound hypercapnia.
The regimen of pharmacotherapy provided to the patients in our series may represent a confounding variable. The standards of care during the pandemic, particularly during the early phases, represented a dynamic set of guidelines supported by varying levels of evidence. The differing treatments provided to our patients reflect this state of flux but were appropriate with respect to the guidelines at the time of the individual patient's hospitalization. We recognize that certain medications and treatment regimens have subsequently fallen out of favor as the medical community's COVID-19 knowledge-base has grown.
In conclusion, further studies are required to investigate the impact of these limitations. Although a previous randomized control trial with ARDS patients demonstrated its utility in reducing intubation rates and consequently reducing the 90-day mortality, new trials are necessary to replicate our outcomes on a larger scale [11].
5 Conclusion
Supplemental oxygen therapy via the hyperbaric helmet is an innovative modality with the potential for widespread utilization in critical care practice. This cost-effective approach is well-tolerated in appropriately selected patients with escalating supplemental oxygen requirements, highlighting the benefits provided by the helmet over other modalities. However, oxygen therapy with the helmet does warrant further study to confirm its efficacy on a larger scale.
Declaration of competing interest
This manuscript has not been presented in whole or in part. No funding was provided and the authors do not have any conflicts of interest to declare.
Acknowledgements
The authors wish to acknowledge the hard work of every team member in our critical care units including the physicians, advance practice providers, nurses, respiratory therapists, patient care assistants, physical therapists, occupational therapists, without whom we could not provide the highest-quality and innovative patient care. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33643838 | 19,721,017 | 2021 |
What was the dosage of drug 'OXYGEN'? | Oxygen therapy via a noninvasive helmet: A COVID-19 novelty with potential post-pandemic uses.
COVID-19 has placed a significant strain upon healthcare resources at a global level and refractory hypoxemia is the leading cause of death among COVID-19 patients. The management of limited resources such as mechanical ventilators has remained a contentious issue both at an individual and institutional level since the beginning of the pandemic. As a result, the COVID-19 pandemic has presented challenges to critical care practitioners to find innovative ways to provide supplemental oxygen therapy to their patients. We present a single-center experience: a case series of five COVID-19 infected patients managed with a novel approach to provide supplemental oxygen and positive end-expiration pressure (PEEP) via the helmet. Three of the five patients responded to therapy, did not require intubation, and survived to discharge. The other two patients continued to deteriorate clinically, required endotracheal intubation, and subsequently expired during their hospitalization. We extrapolated our accumulated experience with non-invasive oxygen support by helmet in COVID-19 patients to a non-COVID-19 postoperative patient who underwent sinus surgery and developed hypoxemic respiratory failure also resulting in avoidance of endotracheal intubation. We conclude that oxygen therapy via a helmet is a safe, cost-effective technique to prevent intubation in carefully selected patients with infectious and non-infectious causes of hypoxic respiratory failure. Our positive experience with the system warrants further large-scale study and possible technique refinement.
1 Introduction
The severe acute respiratory syndrome coronavirus (SARS-CoV-2), commonly referred to as COVID-19, was first reported in Wuhan, China in late 2019 [1], and has since caused a global pandemic [2,3]. The virus primarily affects the lungs and, in serious cases, can lead to acute severe respiratory failure requiring admission to the intensive care unit (ICU) and endotracheal intubation. Mortality predominantly occurs as a result of refractory hypoxemia and the associated sequelae including multi-organ dysfunction and failure [5]. Globally, the volume of patients and the severity of illness overwhelmed the medical resources of hospitals [2] and, in the United States, the Society of Critical Care Medicine projected that our resources were at risk of being insufficient to meet the anticipated needs [6].
Resource management for items such as ICU beds, ventilators, and key health care personnel has been debated through out the ongoing pandemic [5,9,10]. In order to address the appropriate utilization of sparse resources and the possibility to reduce morbidity and increased mortality related to endotracheal intubation, we began to explore novel methods for providing respiratory support to critically ill COVID-19 patients.
European practitioners of hyperbaric oxygen therapy have reported their experience in treating hypoxic patients with a soft, clear, vinyl helmet system that could be used to provide oxygen therapy with high FiO2 and a modest amount of positive end-expiratory pressure (PEEP) outside of a hyperbaric environment [15]. Traditionally, these devices are used to provide intermittent periods of oxygen therapy (FiO2 1.0) while exposed to a hyperbaric environment in a hyperbaric chamber. This technique had been employed in Italy with negligible leakage of exhaled air around viral filters and associated aerosolized droplets [16] thereby decreasing the risk of exposure to aerosolized droplets of infectious material amongst healthcare personnel. These helmets can also create a high FiO2 environment outside of a hyperbaric chamber and thus, we designed a treatment algorithm whereby we would use these helmets in our ICU to potentially prevent the need for intubation and thereby maintain an adequate supply of available ventilators and supplies. This case series describes our experience with using the oxygen helmet in a subset of critically ill COVID-19 patients.
2 Methods
The three models of the helmet (PN 580, PN5200, and PN5202; Sea-Long Medical Systems LLCX, Texas) have a clear plastic hood that covers the patient's head. The helmet is connected to a plastic ring that is supported by a soft, rubber collar that is tailored to each patient by measuring the neck circumference. The rubber collar forms a tight seal against the skin of the patient and permits a modest amount of PEEP within the helmet. The helmet has two connection ports to which expiratory and inspiratory tubing are attached. The inspiratory tubing can be connected to high-flow nasal cannula or NIPPV device, while a viral filter is connected to the expiratory tubing. The helmet is secured to the patient by armpit braces with padding to prevent skin breakdown See Fig. 1.Fig. 1 High-flow (a) and NIPPV (b) via helmet demonstrated in Mayo Clinic physicians.
Fig. 1
At our institution, HFNC was provided in conjunction with the helmet. Additionally, a PEEP valve and a viral filter were added to the circuit. All patients received high-flow nasal cannula with PEEP ranging from 5 to 10 cmH2O, the minimum flow delivered was 50 L of oxygen, and FiO2 was titrated according to the patient's arterial blood gas. A training session was provided to all clinicians and respiratory therapists using this modality in COVID-19 patients.
A systematic approach was used for the management of refractory hypoxemia in COVID-19 patients at our institution. Accordingly, patients with increasing oxygen requirements on the nasal cannula or oxygen mask were placed on a reservoir nasal cannula or non-rebreather mask and encouraged to self-prone as much as tolerated. If they continue to experience desaturations and/or further increases in their work of breathing (tachypnea, retractions, shallow respirations, or subjective fatigue), they were designated to a trial of high-flow oxygen therapy via the helmet. Initial FiO2 and flow rate settings were selected and titrated based on patient need and response to therapy. If the patient was not already on FiO2 1.0, the FiO2 was titrated by at least 0.1 at the initiation of helmet therapy. Respiratory rate, work of breathing, and arterial blood gases were frequently assessed for patients using high-flow via helmet. Patients who did not tolerate the helmet as defined by continued increased work of breathing, continued desaturation (SpO2 <88%) or continued worsening PaO2 (<60) or those who had further clinical decompensation while on high-flow via helmet were intubated endotracheally. There were no objective cutoffs defining non-tolerance to helmet therapy as this was a clinical decision based on the above-mentioned criteria. During this time period, the ICU staffing model included at least one provider, senior nurse, and respiratory therapist who had been trained to monitor patients receiving oxygen therapy via the helmet technique.
Additional COVID-19 therapies were given to patients according to our treatment algorithm (Fig. 2). Patients were assigned to receive different therapies such as dexamethasone, remdesivir, tocilizumab, lenzilumab, or convalescent plasma according to their oxygen requirements and inflammatory markers. The guidelines with respect to pharmacological treatment and standard of care for patients with COVID-19 have represented a dynamic state; the different treatment regimens provide were consistent with the standard of care at the time of the patient's hospitalization. All patients received either prophylactic or therapeutic anticoagulation according to our anticoagulation algorithm. All patients signed a research release at the time of their admission and this retrospective analysis was deemed exempt from IRB review.Fig. 2 Mayo Clinic Florida inpatient treatment algorithm for COVID-19 infection.
Fig. 2
3 Case descriptions
3.1 Case #1
A 70-year-old male with a past medical history of morbid obesity (BMI = 42.0 kg/m2), hypertension, diabetes mellitus type 2, and depression presented to the emergency department with acute respiratory failure in the setting of COVID-19 pneumonia. The patient presented with oxygen saturations <70% (measured by pulse oximetry) with adequate waveforms. His respiratory rate was >40 breaths per minute and was placed on NIPPV with initial settings of inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) of 10/5 cmH2O with FiO2 1.0. He was admitted directly to the ICU but did not tolerate NIPPV support due to agitation. The patient was provided with a trial of therapy with HFNC via helmet along with nitric oxide (40 ppm), but because of persistent hypoxemia and worsening encephalopathy, he was endotracheally intubated for mechanical ventilatory support within 8hrs of admission. His COVID-19 treatment regimen included remdesivir, tocilizumab, and dexamethasone. His 22-day ICU course was complicated by renal failure requiring dialysis, bacteremia, thrombocytopenia, and intracerebral hemorrhages. Life support measures were withdrawn after goals of care discussion as per the patient and family wishes.
3.2 Case #2
A 74-year-old male with a past medical history of obstructive sleep apnea (OSA) and obesity presented with acute hypoxic respiratory failure in the setting of COVID-19 pneumonia. On admission day 3, the patient had increasing oxygen requirements with HFNC (flow 50L, FiO2 1.0) with additional oxygen supplementation via a non-rebreather mask (flow 15L). Having failed to tolerate a brief trial (<15min) of bi-level NIPPV (10/5 cmH2O, FiO2 1.0), he was then transitioned to HFNC (Flow 45L/min, FiO2 1.0) via helmet in combination with inhaled nitric oxide (40 ppm). He received convalescent plasma, remdesivir, dexamethasone, and lenzilumab as part of his COVID-19 treatment. On admission day 6, the patient was transitioned back to the floor and was progressively weaned off helmet ventilation to the nasal cannula. He was subsequently discharged home.
3.3 Case #3
A 68-year-old male with a past medical history of hypertension, gastroesophageal reflux disease, and hyperlipidemia presented with a 4-day history of cough, fever, chest tightness, and weakness after returning from a trip from New Zealand. On admission day 3, his oxygen requirements increased as his dyspnea worsened and work of breathing intensified. He engaged in a self-proning posture with supplemental oxygen provided via a non-rebreather mask (flow 15L/min), and experienced an improvement in his hypoxia (oxygen saturations increased from 92% to 98%) and associated dyspnea. He was then transferred to the ICU for closer monitoring and placed on non-invasive helmet ventilation with HFNC (Flow 80L/min, FiO2 0.8) and inhaled nitric oxide (20 ppm). He received hydroxychloroquine, lenzilumab, and tocilizumab as part of his COVID-19 treatment. After 8 days on noninvasive ventilation via helmet, his condition continued to improve and he was transitioned to an oxygen mask and eventually nasal cannula. He was then discharged home with supplemental oxygen provided via nasal cannula (NC) (2L/min).
3.4 Case #4
A 73-year-old female with a history of hypothyroidism, gastroesophageal reflux disease, hyperlipidemia, and chronic kidney disease presented to the emergency department with nausea, fatigue, and non-productive cough in the setting of COVID-19 pneumonia. Her hospital course was complicated by hypoxemic respiratory failure with a progressively increasing need for O2 via nasal cannula to non-rebreather mask at 15L/min. Her hypoxia continued to worsen and she required HFNC (Flow 80L/min, FiO2 0.8) via helmet therapy. She received lopinavir/ritonavir, remdesivir, ribavirin, tocilizumab, and hydroxychloroquine as part of her COVID-19 treatment. After three days of helmet therapy with HFNC, she was transferred to the floor on 6L NC and was eventually discharged home on 2L NC.
3.5 Case # 5
A 76-year-old male with a past medical history of chronic obstructive pulmonary disease (COPD) and small-cell lung cancer status post-chemotherapy and radiation (>5yrs prior to presentation, in remission) presented with acute hypoxic respiratory failure due to COVID-19 pneumonia. He was initially admitted to the general medical wards; but, due to escalating oxygen requirements, he was transferred to the ICU on the third day of hospitalization. There he was placed on HFNC (Flow 70L/min, FiO2 1.0) via the helmet along with inhaled nitric oxide (40 ppm). He received remdesivir, tocilizumab, and dexamethasone as part of his COVID-19 treatment. Unfortunately, he continued to deteriorate, and due to increasing hypoxia and work of breathing, he required endotracheal intubation on day 8 of hospitalization. His clinical condition deteriorated further and, after goals of care discussion with family, the patient was transitioned to hospice care and expired.
3.6 Scope for the future - helmet therapy for non-covid-19 patients
A 66-year-old male patient with a past medical history of congestive heart failure, associated with a reduced ejection fraction, underwent maxillary sinus repair surgery. His COVID-19 negative status was confirmed pre-operatively. He was extubated postoperatively but developed hypoxia due to flash pulmonary edema while recovering in PACU on a non-rebreather. His surgical procedure presented a contra-indication for NIPPV therapy and the ICU service was consulted for the need for possible reintubation. The patient was instead managed with HFNC (Flow 70L/min, FiO2 1.0) via helmet and intravenous furosemide. He had symptomatic improvements within 24 hours and was subsequently transferred to the general ward. The remainder of his hospitalization was uneventful from a respiratory perspective and he was eventually discharged home.
4 Discussion
We used noninvasive oxygenation via the helmet in carefully selected patients to decrease dispersion of the COVID-19 virus and to reduce the need for endotracheal intubation and mechanical ventilation. We went a step further and use this modality in a COVID-negative patient with hypoxic respiratory failure as an innovative way to explore the potential of this therapy.
Our report demonstrates favorable outcomes in a majority of the patients. Those of our patients who survived their acute hypoxic illness demonstrated increased tissue oxygenation after the application of the oxygen helmet. The patients who died during hospitalization demonstrated many risk factors known for increased mortality associated with COVID-19 and include male sex, obesity, pulmonary disease including COPD and lung cancer, diabetes, hypertension, and thrombocytopenia [[24], [25], [26]]. Table 1 summarizes the main characteristics and the outcomes for the patients included in this case series.Table 1 Patient characteristics and outcomes.
Table 1 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Age 70 74 68 73 76
Sex M M M F M
Duration of hospitalization before helmet treatment 2 days 1 day 3 days 7 days 3 days
Time elapsed between symptom onset and helmet therapy 9 days 6 days 8 days 14 days 13 days
P/F Ratio (Prior to initiation of oxygen helmet) <200 <200 <300 <300 <100
CRP 235.3 168.5 79 229.7 82.8
IL-6 >400 314 30.9 16.2 16.1
d-dimer >42000 678 751 1516 1058
SOFA score (Day of admission) 5 3 3 2 3
Helmet settings
Flow rate (L/min) 60 30 50 80 50
FiO2 1.0 0.8 0.8 0.8 1.0
PEEP (cmH2O) 8 7 5 5 7
Average respiratory rate 24 32 30 22 24
Duration of helmet therapy 1 day 1 day 7 days 5 days 4 days
Duration of NO 16 days 6 days 1 day No 12 days
Intubation (yes/no) Yes No No No Yes
Duration of hospital stay 22 days 9 days 13 days 17 days 14 days
Outcome Deceased Alive Alive Alive Deceased
The patient population who would benefit from this treatment modality should be carefully selected. The most important selection criterion to be considered is the respiratory function of the patient. The helmet is dependent on the patient's ability to generate tidal volume and minute ventilation sufficient to meet their needs. Patients who are unable to tolerate the mask associated with NIPPV due to facial anatomy, facial hair, skin breakdown from prolonged use of mask, or risk of aspiration, can also benefit from this practice. The factors which helped us in selecting the patients include claustrophobia, mask intolerance, degree of CO2 retention, degree of hypoxia, risk of vomiting/aspiration, and patient/family preference.
The usage of oxygen hood in the current COVID-19 pandemic showcased several advantages. The cost of each hood is measured in hundreds of dollars as opposed to the thousands of dollars range when compared with mechanical ventilation. Furthermore, this therapy decreases overall hospital costs associated with the prolonged ICU admission mechanical ventilation entails [17]. While the rubberneck gaskets are used for single patients due to the customized sizing procedure required, the hoods can be sterilized and reused on multiple patients. The hoods are also compatible with adjunct therapy such as nitric oxide (NO) therapy, an approach that has been used with success in COVID-19 patients [[19], [20], [21]]. Oxygen supplementation with the oxygen helmet also provides the patient with the ability to drink fluids through a straw, wear glasses under the helmet, and engage in verbal communication with greater ease. More importantly, the neck seal and the viral filter reduces the risk of aerosol generation and nosocomial infection for healthcare workers and other patients. Thus, not only helmet oxygenation a cost-effective alternative, but it also has the potential to prevent intubation and preserve ventilators in the current pandemic. Table 2 provides a visual reference for relative comparison of multiple modalities of providing supplemental oxygen.Table 2 Relative Comparison of multiple modalities of providing supplemental oxygen.
Table 2 Oxygen helmet HFNC BiPAP MEchanical Ventilation
COST $$ $$ $$$ $$$
RISK OF AEROSOLIZATION Low High High Low
INDICATIONS FOR USE:
-HYPOXIC FAILURE + + + +
-HYPERCARBIC FAILURE – – + +
PATIENT COMFORT Medium Medium Low Low
USE OF INHALED NO ALONG WITH DEVICE + + – +
There is a potential to expand the application of this method of oxygen therapy to other patients for whom traditional NIPPV or intubation is either contraindicated or sought to be avoided. We demonstrated this by preventing intubation in a COVID-negative patient, who underwent maxillary sinus surgery when NIPPV was contraindicated. Preventing intubation has many benefits including preventing ventilator-induced lung injury (VILI), ICU associated delirium, infection, and longer ICU stay & hospitalization. This practice can possibly be applied in surgical patients such as gastric bypass patients with fresh anastomoses, immunocompromised patients at risk of developing ventilator-associated pneumonia, or hypoxic patients with advanced directives precluding intubation (i.e. Do Not Intubate (DNI) orders). Thus, more trials of this innovative type of ventilation with either high-flow or NIPPV in different patient populations are necessary to fully demonstrate its potential.
While there are numerous benefits to the helmet, there are limitations that need to be considered. This includes the inability to titrate PEEP to higher levels as well as the inability to adjust the tidal volume. Furthermore, there is a risk of nitrogen dioxide (NO2) development—a pulmonary irritant with lethal potential [22]. This highlights the need for continuous patient monitoring with a trained team of critical care providers. Though the helmet was used in Europe previously [16], this practice is not widely recognized in North America and thus, its availability is low. Patient mobility was not assessed in our case series due to clinical condition. The patients with COVID-19 were prone to significant desaturation episodes with even minimal movement at the nadir of their course and this correlated with the timing of treatment with the oxygen helmet. Any periods of patient mobility that did occur were limited to repositioning in bed or moving to the bedside chair. Furthermore, while some PEEP is provided, our case series documents the use of helmet therapy to provide increased oxygen support rather than ventilatory support and it is not clear to what degree the helmet therapy may assist in a patient with profound hypercapnia.
The regimen of pharmacotherapy provided to the patients in our series may represent a confounding variable. The standards of care during the pandemic, particularly during the early phases, represented a dynamic set of guidelines supported by varying levels of evidence. The differing treatments provided to our patients reflect this state of flux but were appropriate with respect to the guidelines at the time of the individual patient's hospitalization. We recognize that certain medications and treatment regimens have subsequently fallen out of favor as the medical community's COVID-19 knowledge-base has grown.
In conclusion, further studies are required to investigate the impact of these limitations. Although a previous randomized control trial with ARDS patients demonstrated its utility in reducing intubation rates and consequently reducing the 90-day mortality, new trials are necessary to replicate our outcomes on a larger scale [11].
5 Conclusion
Supplemental oxygen therapy via the hyperbaric helmet is an innovative modality with the potential for widespread utilization in critical care practice. This cost-effective approach is well-tolerated in appropriately selected patients with escalating supplemental oxygen requirements, highlighting the benefits provided by the helmet over other modalities. However, oxygen therapy with the helmet does warrant further study to confirm its efficacy on a larger scale.
Declaration of competing interest
This manuscript has not been presented in whole or in part. No funding was provided and the authors do not have any conflicts of interest to declare.
Acknowledgements
The authors wish to acknowledge the hard work of every team member in our critical care units including the physicians, advance practice providers, nurses, respiratory therapists, patient care assistants, physical therapists, occupational therapists, without whom we could not provide the highest-quality and innovative patient care. | 15 LITER /MIN VIA NASAL CANNULA | DrugDosageText | CC BY-NC-ND | 33643838 | 19,721,017 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anti-neutrophil cytoplasmic antibody positive vasculitis'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'C-reactive protein increased'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug level below therapeutic'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Microscopic polyangiitis'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuropathy peripheral'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peroneal nerve palsy'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vasculitis'. | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | AZATHIOPRINE, INFLIXIMAB, MESALAMINE, METHOTREXATE | DrugsGivenReaction | CC BY | 33643972 | 19,016,969 | 2021 |
What was the administration route of drug 'INFLIXIMAB'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33643972 | 19,016,969 | 2021 |
What was the administration route of drug 'METHOTREXATE'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Oral | DrugAdministrationRoute | CC BY | 33643972 | 19,016,969 | 2021 |
What was the dosage of drug 'AZATHIOPRINE'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | UNKNOWN | DrugDosageText | CC BY | 33643972 | 19,016,969 | 2021 |
What was the dosage of drug 'MESALAMINE'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | UNKNOWN | DrugDosageText | CC BY | 33643972 | 19,016,969 | 2021 |
What was the outcome of reaction 'Anti-neutrophil cytoplasmic antibody positive vasculitis'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered with sequelae (consequent health issues) | ReactionOutcome | CC BY | 33643972 | 19,016,969 | 2021 |
What was the outcome of reaction 'C-reactive protein increased'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33643972 | 19,016,969 | 2021 |
What was the outcome of reaction 'Drug level below therapeutic'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33643972 | 19,016,969 | 2021 |
What was the outcome of reaction 'Neuropathy peripheral'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Not recovered | ReactionOutcome | CC BY | 33643972 | 19,016,969 | 2021 |
What was the outcome of reaction 'Peroneal nerve palsy'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovering | ReactionOutcome | CC BY | 33643972 | 19,016,969 | 2021 |
What was the outcome of reaction 'Vasculitis'? | Case Report: Systemic Small-Vessel Vasculitis in an Adolescent With Active Ulcerative Colitis.
Introduction: Small-vessel vasculitis (SVV) is a rare immunological disease that affects arterioles, capillaries and venules. It causes purpura, but can also manifest in other organs, including the gastrointestinal tract. SVV and inflammatory bowel disease (IBD) co-occur more frequently than would be expected by chance. Case description: A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, developed purpura, progressive abdominal pain with frequent bloody diarrhea and frontotemporal headache and swelling while on azathioprine and mesalamine maintenance therapy. Serology was positive for perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) without antiprotease- or myeloperoixidase antibodies. Endoscopy revealed active left-sided UC and atypical ulcerations in the ascending colon. Biopsies of these ulcerations and of affected skin revealed leukocytoclastic vasculitis. Initially this was interpreted as an extraintestinal manifestation of UC that would subside when remission was induced, consequently infliximab was started. Over the next 3 weeks she developed severe burning pain in her right lower leg that progressed to a foot drop with numbness and the purpura progressed to bullous lesions. The diagnosis was adjusted to ANCA-associated vasculitis with involvement of skin, bowel and peripheral nerves. Infliximab was discontinued and induction treatment with high-dose prednisolone and cyclophosphamide was given until remission of SVV and UC was achieved. Subsequently, infliximab induction and maintenance was re-introduced in combination with methotrexate. Remission has been maintained successfully for over 2 years now. The foot drop only partly resolved and necessitated the use of an orthosis. Conclusion: Pediatric patients with IBD who present with purpuric skin lesions and abdominal pain should be evaluated for systemic involvement of SVV, which includes endoscopic evaluation of the gastrointestinal tract. We discuss a practical approach to the diagnosis, evaluation and management of systemic SVV with a focus on prompt recognition and early aggressive therapy to improve outcome.
Introduction
Vasculitis comprises a heterogeneous group of disorders in which inflammation of blood vessel walls is present. Epidemiological data on childhood vasculitis is scarce and poorly characterized. The estimated overall annual incidence rate of primary childhood vasculitis is 22.8 per 100,000, but this includes the relatively common childhood vasculitides Henoch Schönlein purpura (HSP) and Kawasaki disease (1). When these types, with their typical pattern of (muco)cutaneous inflammation, are disregarded, the incidence rate drops to 0.24 per 100,000. Due to its rarity and broad spectrum of clinical presentations, diagnosis of childhood vasculitis is often delayed, leading to significant morbidity and mortality (2–4).
According to the internationally accepted 2012 Chapel Hill Consensus Conference nomenclature, vasculitis is defined by histopathology, immunological findings and, above all, the size of the predominantly affected vessel (i.e., small, medium, or large) (5–7). Small vessel vasculitis (SVV) is characterized by inflammation of parenchymal arteries, arterioles, capillaries and venules and is subdivided into antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and immune-complex-mediated vasculitis (including HSP) (7).
Some patients with SVV are originally diagnosed as having single-organ involvement (e.g., cutaneous SVV), but many will develop additional disease manifestations that warrant redefining the case as a multi-organ SVV.
Inflammatory bowel disease (IBD) and SVV co-occur more often than would be expected by chance (8–10). Additionally, SVV itself can also present with gastrointestinal symptoms. When the small or medium vessels of the gastrointestinal tract are involved, patients can present with symptoms ranging from mild abdominal pain and diarrhea to life-threatening colonic ischemic ulcers, peritonitis and bowel perforations (11, 12). In patients who were previously diagnosed with IBD, distinguishing between these two clinical entities can be challenging. Increased fecal calprotectin levels are found in both active IBD and SVV with bowel involvement and are therefore not indicative (13, 14).
Case Description
A 16-year-old girl, who had been diagnosed with ulcerative colitis (UC) 2 years earlier at a general hospital, recently had several flares of UC despite treatment with azathioprine, mesalamine, and several tapering courses of corticosteroids. She was referred to our University Hospital for a second opinion with respect to a possible step-up to anti-TNF therapy. In the week prior to colonoscopy the patient developed painful purpura on the lower leg (causing an antalgic gait) and dorsal trunk. One day prior to the planned colonoscopy she was admitted to our hospital with progressive abdominal pain and frequent bloody diarrhea. Some of the purpura had faded while new ones had appeared (Figure 1A). Peripheral blood analysis revealed increased C-reactive protein (CRP 71 mg/L; normal range <5 mg/L) and erythrocyte sedimentation rate (71 mm/h; normal range <20 mm/h). Coagulation tests, creatinine, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transferase were within normal limits. Fecal calprotectin was 4,010 μg/g (target range <150 μg/g). Urinalysis was normal.
Figure 1 Purpura. (A) Purpura located on the lower back. (B) Purpura with blistering located on the dorsal side of the right foot.
That night the girl woke up with excruciating right temporal headache similar to the pain she experienced a week before at the site of the purpura. The headache was accompanied by frontotemporal swelling. A cranial MRI was performed, which showed diffuse subcutaneous edema without intracranial pathology (Figure 2).
Figure 2 Cranial MRI showing diffuse subcutaneous edema (indicated by arrows).
The next day, colonoscopic examination showed continuous inflammation in the left transverse (Figure 3A), descending and sigmoid colon with rectal sparing, suggestive of active UC. In the ascending colon three atypical ulcerations were seen (Figure 3B). Histological examination of these ulcerations showed necrosis of the mucosa and submucosa with thrombosis and perivascular infiltrates with neutrophils and nuclear debris, consistent with leukocytoclastic vasculitis. There were no granulomatous changes or immune deposits. Biopsies of the terminal ileum, cecum, right transverse colon and rectum showed no abnormalities. The descending and sigmoid colon showed a histological pattern of chronic inflammation defined by crypt architectural distortion and basal lymphoplasmacytosis. A punch biopsy from the skin of the left lower leg, obtained during the colonoscopic session, showed perivascular infiltrates with neutrophils in the dermis, with affected vessel walls and extravasation of erythrocytes, and was also consistent with leukocytoclastic vasculitis. Immunofluorescence was negative. Serum perinuclear (p)-ANCA was positive (titer >1:640) without antiprotease- or myeloperoxidase antibodies. Rheumatoid factor, anticardiolipin antibodies, cryoglobulins and antinuclear antibodies were negative. Neither did we find antibodies against hepatitis A and B virus, cytomegalovirus and Epstein-Barr virus. Chest X-ray was normal.
Figure 3 Findings during colonoscopic evaluation. (A) Inflammation of the transverse colon, including erythema, a granular appearance, friability and loss of the normal fine vascular pattern. (B) Ulcerations located in the ascending colon. (C) Healed ascending colon after 5 weeks of chemotherapy.
It was reasoned that the increased serological and fecal markers of inflammation and leukocytoclastic vasculitis were manifestations of active UC, and that these symptoms would subside upon reaching remission. Positivity for p-ANCA is observed in the majority of cases of UC and was interpreted as an immune response associated with the disease process itself. Intravenous administration of infliximab 5 mg/kg was planned with three induction doses over 6 weeks (week 0-2-6), followed by maintenance therapy every 8 weeks. Azathioprine and mesalamine maintenance therapy was continued.
The frontotemporal subcutaneous edema resolved, but after the second infliximab administration fever appeared, CRP gradually rose to 230 mg/L, the purpura progressed to purple blisters (Figure 1B) and the patient developed a progressive paralysis of the right lower leg, resulting in a complete foot drop. Neurological examination revealed absence of the Achilles stretch reflex and plantar reflex on the right side, and sensory disturbances on the right foot and left hand. Electromyography showed active axonal damage of the left median nerve and the right peroneal and tibial nerve (i.e., multiple peripheral mononeuropathy). Spinal MRI was normal.
The multitude of clinical signs (blistering purpura, mononeuritis multiplex, fever and involvement of the gastro-intestinal tract), in combination with histopathology (leukocytoclastic vasculitis without immune deposits) and immunological findings (p-ANCA positivity and high CRP), made us reconsider our initial frame of mind. We ascertained the diagnosis as ANCA-associated vasculitis (subclassified as microscopic polyangiitis), with damage of the small blood vessels in skin, colon and peripheral nerves. Because of the severe presentation, induction therapy was started consisting of high-dose intravenous prednisolone (60 mg/day) and intravenous cyclophosphamide (15 mg/kg at week 0-2-4, followed by once every 3 weeks until 3 months of stable remission). Infliximab and azathioprine were discontinued. As a result, UC treatment was de-escalated to mesalamine monotherapy (Figure 4).
Figure 4 Timeline showing disease intensity per organ and medication. The black triangles mark the infusions. PUCAI, Pediatric Ulcerative Colitis Activity Index; FC, Fecal calprotectin.
Remission of cutaneous and colonic vasculitis (Figure 3C) and normalization of CRP were achieved after 5 weeks of chemotherapy. Prednisolone was tapered and stopped after 4 months and cyclophosphamide was discontinued after seven infusions. Infliximab was re-introduced with three induction doses (5 mg/kg) over 6 weeks, after which fecal calprotectin had declined to the target range (77 μg/g). Before the fourth infusion we measured a suboptimal infliximab trough level and consequently escalated to 10 mg/kg every 8 weeks. All subsequent trough levels were in range (i.e., ≥5 μg/ml). Oral methotrexate 20 mg once weekly was started to reduce the risk for recurrence of vasculitis. Biochemical and clinical remission of both ANCA-associated vasculitis and ulcerative colitis have been maintained successfully for over 2 years now, with persistent normal CRP and fecal calprotectin levels. Neurological sequelae including a partial foot drop (necessitating the use of an orthosis) and neuropathic pain remain.
Discussion
We present the case of a 16-year-old girl with active UC complicated by systemic ANCA-associated SVV, resulting in neurological damage. In ANCA-associated SVV, systemic involvement is common, which necessitates a structured organ-based medical history and physical examination in all patients, even when they present with apparently isolated skin lesions. Use of a clinical tool such as the Birmingham Vasculitis Activity Score (15) and the Five Factor Score (16) help the physician with a structured clinical assessment. ANCA testing and a skin punch biopsy with immunofluorescence should be performed to help confirm and (sub)classify SVV. Organ-oriented laboratory panels (such as urinalysis, serum creatinine and blood urea nitrogen for kidney function), imaging and tissue sampling may aid to diagnose systemic SVV (17, 18). In IBD patients with suspected vasculitis and gastrointestinal symptoms, this implies endoscopic evaluation to distinguish active IBD from SVV with bowel involvement.
Why Did we Initially Miss the Diagnosis?
We had histological proof of involvement of vasculitis in two organs (skin and bowel) at an early stage, yet we failed to link the serological test results to ANCA-associated vasculitis. In our patient p-ANCA positivity was observed in the absence of antiprotease- and myeloperoxidase antibodies. This pattern is called atypical p-ANCA and is frequently seen in patients with UC (19), while ANCA-associated SVV in IBD is extremely rare.
The notion that the vasculitis in our patient was an extraintestinal manifestation of IBD that would subside after treatment with intravenous infliximab was incorrect. Although erythema nodosum, a well-recognized extra-intestinal manifestations of IBD, usually resolves with treatment of the underlying IBD (20), this is not the case for IBD-associated vasculitis. This misconception contributed to a serious delay in adequate treatment. Another sign that should have raised suspicion toward severe systemic vasculitis was the exceptionally high CRP, whereas, in active UC the CRP response is usually limited (21).
Why Is Early Recognition Important?
Peripheral nerve damage was recognized only after the patient developed a complete foot drop, while in retrospect, an abnormal gait had already been observed during the first clinical assessment when it was thought to be caused by the painful skin lesions. In fact, when purpura and excruciating pain develop concurrently, the index of suspicion for SVV, in particular ANCA-associated vasculitis should be high. Failure to recognize systemic involvement at an early stage delays treatment, increases organ damage and decreases quality of life (22). In an international cohort study consisting of 105 patients with childhood-onset ANCA-associated vasculitis, evidence of damage was still present in over 60% of patients 12 months after diagnosis (23). In a French nationwide cohort study kidney damage was most frequently seen with 34% of patients developing end-stage renal disease after a median follow-up of 5.2 years (24). We feel that reducing the time before consulting a specialized (pediatric) immunologist and instituting early aggressive therapy will probably improve patient outcome.
How to Treat Systemic SVV?
Because of its rarity, specific guidelines on the management of systemic vasculitis in children are lacking. To fill this gap, the European initiative Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) developed best practice recommendations (18). In addition, The European League Against Rheumatism, the European Renal Association and the European Vasculitis Society have published recommendations for the management of ANCA-associated vasculitis in adults (25). Our patient was ultimately treated with high-dose prednisolone and intravenous cyclophosphamide. This is in accordance with the SHARE recommendations, that advise prednisolone to be dosed at 1–2 mg/kg/day, to a maximum of 60 mg/day and cyclophosphamide every 3 weeks at 500–1,000 mg/m2 to a maximum of 1.2 g. Rituximab (especially in ANCA-associated vasculitis), methotrexate or mycophenolate mofetil (MMF) can also be used as induction therapy, always in combination with high-dose prednisolone. We chose pulse intravenous cyclophosphamide as there is anecdotal evidence that it also has a remission-inducing effect in UC (26, 27). Usually, induction therapy is continued for 3–6 months and prednisolone is tapered during this period. First-line maintenance therapeutic agents recommended by SHARE are azathioprine or MMF. Second-line maintenance therapy includes methotrexate and rituximab. In our patient who suffered from both SVV and UC, maintenance therapy consisted of infliximab and methotrexate. Azathioprine immunomodulation would have been a more logical choice, but we followed the patient's personal preference based on earlier experienced side effects. Once-weekly oral methotrexate administered concomitantly with infliximab is known to reduce the likelihood of anti-infliximab antibody development and the associated secondary loss of response (28). The common duration of maintenance therapy for SVV is about 1–1.5 year. Stopping methotrexate could be considered when infliximab trough levels are in the target range and endoscopic healing is achieved.
There are numerous reports that anti-TNF therapy by itself increases the risk of vasculitis, in particular the immune-complex-mediated type including HSP (29, 30). The association between anti-TNF and HSP is supported by a resolution of vasculitis when the biological agent is discontinued, and by reappearance of symptoms during a rechallenge. In our patient SVV manifested before the onset of anti-TNF therapy, which makes a causal relation highly unlikely, although we cannot exclude that infliximab might have played a role in the aggravation of the vasculitis. We were of the opinion that in this particular case re-introduction of infliximab was a safe option to maintain remission in UC. If vasculitis manifests in a patient receiving anti-TNF therapy, an association between the two should be considered and, if possible, excluded. In case of a (suspected) association, biological therapy with a different class of agent (such as vedolizumab or ustekinumab) could be considered.
This case illustrates the difficulties and misconceptions that can be encountered in the diagnosis and treatment of SVV in the pediatric age group. Prompt recognition and early aggressive therapy are key in order to prevent morbidity and mortality. If induction therapy would have been started earlier, the neurological sequelae in our patient could have been prevented.
Patient Perspective
“When the first skin lesions appeared, I did not think much of it, but from then on new lesions appeared almost every day. It always started with a terrible burning pain, followed by wounds and swellings, the scars of which are still visible. In the beginning I felt my complaints were waved aside, which was very frustrating. It was said that things would get better when my ulcerative colitis would calm down, but at the same time my condition deteriorated quickly. I had the feeling that something serious was going on. When my nerves stopped working and my entire foot became paralyzed the vasculitis was finally recognized and dealt with. It was a bit of a shock to hear that I had to have chemotherapy, but after the first infusion I could already tell that my symptoms were getting better. Compared to the symptoms I experienced earlier, the treatment was not a big deal and I found a lot of comfort in talking with my doctor. Looking back, I think it is regrettable that treatment was not started earlier, maybe then I would not have had the nerve damage that causes pain and other struggles up to this day.”
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.
Author Contributions
MB drafted and revised the manuscript and approved the final manuscript as submitted. PR drafted, reviewed and revised the manuscript, and approved the final manuscript as submitted. WA reviewed and revised the manuscript, and approved the final manuscript as submitted. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered with sequelae (consequent health issues) | ReactionOutcome | CC BY | 33643972 | 19,016,969 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | The Application of Neurodiagnostic Studies to Inform the Acute Management of a Newborn Presenting With Sarbamoyl Shosphate Synthetase 1 Deficiency.
Neonatal-onset urea cycle disorders (UCDs) may result in hyperammonemic (HA) encephalopathy presenting with several neurologic sequelae including seizures, coma, and death. However, no recommendations are given in how and when neurodiagnostic studies should be used to screen or assess for these neurologic complications. We present a case of carbamoyl phosphate synthetase 1 (CPS1) deficiency in a newborn female in which electroencephalogram monitoring to assess encephalopathy and seizures, and magnetic resonance imaging measurements of brain metabolites were used to guide care during her hyperammonemic crisis. Her neurologic course and response to treatment characterizes the significant neurologic impact of HA encephalopathy. Our group herein proposes a clinical neurodiagnostic pathway for managing acute HA encephalopathy.
Introduction
The urea cycle is the body’s primary biochemical route of nitrogen excretion and mutations affecting this pathway lead to elevated levels of ammonia (NH3) and glutamine. Severe enzymatic deficits may result in hyperammonemic (HA) encephalopathy with possible seizures, coma, and even death. 1 They may occur across the lifespan with the most compromised enzyme activity presenting in the newborn period.
In neonatal-onset urea cycle disorders (UCDs), there is no standard guideline for using electroencephalogram (EEG) monitoring and magnetic resonance (MR) imaging to guide treatment and predict prognosis as are available for neonatal hypoxic ischemic encephalopathy. 2,3 Several small studies have demonstrated the potential of neurodiagnostic tools to expedite treatment and assess prognosis in newborns with UCDs. 4 -6 However, no one has proposed a clinical protocol for appropriate neuromonitoring or seizure management of neonates with UCDs.
The true incidence of seizures and their relation to absolute ammonia level and clinical outcomes in UCDs remains unknown, but recent increase in access to bedside EEG monitoring has shown that seizures are common in UCDs, including subclinical seizures. 7 Whether seizure burden promotes additional brain injury has not been examined.
We propose that use of neurodiagnostic studies can inform and guide the acute management of neonatal-onset UCDs, improve our understanding of the neurologic disease progression of these newborns, and may protect the brain from additional injury. We present a case of neonatal-onset carbamoyl phosphate synthetase 1 (CPS1) deficiency co-managed between Genetics, Neonatal Neurocritical Care, and Neonatology after instating a neurodiagnostic pathway including prolonged continuous EEG monitoring and advance MR imaging to examine potential early proximal biomarkers of brain injury in UCD.
Case Presentation
This 5-day-old female infant born at 36 and 5/7 weeks gestational age was transferred to our neonatal intensive care unit (NICU) in hyperammonemic crisis. She was born via cesarean section to a mother with a history of polyhydramnios, pre-eclampsia, and diabetes mellitus and had a prenatal diagnosis of fetal ventriculoseptal defect. She remained in the nursery for conservative management of desaturations and hypoglycemia, and was discharged after resolution on day 3 of life. She presented to the outside emergency department the next day with lethargy, hypothermia, and decreased responsiveness and was found to have clinical seizures after admission. Her blood gases were normal, but her plasma ammonia level was exceedingly high, >925 µmol/L (normal <100 µmol/L), and so emergently transferred to our tertiary care NICU for management.
On admission in the NICU, she was encephalopathic, intubated, and her ammonia level was 1,677 µmol/L and glutamine level was 3,989 µmol/L. She was started on hemodialysis, intravenous sodium benzoate/sodium phenylacetate, and a continuous video EEG was placed (Figure 1). She required dopamine support for hypotension throughout the night, thus, arginine was not started. Arginine infusions can lead to hypotension. Since the child already had hypotension and required dopamine, arginine was withheld. By the next day, ammonia level decreased to 569 µmol/L and so she was transitioned to continuous renal replacement therapy.
Figure 1. Top graph depicts ammonia (blue diamonds), glutamine (red squares), glutamate (green diamonds) levels (μmol/L) and the rate of an intravenous commercial preparation of ammonia scavengers and arginine (Ammonul) (gray line) over the first 18 days of hospitalization. Middle graph depicts the seizures (black diamonds) and anti-seizure medication (ASM) boluses or changes (purple squares) by day of hospital admission. The bottom graph is an enhancement of isochemical levels and seizure events preceding and during a relapse in hyperammonemia with the initial removal of intravenous scavengers.
On hospital day 3 (HD3), she experienced 10 multifocal electrographic seizures arising from the left central, right central, and left temporal regions and subsequently received a phenobarbital loading dose. Subsequent urine organic acids and plasma amino acid analysis revealed an absence of orotic acid and citrulline, respectively. She was later confirmed to have a homozygous deletion within CPS1, including exon 32. The ammonia continued to decrease to normal levels, and eventually she was transitioned to oral scavenger therapy.
On HD4, she had several refractory electrographic seizures and was started on fosphenytoin. The next day, her ammonia level rapidly increased to 1,293 µmol/L, with a concomitant increase in glutamine concentration to 620 µmol/L; she continued to have refractory electrographic only seizures. Hemodialysis and intravenous ammonia scavengers were resumed, and a midazolam infusion was initiated on HD6 to regain control of her seizures. Although her ammonia level improved with dialysis, her seizures persisted even with the addition of a fourth seizure medication, levetiracetam.
At 2 weeks of age, the patient underwent neuroimaging. MRI demonstrated diffuse white matter signal changes with reduced diffusion involving the corpus callosum, sagittal stratum, internal capsules, and frontal white matter and facilitated diffusion diffusely throughout the remainder of the cerebral white matter, extensive bilateral cerebral laminar necrosis, and heterogeneous cerebral blood flow consistent with a urea cycle disorder (Figure 2A–E). 1 H magnetic resonance spectroscopy (1HMRS) demonstrated elevated lactate suggesting anaerobic metabolism, elevated glutamine (+glutamate, Glx), decreased myo-inositol, and decreased N-acetylaspartate (NAA). An abnormal peak was also noted at 2.8 ppm, most likely representing elevated aspartate, a breakdown product of NAA (Figure 2F-G). A repeat MRI/MRS was performed on day of life 18 with improved perfusion and spectroscopy indicating smaller Glx peaks (Figure 2H).
Figure 2. Selected axial brain MR images at the level of the basal ganglia at day of life 14 (a-d) and 18 (e). Heterogeneous cerebral hyperperfusion improves over time between exams (a and e). Reduced diffusion is present with hyperintense signal in the callosal splenium and genu, sagittal stratum, internal capsules, frontal white matter, and to a lesser extent (with partial pseudonormalization) in the cerebral cortex and deep gray nuclei in correlation with the apparent diffusion coefficient (ADC) map (not shown) (b). Hyperintensity on T1WI (c) and hypointensity onT2WI (d) is present extensively throughout most of the cerebral cortex and mild signal changes are present affecting the cerebral deep gray nuclei. The cortical signal changes on the T1 and T1WI represent laminar necrosis. The unmyelinated cerebral white matter demonstrates excessive T1 and T2 prolongation. There is mild diffuse cerebral volume loss with prominent sulci and ventricles. Single voxel proton MR spectroscopy (MRS) over the left basal ganglia at day 14 (f and g) and 18 (h). Initially, ultrashort TE MRS (STEAM; TR 1500 ms, TE 14 ms) and short TE MRS (PRESS; TR 1500ms, TE 35ms) reveal substantial metabolic alterations including elevated glutamine/glutamate (Glx) reflecting the urea cycle deficit and hyperammonemia induced glutamine synthetase activation, reduced myoinositol (MI) due to osmotic buffering, marked actate (lac) reflecting anaerobic metabolism, elevated lipid, and reduced NAA: Creatine and Choline:Creatine ratios. Aspartate (Asp) is also elevated, only visible with the ultrashort TE sequence (f). On follow-up, metabolic disturbances improved, with decreasing glutamine, lactate, and lipid and increasing myoinositol and creatine (h).
Despite stable ammonia levels (15-110 µmol/L) in the following weeks, she continued to have electrographic only seizures despite maximized phenobarbital, levetiracetam, and midazolam infusion. Because these breakthrough seizures likely represented ongoing cortical injury despite normalized ammonia levels rather than a primary seizure condition, anti-epileptic drugs (AEDs) were slowly weaned along with sodium benzoate/sodium phenylacetate. Her last electrographic seizure was on day of life 21, and she continues to receive maintenance doses of topiramate and levetiracetam while awaiting liver transplantation for definitive enzymatic correction.
Discussion
Hyperammonemia can be the first clinical presentation of an inborn error of metabolism including a urea cycle disorder or organic acidemia and can provoke irreversible damage to the developing central nervous system (CNS), leading to cognitive impairment, seizures and cerebral palsy. 8 Hyperammonemic neonates and infants develop cortical atrophy with ventricular enlargement. 8 -10 The extent of the irreversible damages depends upon the maturation of the brain and on the magnitude and duration of the ammonia exposure. 11 Irreversibility mainly occurs in case of prolonged hyperammonemic crises and/or when blood ammonia reaches levels between 200 and 500 µM, during the 2 first years of life. 12 -17
It has previously shown that neonates with UCDs may present with seizures during HA. 7,18 However, most of the seizures are subclinical, and therefore only identified with prolonged continuous EEG. The mechanism of how hyperammonemia leads to the dysfunction of inhibitory neurotransmission has been explored in studies on astrocyte potassium buffering. It is proposed that the increase in brain glutamine and the resulting disturbed osmotic balance leads to impaired GABA-mediated neurotransmission. 19
The pattern of metabolites in this patient in relation to seizure occurrence shown in Figure 1B is interesting to note several features. Seizures began after stable ammonia levels (72-130 µmol/L) were achieved with hemodialysis (HD 2-4), representing initial acute brain injury. Early re-emergence of seizures was a proximal indicator of brain ammonia and glutamine re-elevation after the discontinuation of intravenous ammonia scavengers before detection remotely in plasma levels (HD4-5). Plasma glutamine remained within normal levels (376-819 µmol/L) for several days before, during, and after the second HA crisis despite ongoing refractory seizures. The persistent refractory seizures days after both plasma ammonia and glutamine levels were stable and the patient recovering suggests those seizures represent ongoing neuronal death rather than a primary seizure disorder or biochemical imbalance.
Although, the mechanism of ammonia neurotoxicity is still poorly understood and no specific treatment targeted for ammonia neuroprotection is available, there have been frequent reports of seizures in patients with urea cycle disorders. 4,9,20 Accumulations of ammonia, glutamine, and glutamate have been shown to exert toxic effects upon the brain. In animal models, the HA state leads to excitotoxic cell death and, with prolonged exposure, to the loss of NMDA receptors. These same receptors are altered in the sparse fur (Spf) mouse model of ornithine transcarbamylase deficiency (OTCD). 14 The postulated effects of elevated ammonia and glutamine include astrocytic swelling, an increase in blood brain barrier permeability, and disruption of energy through depletion of intermediaries of metabolism including altered amino acid and neurotransmitter levels. 15 -17,21
It has been hypothesized that brain MRI findings may reflect the differential distribution of brain injury involvement in UCD and may aid in assessing neurologic outcomes. 5,10,22 One previous report presented serial imaging in a patient with a UCD (OTCD) that show the progression of the disease. 22 Another study investigated the pattern of MRI findings in patients with neonatal UCDs as it relates to the severity of disease and neurodevelopmental outcomes at 2 years of age. It was concluded that cerebral involvement of injury on MRI and levels of biomarkers such as glutamine have the potential to be prognostic for outcome, although the limited data on this subject prevents imaging from being the sole determinate of decision-making. 21 MR spectroscopy allows us to determine that brain ammonia levels are elevated (by seeing elevations of the surrogate metabolite, glutamine) which may occur even with normal plasma ammonia and glutamine levels. Limited neuroimaging literature on CPS1 deficiency has previously demonstrated a territorial infarction, nonspecific widespread brain injury, and more specific patterns similar to what has been described with OTCD with involvement of the insular, deep perisylvian and basal ganglia regions. 6,23 -26 The diffuse, severe involvement of most components of both cerebral hemispheres with associated laminar necrosis suggests that the brain sustained a substantial insult that is unlikely to be entirely reversible in our patient. The reduced diffusion in parts of the cerebral white matter discovered on the first MR at 2 weeks of age could represent any combination of pre-Wallerian degeneration associated with the cortical injury, intramyelinic edema, and/or demyelination in the setting of residual/ongoing myelin injury or recurrent injury. While MRS using PRESS sequences have been preferred due to the higher signal to noise ratio, STEAM MRS enables visualization of the shorter echo-time (TE) metabolites. Previous work by our group has shown elevated glutamine and glutamate representing the hyperammonemia-induced glutamine synthetase activation and reduced myoinositol due to loss of osmotic buffering (Figure 1). STEAM MRS allowed visualization of the elevated Aspartate (Asp), which can be inferred to be a breakdown product of N-acetylaspartate (NAA) and marker of neuronal loss.
Conclusion
Based on our experience with this and prior UCD newborns, we propose a clinical neurodiagnostic protocol that can be implemented to better understand the clinical and biochemical time course of neonatal-onset UCDs and lead to early recognition and treatment of their neurologic complications (Figure 3). Early and comprehensive neurologic evaluation throughout the patient’s acute course may improve neurologic outcomes. We propose early prolonged continuous EEG monitoring with acute HA and monitoring during withdrawal of hemodialysis and intravenous scavengers to identify and treat acute seizures and to identify early relapse of HA. MRS TE settings should be adjusted to a lower level, from 35 ms to STEAM TE ultrashort (14 ms) sequences, in order to better understand the biochemical profile of proximal UCDs. We plan long term follow up of this infant with sequential MRI/MRS and neurocognitive screening to better characterize the pattern of brain injury and correlate with later functional issues and risk of developing of epilepsy.
Figure 3. Clinical protocol used for the management of neonatal hyperammonemia by the neurology consult service. Abbreviations: Magnetic Resonance Spectrometry (MRS), Time Echo (TE), Diffusion Tensor Imaging (DTI), Spoiled Gradient Recall (SPGR), Arterial Spin Labeling (ASL), video Electroencephalography (vEEG), Head Ultrasound (HUS), continuous Near-Infrared Spectrometry (cNIRS), Plasma Amino Acids (PAA), Urine Organic Acid (UOA), Continuous Renal Replacement Therapy (CRRT).
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NIH U54 HD061221 (AG); O’Malley Family Foundation grant (AG).
ORCID iD: Andrea Gropman, MD https://orcid.org/0000-0002-2106-6776 | FOSPHENYTOIN SODIUM, LEVETIRACETAM, MIDAZOLAM, PHENOBARBITAL | DrugsGivenReaction | CC BY-NC | 33644249 | 19,166,404 | 2021 |
What was the administration route of drug 'LEVETIRACETAM'? | The Application of Neurodiagnostic Studies to Inform the Acute Management of a Newborn Presenting With Sarbamoyl Shosphate Synthetase 1 Deficiency.
Neonatal-onset urea cycle disorders (UCDs) may result in hyperammonemic (HA) encephalopathy presenting with several neurologic sequelae including seizures, coma, and death. However, no recommendations are given in how and when neurodiagnostic studies should be used to screen or assess for these neurologic complications. We present a case of carbamoyl phosphate synthetase 1 (CPS1) deficiency in a newborn female in which electroencephalogram monitoring to assess encephalopathy and seizures, and magnetic resonance imaging measurements of brain metabolites were used to guide care during her hyperammonemic crisis. Her neurologic course and response to treatment characterizes the significant neurologic impact of HA encephalopathy. Our group herein proposes a clinical neurodiagnostic pathway for managing acute HA encephalopathy.
Introduction
The urea cycle is the body’s primary biochemical route of nitrogen excretion and mutations affecting this pathway lead to elevated levels of ammonia (NH3) and glutamine. Severe enzymatic deficits may result in hyperammonemic (HA) encephalopathy with possible seizures, coma, and even death. 1 They may occur across the lifespan with the most compromised enzyme activity presenting in the newborn period.
In neonatal-onset urea cycle disorders (UCDs), there is no standard guideline for using electroencephalogram (EEG) monitoring and magnetic resonance (MR) imaging to guide treatment and predict prognosis as are available for neonatal hypoxic ischemic encephalopathy. 2,3 Several small studies have demonstrated the potential of neurodiagnostic tools to expedite treatment and assess prognosis in newborns with UCDs. 4 -6 However, no one has proposed a clinical protocol for appropriate neuromonitoring or seizure management of neonates with UCDs.
The true incidence of seizures and their relation to absolute ammonia level and clinical outcomes in UCDs remains unknown, but recent increase in access to bedside EEG monitoring has shown that seizures are common in UCDs, including subclinical seizures. 7 Whether seizure burden promotes additional brain injury has not been examined.
We propose that use of neurodiagnostic studies can inform and guide the acute management of neonatal-onset UCDs, improve our understanding of the neurologic disease progression of these newborns, and may protect the brain from additional injury. We present a case of neonatal-onset carbamoyl phosphate synthetase 1 (CPS1) deficiency co-managed between Genetics, Neonatal Neurocritical Care, and Neonatology after instating a neurodiagnostic pathway including prolonged continuous EEG monitoring and advance MR imaging to examine potential early proximal biomarkers of brain injury in UCD.
Case Presentation
This 5-day-old female infant born at 36 and 5/7 weeks gestational age was transferred to our neonatal intensive care unit (NICU) in hyperammonemic crisis. She was born via cesarean section to a mother with a history of polyhydramnios, pre-eclampsia, and diabetes mellitus and had a prenatal diagnosis of fetal ventriculoseptal defect. She remained in the nursery for conservative management of desaturations and hypoglycemia, and was discharged after resolution on day 3 of life. She presented to the outside emergency department the next day with lethargy, hypothermia, and decreased responsiveness and was found to have clinical seizures after admission. Her blood gases were normal, but her plasma ammonia level was exceedingly high, >925 µmol/L (normal <100 µmol/L), and so emergently transferred to our tertiary care NICU for management.
On admission in the NICU, she was encephalopathic, intubated, and her ammonia level was 1,677 µmol/L and glutamine level was 3,989 µmol/L. She was started on hemodialysis, intravenous sodium benzoate/sodium phenylacetate, and a continuous video EEG was placed (Figure 1). She required dopamine support for hypotension throughout the night, thus, arginine was not started. Arginine infusions can lead to hypotension. Since the child already had hypotension and required dopamine, arginine was withheld. By the next day, ammonia level decreased to 569 µmol/L and so she was transitioned to continuous renal replacement therapy.
Figure 1. Top graph depicts ammonia (blue diamonds), glutamine (red squares), glutamate (green diamonds) levels (μmol/L) and the rate of an intravenous commercial preparation of ammonia scavengers and arginine (Ammonul) (gray line) over the first 18 days of hospitalization. Middle graph depicts the seizures (black diamonds) and anti-seizure medication (ASM) boluses or changes (purple squares) by day of hospital admission. The bottom graph is an enhancement of isochemical levels and seizure events preceding and during a relapse in hyperammonemia with the initial removal of intravenous scavengers.
On hospital day 3 (HD3), she experienced 10 multifocal electrographic seizures arising from the left central, right central, and left temporal regions and subsequently received a phenobarbital loading dose. Subsequent urine organic acids and plasma amino acid analysis revealed an absence of orotic acid and citrulline, respectively. She was later confirmed to have a homozygous deletion within CPS1, including exon 32. The ammonia continued to decrease to normal levels, and eventually she was transitioned to oral scavenger therapy.
On HD4, she had several refractory electrographic seizures and was started on fosphenytoin. The next day, her ammonia level rapidly increased to 1,293 µmol/L, with a concomitant increase in glutamine concentration to 620 µmol/L; she continued to have refractory electrographic only seizures. Hemodialysis and intravenous ammonia scavengers were resumed, and a midazolam infusion was initiated on HD6 to regain control of her seizures. Although her ammonia level improved with dialysis, her seizures persisted even with the addition of a fourth seizure medication, levetiracetam.
At 2 weeks of age, the patient underwent neuroimaging. MRI demonstrated diffuse white matter signal changes with reduced diffusion involving the corpus callosum, sagittal stratum, internal capsules, and frontal white matter and facilitated diffusion diffusely throughout the remainder of the cerebral white matter, extensive bilateral cerebral laminar necrosis, and heterogeneous cerebral blood flow consistent with a urea cycle disorder (Figure 2A–E). 1 H magnetic resonance spectroscopy (1HMRS) demonstrated elevated lactate suggesting anaerobic metabolism, elevated glutamine (+glutamate, Glx), decreased myo-inositol, and decreased N-acetylaspartate (NAA). An abnormal peak was also noted at 2.8 ppm, most likely representing elevated aspartate, a breakdown product of NAA (Figure 2F-G). A repeat MRI/MRS was performed on day of life 18 with improved perfusion and spectroscopy indicating smaller Glx peaks (Figure 2H).
Figure 2. Selected axial brain MR images at the level of the basal ganglia at day of life 14 (a-d) and 18 (e). Heterogeneous cerebral hyperperfusion improves over time between exams (a and e). Reduced diffusion is present with hyperintense signal in the callosal splenium and genu, sagittal stratum, internal capsules, frontal white matter, and to a lesser extent (with partial pseudonormalization) in the cerebral cortex and deep gray nuclei in correlation with the apparent diffusion coefficient (ADC) map (not shown) (b). Hyperintensity on T1WI (c) and hypointensity onT2WI (d) is present extensively throughout most of the cerebral cortex and mild signal changes are present affecting the cerebral deep gray nuclei. The cortical signal changes on the T1 and T1WI represent laminar necrosis. The unmyelinated cerebral white matter demonstrates excessive T1 and T2 prolongation. There is mild diffuse cerebral volume loss with prominent sulci and ventricles. Single voxel proton MR spectroscopy (MRS) over the left basal ganglia at day 14 (f and g) and 18 (h). Initially, ultrashort TE MRS (STEAM; TR 1500 ms, TE 14 ms) and short TE MRS (PRESS; TR 1500ms, TE 35ms) reveal substantial metabolic alterations including elevated glutamine/glutamate (Glx) reflecting the urea cycle deficit and hyperammonemia induced glutamine synthetase activation, reduced myoinositol (MI) due to osmotic buffering, marked actate (lac) reflecting anaerobic metabolism, elevated lipid, and reduced NAA: Creatine and Choline:Creatine ratios. Aspartate (Asp) is also elevated, only visible with the ultrashort TE sequence (f). On follow-up, metabolic disturbances improved, with decreasing glutamine, lactate, and lipid and increasing myoinositol and creatine (h).
Despite stable ammonia levels (15-110 µmol/L) in the following weeks, she continued to have electrographic only seizures despite maximized phenobarbital, levetiracetam, and midazolam infusion. Because these breakthrough seizures likely represented ongoing cortical injury despite normalized ammonia levels rather than a primary seizure condition, anti-epileptic drugs (AEDs) were slowly weaned along with sodium benzoate/sodium phenylacetate. Her last electrographic seizure was on day of life 21, and she continues to receive maintenance doses of topiramate and levetiracetam while awaiting liver transplantation for definitive enzymatic correction.
Discussion
Hyperammonemia can be the first clinical presentation of an inborn error of metabolism including a urea cycle disorder or organic acidemia and can provoke irreversible damage to the developing central nervous system (CNS), leading to cognitive impairment, seizures and cerebral palsy. 8 Hyperammonemic neonates and infants develop cortical atrophy with ventricular enlargement. 8 -10 The extent of the irreversible damages depends upon the maturation of the brain and on the magnitude and duration of the ammonia exposure. 11 Irreversibility mainly occurs in case of prolonged hyperammonemic crises and/or when blood ammonia reaches levels between 200 and 500 µM, during the 2 first years of life. 12 -17
It has previously shown that neonates with UCDs may present with seizures during HA. 7,18 However, most of the seizures are subclinical, and therefore only identified with prolonged continuous EEG. The mechanism of how hyperammonemia leads to the dysfunction of inhibitory neurotransmission has been explored in studies on astrocyte potassium buffering. It is proposed that the increase in brain glutamine and the resulting disturbed osmotic balance leads to impaired GABA-mediated neurotransmission. 19
The pattern of metabolites in this patient in relation to seizure occurrence shown in Figure 1B is interesting to note several features. Seizures began after stable ammonia levels (72-130 µmol/L) were achieved with hemodialysis (HD 2-4), representing initial acute brain injury. Early re-emergence of seizures was a proximal indicator of brain ammonia and glutamine re-elevation after the discontinuation of intravenous ammonia scavengers before detection remotely in plasma levels (HD4-5). Plasma glutamine remained within normal levels (376-819 µmol/L) for several days before, during, and after the second HA crisis despite ongoing refractory seizures. The persistent refractory seizures days after both plasma ammonia and glutamine levels were stable and the patient recovering suggests those seizures represent ongoing neuronal death rather than a primary seizure disorder or biochemical imbalance.
Although, the mechanism of ammonia neurotoxicity is still poorly understood and no specific treatment targeted for ammonia neuroprotection is available, there have been frequent reports of seizures in patients with urea cycle disorders. 4,9,20 Accumulations of ammonia, glutamine, and glutamate have been shown to exert toxic effects upon the brain. In animal models, the HA state leads to excitotoxic cell death and, with prolonged exposure, to the loss of NMDA receptors. These same receptors are altered in the sparse fur (Spf) mouse model of ornithine transcarbamylase deficiency (OTCD). 14 The postulated effects of elevated ammonia and glutamine include astrocytic swelling, an increase in blood brain barrier permeability, and disruption of energy through depletion of intermediaries of metabolism including altered amino acid and neurotransmitter levels. 15 -17,21
It has been hypothesized that brain MRI findings may reflect the differential distribution of brain injury involvement in UCD and may aid in assessing neurologic outcomes. 5,10,22 One previous report presented serial imaging in a patient with a UCD (OTCD) that show the progression of the disease. 22 Another study investigated the pattern of MRI findings in patients with neonatal UCDs as it relates to the severity of disease and neurodevelopmental outcomes at 2 years of age. It was concluded that cerebral involvement of injury on MRI and levels of biomarkers such as glutamine have the potential to be prognostic for outcome, although the limited data on this subject prevents imaging from being the sole determinate of decision-making. 21 MR spectroscopy allows us to determine that brain ammonia levels are elevated (by seeing elevations of the surrogate metabolite, glutamine) which may occur even with normal plasma ammonia and glutamine levels. Limited neuroimaging literature on CPS1 deficiency has previously demonstrated a territorial infarction, nonspecific widespread brain injury, and more specific patterns similar to what has been described with OTCD with involvement of the insular, deep perisylvian and basal ganglia regions. 6,23 -26 The diffuse, severe involvement of most components of both cerebral hemispheres with associated laminar necrosis suggests that the brain sustained a substantial insult that is unlikely to be entirely reversible in our patient. The reduced diffusion in parts of the cerebral white matter discovered on the first MR at 2 weeks of age could represent any combination of pre-Wallerian degeneration associated with the cortical injury, intramyelinic edema, and/or demyelination in the setting of residual/ongoing myelin injury or recurrent injury. While MRS using PRESS sequences have been preferred due to the higher signal to noise ratio, STEAM MRS enables visualization of the shorter echo-time (TE) metabolites. Previous work by our group has shown elevated glutamine and glutamate representing the hyperammonemia-induced glutamine synthetase activation and reduced myoinositol due to loss of osmotic buffering (Figure 1). STEAM MRS allowed visualization of the elevated Aspartate (Asp), which can be inferred to be a breakdown product of N-acetylaspartate (NAA) and marker of neuronal loss.
Conclusion
Based on our experience with this and prior UCD newborns, we propose a clinical neurodiagnostic protocol that can be implemented to better understand the clinical and biochemical time course of neonatal-onset UCDs and lead to early recognition and treatment of their neurologic complications (Figure 3). Early and comprehensive neurologic evaluation throughout the patient’s acute course may improve neurologic outcomes. We propose early prolonged continuous EEG monitoring with acute HA and monitoring during withdrawal of hemodialysis and intravenous scavengers to identify and treat acute seizures and to identify early relapse of HA. MRS TE settings should be adjusted to a lower level, from 35 ms to STEAM TE ultrashort (14 ms) sequences, in order to better understand the biochemical profile of proximal UCDs. We plan long term follow up of this infant with sequential MRI/MRS and neurocognitive screening to better characterize the pattern of brain injury and correlate with later functional issues and risk of developing of epilepsy.
Figure 3. Clinical protocol used for the management of neonatal hyperammonemia by the neurology consult service. Abbreviations: Magnetic Resonance Spectrometry (MRS), Time Echo (TE), Diffusion Tensor Imaging (DTI), Spoiled Gradient Recall (SPGR), Arterial Spin Labeling (ASL), video Electroencephalography (vEEG), Head Ultrasound (HUS), continuous Near-Infrared Spectrometry (cNIRS), Plasma Amino Acids (PAA), Urine Organic Acid (UOA), Continuous Renal Replacement Therapy (CRRT).
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NIH U54 HD061221 (AG); O’Malley Family Foundation grant (AG).
ORCID iD: Andrea Gropman, MD https://orcid.org/0000-0002-2106-6776 | Oral | DrugAdministrationRoute | CC BY-NC | 33644249 | 19,166,404 | 2021 |
What was the outcome of reaction 'COVID-19'? | Case series: COVID-19 in patients with mild to moderate myasthenia gravis in a National Referral Hospital in Indonesia.
During the COVID-19 pandemic, patients with myasthenia gravis (MG) are most likely to be affected by this situation. Corticosteroids and immunosuppressant agents increase the risk of severe infection. Furthermore, viral infection and some medications in COVID-19 may exacerbate MG symptoms.
We presented three patients with MG who contracted COVID-19. All of the patients had a favourable outcome. Only one patient who was not treated with corticosteroids or immunosuppressant therapy experienced deterioration of MG symptoms, while the other patients who received immunosuppressant therapy did not develop MG exacerbation. Surprisingly, azithromycin did not provoke myasthenic crisis (MC) in patients with normal MGFA classification.
Using immunosuppressant agents may not lead to MG deterioration and may not be related to unfavourable outcomes.
1 Introduction
Coronavirus disease 2019 (COVID-19) has developed rapidly into a global pandemic. New COVID-19 cases have continued to rise in Indonesia, especially in Jakarta, the capital, which has a dense population. As in other studies of patients with autoimmune disorders, myasthenia gravis (MG) patients are at increased risk of contracting severe COVID-19. Long-term immunosuppressive treatments in MG are predicted to increase the risk of serious infection. [1] Therefore, this population may be at risk of developing severe COVID-19 infection. Corticosteroid treatment in MG may act as a double-edged knife, as it gives an advantage in some stages of COVID-19 infection but can also worsen it. [2] On the other hand, some treatments for COVID-19, such as hydroxychloroquine [3] and azithromycin, are widely known to exacerbate MG symptoms or even cause myasthenic crisis.
There have been some case reports regarding COVID-19 in MG patients. [[4], [5], [6], [7]] The course of disease and outcomes varied greatly. More than 50% of MG patients hospitalized due to COVID-19 had severe courses and that led to death in 30% of patients. [5] COVID-19 may precipitate myasthenic crisis [6]. However, some cases had favourable outcomes. [4] [7] Here, we present three MG patients admitted with COVID-19 between July and October 2020. To the best of our knowledge, this is the first reported case series of resolved COVID-19 in MG patients in South-East Asia.
2 Case 1
This was a 25-year-old woman with an eight-year history of seropositive MG without episodes of severe exacerbations who was well controlled with 180 mg/day of pyridostigmine. Eight days before hospital admission, she developed fever, dry cough, muscle pain, and difficulty swallowing solid food. Subsequently, four days later she had diarrhoea.
Upon admission, she had fever, anosmia, and dry cough and was haemodynamically stable. The myasthenic symptoms were bilateral ptosis, nasal speech, difficulty swallowing, fatigue in chewing solid food, and mild weakness of neck flexion and shoulder abduction. The MG composite score was 9, and the MGFA classification at admission was IIIB (See Table 1). The SARS-CoV-2 PCR test by naso-oropharyngeal swabs was positive. Serum C-reactive protein, procalcitonin, and D-dimer levels were unremarkable. Although chest X-ray was normal, chest CT scan showed ground glass opacity (GGO) in both lungs (Fig. 1A, B).Table 1 Characteristics of patients with MG with COVID-19.
Table 1 Case 1 Case 2 Case 3
Age (sex) 25 (F) 49 (M) 42 (F)
History of MG (y) 2 4 6
Chronic MG treatment Pyridostigmine Pyridostigmine, azathioprine Pyridostigmine, methylprednisolone, mycophenolate mofetil
MGCS at admission 9 0 1
MGFA before COVID-19 I 0 I
MGFA classification at admission IIIb Normal I
MGCS at discharge 3 0 1
MGFA classification at discharge IIa Normal I
MG symptoms during COVID-19 Ptosis, nasal speech, shoulder and proximal limb weakness None Ptosis
COVID-19 symptoms Fever, anosmia, dry cough, myalgia, diarrhoea Fever, dry cough Fever, cough with mucus, tiredness
COVID-19 medication Vitamin C, N-acetylcysteine, ceftriaxone, azithromycin (discontinued) Azithromycin, vitamin C, paracetamol Hydroxychloroquine, N-acetylcysteine
Outcome Discharged home Discharged home Discharged home
Note: MGCS: myasthenia gravis composite score, y: years.
Fig. 1 Chest X-ray of Case 1 was normal (A). Chest CT scan of case 1 showed ground glass opacity (GGO) in bilateral lower lungs (B). Chest X-ray of case 2 showed left pleural effusion and infiltrates in bilateral lower lungs (C). Chest X-ray of case 3 showed left pleural effusion and infiltrates bilaterally perihilar and paracardial (D).
Fig. 1
She was admitted to the high care unit (HCU), supported with O2 2 L/min by nasal cannula, and her O2 saturation was 98%. She was treated with vitamin C 500 mg/day, N-acetylcysteine 600 mg/day, and ceftriaxone 2 g/day for 6 days. Azithromycin 500 mg/day was given only for one day by the internist and was stopped after consulting the neurologist regarding azithromycin-induced deterioration potential in MG. Pyridostigmine 240 mg/day was continued. Her myasthenic symptoms resolved on the 5th day, and she was transferred to theisolation ward without routine O2. She was discharged on the 14th day and continued to undergo home self-quarantine for the next 2 weeks.
3 Case 2
This was a 49-year-old man with a four year history of MG. He had been treated with pyridostigmine 180 mg/day and azathioprine 100 mg/day as routine MG treatment. Acetylcholine receptor antibody was never tested. He used to have unilateral ptosis that had been resolved for the last 3 years. One week before admission, he had fever and dry cough intermittently. Upon admission, his temperature was 37.8 °C, and he had no cough and was haemodynamically stable. There were no myasthenic symptoms during admission to the hospital or during hospitalization. His MG composite score was 0. The SARS-CoV-2 PCR test by naso-oropharyngeal swabs was positive. Chest X-ray showed left pleural effusion and infiltrates in bilateral lower lungs (Fig. 1C). The blood test showed increased CRP (35.7 mg/L), SGOT and SGPT levels (101 u/L and 148 u/L, respectively), and D-dimer (537 ng/mL). His O2 saturation was 96–98% with O2 2 L/min by nasal cannula intermittently. He was treated with azithromycin 500 mg/day for 5 days, vitamin C 3000 mg/day and paracetamol 1500 mg/day. Pyridostigmine and azathioprine were continued since his condition was stable and there was no deterioration. He was discharged 14 days after the SARS CoV-2 PCR test was negative.
4 Case 3
This was a 42-year-old woman with a 6-year history of MG who was treated with pyridostigmine 240 mg/day, methylprednisolone 4 mg/day, and mycophenolate mofetil 720 mg/day. Her myasthenic symptom was bilateral ptosis. For the last week before admission, she had fever, cough with mucus and tiredness. Physical examination revealed fever (38 °C), bilateral ptosis, and ronchi at bilateral lower chest auscultation. The MG composite score was 1, and the MGFA class was I. The SARS-CoV-2 PCR test by naso-oropharyngeal swabs was positive. Chest X-ray showed left pleural effusion and infiltrates bilaterally perihilar and paracardial. Blood tests showed leukocytosis with neutrophil dominance and increased CRP (167 mg/L). Her O2 saturation was 96–98% with O2 2 L/min by nasal cannula intermittently. She was treated with 200 mg/day hydroxychloroquine and 600 mg/day N-acetylcysteine for 7 days. The methylprednisolone dose was increased to 16 mg/day, and pyridostigmine and mycophenolate mofetil were continued as routine daily doses. She was discharged 14 days after the SARS-CoV-2 PCR test was negative. Her myasthenic symptoms did not deteriorate during hospitalization.
5 Discussion
Patients with autoimmune conditions such as MG are thought to be more prone to severe infection, including viral upper respiratory infection. Immunosuppressant treatment, such as corticosteroid and nonsteroid agents, increases the risk of infection in MG patients. [1] On the other hand, viral upper respiratory infection may lead to MG exacerbation. [8] The mechanism includes activation of the immune system triggered by infection, followed by enhanced T-cell signalling and upregulation of cytokines and proinflammatory molecules. [9] Among all three cases, none of them showed severe MG exacerbation, myasthenic crises during hospitalization, or severe COVID-19.
Despite continuing steroid and nonsteroid immunosuppressants in case 2 and case 3, those patients had favourable outcomes. Although the methylprednisolone dose was increased in case 3, her MG symptoms did not deteriorate, and COVID-19-related symptoms resolved. On the other hand, Case 1, who was not on corticosteroids or immunosuppressants, experienced deterioration in her MG symptoms. Corticosteroids can be beneficial for improving MG as well as COVID-19 symptoms. [2] Long-term use of steroids in MG does not worsen COVID-19. [4] Using immunosuppressant agents in MG during the COVID-19 pandemic remains a challenge. A report from Brazil of MG patients with COVID-19 who were already on immunosuppressants showed favourable outcomes. On the other hand, 4 out of 5 patients who died did not receive immunosuppressant agents. [5] Immunosuppressant therapy is likely to be beneficial in COVID-19 cases with MG by reducing hyperinflammation and cytokine storms. [10] Therefore, corticosteroid and immunosuppressant agents should be continued in MG patients with or without SARS-CoV-2 infection. Despite these results, MG patients should practice vigilance and take extra precautions to reduce the risk of contracting COVID-19.
Azithromycin and hydroxychloroquine have been considered to contribute to MG exacerbation. [3,8] Cases 2 and 3 did not show any deterioration of MG symptoms during hospitalization despite administration of azithromycin and hydroxychloroquine. Thus, azithromycin and hydroxychloroquine may not be harmful in MG patients with mild MGFA classification but still require caution.
Acknowledgements
This publication is funded by 10.13039/501100006378 Universitas Indonesia . | Recovered | ReactionOutcome | CC BY-NC-ND | 33644426 | 19,587,759 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute myocardial infarction'. | Multiple spontaneous coronary artery dissections associated with intravenous daunorubicin treatment for acute myelocytic leukaemia: a case report.
Multiple spontaneous coronary artery dissection (SCAD) is a rare condition which may lead to serious consequences such as sudden cardiac death, acute myocardial infarction (AMI), and acute heart failure.
In this paper, we report the case of a 57-year-old woman with acute myelocytic leukaemia who was undergoing her second phase of chemotherapy. After the first induction cycle of intravenous infusion of daunorubicin, the patient experienced chest pain, shortness of breath, and low blood pressure. The electrocardiograms revealed significant ST-elevation in the D1, aVL, and V2-V6 leads, which indicated AMI. Coronary catheterization showed spontaneous coronary dissection in the mid-left descending coronary artery and first obtuse marginal artery of the circumflex. The patient died immediately.
This is the first reported case of multiple SCAD associated with intravenous (IV) daunorubicin infusion. We also reviewed the literature and proposed the mechanism of this complication.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Multiple spontaneous coronary artery dissection is a rare condition. It can cause fatal consequences such as sudden cardiac death, acute myocardial infarction, and acute heart failure.
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of daunorubicin for 3 days and cytarabine for 7 days.
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections.
Introduction
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of 45 mg/m2 daunorubicin for 3 days with 100–200 mg/m2 cytarabine infusion for 7 days.1 Löwenberg et al.2 reported an early mortality rate of 12% after the first two cycles of conventional dose of daunorubicin. However, sudden cardiac death following spontaneous dissection has not been reported yet.
Spontaneous coronary artery dissection (SCAD) is defined as a non-iatrogenic, non-atherosclerotic, and non-traumatic spontaneous separation of the coronary artery wall.3 More than 90% of SCAD cases occurs in women with negligible cardiovascular risk factors.4 Moreover, SCAD is highly associated with fibromuscular dysplasia (FMD)5 and caused by other risk factors such as hormonal therapy, Marfan syndrome, vascular Ehlers–Danlos, Loyes–Dietz syndrome, and polycystic kidney.6 However, no study has indicated that daunorubicin could be associated with SCAD.
Herein, we report a case of multiple SCAD in a patient with AML type M3. During the second phase of chemotherapy with daunorubicin and cytarabine, she experienced acute myocardial infarction (AMI) with ST-elevation and died suddenly.
Timeline
Day 0 A 57-year-old woman presented with left lower arm purpura and several weeks old of left thigh intra-muscle haemorrhage in the left thigh.
Day 1 She was diagnosed with acute myeloid leukaemia type M3. Chemotherapy with cytarabine and tretinoin was administered.
Day 3 The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
Day 30 (1 month after discharge) The patient was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura.
Day 31 The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Day 31 Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain.
Day 31 The patient was intubated and transferred to the intensive care unit for mechanical ventilation.
Day 31 The patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections. Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Case presentation
A 57-year-old woman presented with left lower arm purpura and several weeks of left thigh intra-muscle haemorrhage (IMH) in the left thigh. She was diagnosed with AML type M3. Chemotherapy with cytarabine and tretinoin was administered. The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
One month later, she was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura. She had no history of hypertension, diabetes, smoking, heart failure, or other risk factors for coronary diseases. She had no complaint of fever, weight loss, or chest pain. She denied any occurrence of lung diseases in the past. On admission, a chest X-ray showed the lung was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion (Figure 1).
Figure 1 Chest X-ray on admission showed lung clear, no pulmonary infiltration or pleuro-pericardial effusion.
The complete blood count showed anaemia with Hb of 7.5 g/dL, significant leucocytosis with leucocyte count of 67.7 × 109/L, neutrophil concentration of 86.1%, and thrombocytopenia (42 G/L). The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain. Physical examination showed wheezing, respiratory coarse crackles, and a 100-150 b.p.m. heart rate. Blood pressure dropped from 130/70 to 100/60 mmHg. The SpO2 decreased from 95% to 73% with 15 L O2/min. D-dimer, prothrombin, and fibrinogen were 65.230 ng/mL, 61%, and 1.04 g/L, respectively.
Arterial blood gas analysis revealed a developed respiratory failure with 7.23 pH, PaCO2 of 52 mmHg, and a PaO2 of 54 mmHg. Therefore, she was intubated and transferred to the intensive care unit for mechanical ventilation. The chest radiograph revealed bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces (Figure 2). And the 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2 to V6, and DI, aVL, which suggested a typical AMI (Figure 3).
Figure 2 Chest radiograph revealing bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces.
Figure 3 A 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2–V6, and DI, aVL.
Transthoracic echocardiography showed the left ventricular ejection fraction of 50%, apical and septal hypokinaesia, with systolic pulmonary arterial pressure of 48 mmHg.
Due to suspected AMI, the patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections (Figures 4–6). Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Figure 4 Left caudal angiographic view showing mid-circumflex dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 5 Left cranial angiographic view showing mid-descending artery dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 6 Contrast remained at the positions of dissections (arrows).
Discussion
To the best of our knowledge, this is first report on multiple SCAD associated with daunorubicin intravenous infusion for AML. According to the American Heart Association scientific statement on SCAD, predisposing conditions for SCAD include FMD, pregnancy, multiparity, hereditary arteriopathy, connective tissue disorders, exogenous hormonal therapy, systemic inflammatory diseases, migraine headaches, and coronary spasms.7 However, a paucity of case reports exists regarding the usage of intravenous daunorubicin in AML treatment.
Spontaneous coronary artery dissection is characterized by spontaneous IMH within the coronary artery wall, which is confirmed by intravascular ultrasound,8 histopathology, case reports, and case series.9–11 Clinical symptoms of SCAD are usually chest pain, typically consistent with acute coronary syndrome, while 26–87% and 13–69% patients present with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), respectively.12 Our case presented with typical chest pain and ST-elevation on electrocardiogram (ECG). Thereafter, the patient immediately experienced a cardiogenic shock, which primarily caused the collapse.
We performed an in-depth literature searches to uncover the pathological mechanism underlying this episode of cardiovascular complication of daunorubicin. However, we could not find any published literature pertaining to this condition. Daunorubicin is an anthracycline, antineoplastic, antibiotic drug. It exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication; DNA repair; and RNA and protein synthesis.13 Lawrence et al. reported a case of AML involving acute heart failure as a complication after intensified treatment with daunorubicin, with decrease in ejection fraction (EF) from 60% to 10%, which is recovered after few months of medical treatment. Additionally, Takotsubo cardiomyopathy was associated with the use of daunorubicin.14 Thus, these cases indicate the acute cardiotoxicity of daunorubicin.
Disseminated intravascular coagulation (DIC) or ‘late’ differentiate syndrome may contribute to the severity of the patient’s condition. According to the diagnostic scoring system for DIC, this patient had platelet count <50 (2 points) and D-dimer was five times above the upper limit of normal (3 points).15 Consequently, she got an overt DIC. However, changes in ECG tracing and coronary dissections cannot be explained by DIC. Disseminated intravascular coagulation maybe a contributory factor but not a cause of the patient’s collapse. Regarding ‘late’ differentiate syndrome, a chest X-ray at admission was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion. Moreover, clinical symptoms/signs that lead to high suspicion of DS include dyspnoea, oedema, unexplained fever, hypotension, weight gain more than 5 kg, and/or vascular leakage syndrome, were absent. Therefore, it was less likely that the patient had a ‘late’ differentiate syndrome.
We treated the patient according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML.16 However, the risk of cardiotoxicity, specifically that of spontaneous coronary dissection, has not yet been established. We believe that our report can create awareness regarding the adverse effects of daunorubicin among physicians who prescribe daunorubicin for the treatment of AML regardless of the drug’s dosage and timing.
We could not ascertain whether the treatment of the complication in our case was adequate. Initially, we intended to perform diagnostic angiography followed by coronary stenting or coronary artery bypass grafting (CABG) surgery. However, as the patient collapsed sooner, we were unable to perform percutaneous coronary intervention (PCI). We believe that PCI may not be a suitable treatment of SCAD because guidewires may enter the false lumen and occlude the true lumen. In our patient, there were multiple dissections of the mid-left descending coronary artery and left circumflex (LCX) that led to more complications. Meanwhile, we also found a paucity of evidence to support CABG in SCAD. Only one small study showed the initial success of CABG for treatment of SCAD.17
Conclusion
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections as illustrated in this case. Following the evaluation of the patient, immediate medical decision-making and accurate treatment are warranted in such cases as the risks of mortality is quite high.
Lead author biography
Dr Do Van Chien, MD, PhD, graduated from Volgograd Medical School, Russia with distinction in 2006 and currently works as Deputy Head, Department of Cardiology, 108 Central Military Hospital, Hanoi, Vietnam. He was also a fellow of interventional cardiology at Sydney Concord Repatriation, Australia in 2011 and National Heart Centre Singapore in 2014. His clinical and research interests include interventional cardiology, echocardiography, and cardiomyopathy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: This report is funded by 108 Central Military Hospital, Hanoi, Vietnam.
Supplementary Material
ytaa427_Supplementary_Data Click here for additional data file. | CYTARABINE, DAUNORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33644638 | 19,020,123 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiogenic shock'. | Multiple spontaneous coronary artery dissections associated with intravenous daunorubicin treatment for acute myelocytic leukaemia: a case report.
Multiple spontaneous coronary artery dissection (SCAD) is a rare condition which may lead to serious consequences such as sudden cardiac death, acute myocardial infarction (AMI), and acute heart failure.
In this paper, we report the case of a 57-year-old woman with acute myelocytic leukaemia who was undergoing her second phase of chemotherapy. After the first induction cycle of intravenous infusion of daunorubicin, the patient experienced chest pain, shortness of breath, and low blood pressure. The electrocardiograms revealed significant ST-elevation in the D1, aVL, and V2-V6 leads, which indicated AMI. Coronary catheterization showed spontaneous coronary dissection in the mid-left descending coronary artery and first obtuse marginal artery of the circumflex. The patient died immediately.
This is the first reported case of multiple SCAD associated with intravenous (IV) daunorubicin infusion. We also reviewed the literature and proposed the mechanism of this complication.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Multiple spontaneous coronary artery dissection is a rare condition. It can cause fatal consequences such as sudden cardiac death, acute myocardial infarction, and acute heart failure.
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of daunorubicin for 3 days and cytarabine for 7 days.
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections.
Introduction
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of 45 mg/m2 daunorubicin for 3 days with 100–200 mg/m2 cytarabine infusion for 7 days.1 Löwenberg et al.2 reported an early mortality rate of 12% after the first two cycles of conventional dose of daunorubicin. However, sudden cardiac death following spontaneous dissection has not been reported yet.
Spontaneous coronary artery dissection (SCAD) is defined as a non-iatrogenic, non-atherosclerotic, and non-traumatic spontaneous separation of the coronary artery wall.3 More than 90% of SCAD cases occurs in women with negligible cardiovascular risk factors.4 Moreover, SCAD is highly associated with fibromuscular dysplasia (FMD)5 and caused by other risk factors such as hormonal therapy, Marfan syndrome, vascular Ehlers–Danlos, Loyes–Dietz syndrome, and polycystic kidney.6 However, no study has indicated that daunorubicin could be associated with SCAD.
Herein, we report a case of multiple SCAD in a patient with AML type M3. During the second phase of chemotherapy with daunorubicin and cytarabine, she experienced acute myocardial infarction (AMI) with ST-elevation and died suddenly.
Timeline
Day 0 A 57-year-old woman presented with left lower arm purpura and several weeks old of left thigh intra-muscle haemorrhage in the left thigh.
Day 1 She was diagnosed with acute myeloid leukaemia type M3. Chemotherapy with cytarabine and tretinoin was administered.
Day 3 The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
Day 30 (1 month after discharge) The patient was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura.
Day 31 The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Day 31 Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain.
Day 31 The patient was intubated and transferred to the intensive care unit for mechanical ventilation.
Day 31 The patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections. Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Case presentation
A 57-year-old woman presented with left lower arm purpura and several weeks of left thigh intra-muscle haemorrhage (IMH) in the left thigh. She was diagnosed with AML type M3. Chemotherapy with cytarabine and tretinoin was administered. The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
One month later, she was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura. She had no history of hypertension, diabetes, smoking, heart failure, or other risk factors for coronary diseases. She had no complaint of fever, weight loss, or chest pain. She denied any occurrence of lung diseases in the past. On admission, a chest X-ray showed the lung was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion (Figure 1).
Figure 1 Chest X-ray on admission showed lung clear, no pulmonary infiltration or pleuro-pericardial effusion.
The complete blood count showed anaemia with Hb of 7.5 g/dL, significant leucocytosis with leucocyte count of 67.7 × 109/L, neutrophil concentration of 86.1%, and thrombocytopenia (42 G/L). The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain. Physical examination showed wheezing, respiratory coarse crackles, and a 100-150 b.p.m. heart rate. Blood pressure dropped from 130/70 to 100/60 mmHg. The SpO2 decreased from 95% to 73% with 15 L O2/min. D-dimer, prothrombin, and fibrinogen were 65.230 ng/mL, 61%, and 1.04 g/L, respectively.
Arterial blood gas analysis revealed a developed respiratory failure with 7.23 pH, PaCO2 of 52 mmHg, and a PaO2 of 54 mmHg. Therefore, she was intubated and transferred to the intensive care unit for mechanical ventilation. The chest radiograph revealed bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces (Figure 2). And the 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2 to V6, and DI, aVL, which suggested a typical AMI (Figure 3).
Figure 2 Chest radiograph revealing bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces.
Figure 3 A 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2–V6, and DI, aVL.
Transthoracic echocardiography showed the left ventricular ejection fraction of 50%, apical and septal hypokinaesia, with systolic pulmonary arterial pressure of 48 mmHg.
Due to suspected AMI, the patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections (Figures 4–6). Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Figure 4 Left caudal angiographic view showing mid-circumflex dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 5 Left cranial angiographic view showing mid-descending artery dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 6 Contrast remained at the positions of dissections (arrows).
Discussion
To the best of our knowledge, this is first report on multiple SCAD associated with daunorubicin intravenous infusion for AML. According to the American Heart Association scientific statement on SCAD, predisposing conditions for SCAD include FMD, pregnancy, multiparity, hereditary arteriopathy, connective tissue disorders, exogenous hormonal therapy, systemic inflammatory diseases, migraine headaches, and coronary spasms.7 However, a paucity of case reports exists regarding the usage of intravenous daunorubicin in AML treatment.
Spontaneous coronary artery dissection is characterized by spontaneous IMH within the coronary artery wall, which is confirmed by intravascular ultrasound,8 histopathology, case reports, and case series.9–11 Clinical symptoms of SCAD are usually chest pain, typically consistent with acute coronary syndrome, while 26–87% and 13–69% patients present with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), respectively.12 Our case presented with typical chest pain and ST-elevation on electrocardiogram (ECG). Thereafter, the patient immediately experienced a cardiogenic shock, which primarily caused the collapse.
We performed an in-depth literature searches to uncover the pathological mechanism underlying this episode of cardiovascular complication of daunorubicin. However, we could not find any published literature pertaining to this condition. Daunorubicin is an anthracycline, antineoplastic, antibiotic drug. It exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication; DNA repair; and RNA and protein synthesis.13 Lawrence et al. reported a case of AML involving acute heart failure as a complication after intensified treatment with daunorubicin, with decrease in ejection fraction (EF) from 60% to 10%, which is recovered after few months of medical treatment. Additionally, Takotsubo cardiomyopathy was associated with the use of daunorubicin.14 Thus, these cases indicate the acute cardiotoxicity of daunorubicin.
Disseminated intravascular coagulation (DIC) or ‘late’ differentiate syndrome may contribute to the severity of the patient’s condition. According to the diagnostic scoring system for DIC, this patient had platelet count <50 (2 points) and D-dimer was five times above the upper limit of normal (3 points).15 Consequently, she got an overt DIC. However, changes in ECG tracing and coronary dissections cannot be explained by DIC. Disseminated intravascular coagulation maybe a contributory factor but not a cause of the patient’s collapse. Regarding ‘late’ differentiate syndrome, a chest X-ray at admission was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion. Moreover, clinical symptoms/signs that lead to high suspicion of DS include dyspnoea, oedema, unexplained fever, hypotension, weight gain more than 5 kg, and/or vascular leakage syndrome, were absent. Therefore, it was less likely that the patient had a ‘late’ differentiate syndrome.
We treated the patient according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML.16 However, the risk of cardiotoxicity, specifically that of spontaneous coronary dissection, has not yet been established. We believe that our report can create awareness regarding the adverse effects of daunorubicin among physicians who prescribe daunorubicin for the treatment of AML regardless of the drug’s dosage and timing.
We could not ascertain whether the treatment of the complication in our case was adequate. Initially, we intended to perform diagnostic angiography followed by coronary stenting or coronary artery bypass grafting (CABG) surgery. However, as the patient collapsed sooner, we were unable to perform percutaneous coronary intervention (PCI). We believe that PCI may not be a suitable treatment of SCAD because guidewires may enter the false lumen and occlude the true lumen. In our patient, there were multiple dissections of the mid-left descending coronary artery and left circumflex (LCX) that led to more complications. Meanwhile, we also found a paucity of evidence to support CABG in SCAD. Only one small study showed the initial success of CABG for treatment of SCAD.17
Conclusion
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections as illustrated in this case. Following the evaluation of the patient, immediate medical decision-making and accurate treatment are warranted in such cases as the risks of mortality is quite high.
Lead author biography
Dr Do Van Chien, MD, PhD, graduated from Volgograd Medical School, Russia with distinction in 2006 and currently works as Deputy Head, Department of Cardiology, 108 Central Military Hospital, Hanoi, Vietnam. He was also a fellow of interventional cardiology at Sydney Concord Repatriation, Australia in 2011 and National Heart Centre Singapore in 2014. His clinical and research interests include interventional cardiology, echocardiography, and cardiomyopathy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: This report is funded by 108 Central Military Hospital, Hanoi, Vietnam.
Supplementary Material
ytaa427_Supplementary_Data Click here for additional data file. | CYTARABINE, DAUNORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33644638 | 19,020,123 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coronary artery dissection'. | Multiple spontaneous coronary artery dissections associated with intravenous daunorubicin treatment for acute myelocytic leukaemia: a case report.
Multiple spontaneous coronary artery dissection (SCAD) is a rare condition which may lead to serious consequences such as sudden cardiac death, acute myocardial infarction (AMI), and acute heart failure.
In this paper, we report the case of a 57-year-old woman with acute myelocytic leukaemia who was undergoing her second phase of chemotherapy. After the first induction cycle of intravenous infusion of daunorubicin, the patient experienced chest pain, shortness of breath, and low blood pressure. The electrocardiograms revealed significant ST-elevation in the D1, aVL, and V2-V6 leads, which indicated AMI. Coronary catheterization showed spontaneous coronary dissection in the mid-left descending coronary artery and first obtuse marginal artery of the circumflex. The patient died immediately.
This is the first reported case of multiple SCAD associated with intravenous (IV) daunorubicin infusion. We also reviewed the literature and proposed the mechanism of this complication.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Multiple spontaneous coronary artery dissection is a rare condition. It can cause fatal consequences such as sudden cardiac death, acute myocardial infarction, and acute heart failure.
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of daunorubicin for 3 days and cytarabine for 7 days.
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections.
Introduction
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of 45 mg/m2 daunorubicin for 3 days with 100–200 mg/m2 cytarabine infusion for 7 days.1 Löwenberg et al.2 reported an early mortality rate of 12% after the first two cycles of conventional dose of daunorubicin. However, sudden cardiac death following spontaneous dissection has not been reported yet.
Spontaneous coronary artery dissection (SCAD) is defined as a non-iatrogenic, non-atherosclerotic, and non-traumatic spontaneous separation of the coronary artery wall.3 More than 90% of SCAD cases occurs in women with negligible cardiovascular risk factors.4 Moreover, SCAD is highly associated with fibromuscular dysplasia (FMD)5 and caused by other risk factors such as hormonal therapy, Marfan syndrome, vascular Ehlers–Danlos, Loyes–Dietz syndrome, and polycystic kidney.6 However, no study has indicated that daunorubicin could be associated with SCAD.
Herein, we report a case of multiple SCAD in a patient with AML type M3. During the second phase of chemotherapy with daunorubicin and cytarabine, she experienced acute myocardial infarction (AMI) with ST-elevation and died suddenly.
Timeline
Day 0 A 57-year-old woman presented with left lower arm purpura and several weeks old of left thigh intra-muscle haemorrhage in the left thigh.
Day 1 She was diagnosed with acute myeloid leukaemia type M3. Chemotherapy with cytarabine and tretinoin was administered.
Day 3 The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
Day 30 (1 month after discharge) The patient was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura.
Day 31 The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Day 31 Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain.
Day 31 The patient was intubated and transferred to the intensive care unit for mechanical ventilation.
Day 31 The patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections. Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Case presentation
A 57-year-old woman presented with left lower arm purpura and several weeks of left thigh intra-muscle haemorrhage (IMH) in the left thigh. She was diagnosed with AML type M3. Chemotherapy with cytarabine and tretinoin was administered. The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
One month later, she was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura. She had no history of hypertension, diabetes, smoking, heart failure, or other risk factors for coronary diseases. She had no complaint of fever, weight loss, or chest pain. She denied any occurrence of lung diseases in the past. On admission, a chest X-ray showed the lung was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion (Figure 1).
Figure 1 Chest X-ray on admission showed lung clear, no pulmonary infiltration or pleuro-pericardial effusion.
The complete blood count showed anaemia with Hb of 7.5 g/dL, significant leucocytosis with leucocyte count of 67.7 × 109/L, neutrophil concentration of 86.1%, and thrombocytopenia (42 G/L). The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain. Physical examination showed wheezing, respiratory coarse crackles, and a 100-150 b.p.m. heart rate. Blood pressure dropped from 130/70 to 100/60 mmHg. The SpO2 decreased from 95% to 73% with 15 L O2/min. D-dimer, prothrombin, and fibrinogen were 65.230 ng/mL, 61%, and 1.04 g/L, respectively.
Arterial blood gas analysis revealed a developed respiratory failure with 7.23 pH, PaCO2 of 52 mmHg, and a PaO2 of 54 mmHg. Therefore, she was intubated and transferred to the intensive care unit for mechanical ventilation. The chest radiograph revealed bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces (Figure 2). And the 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2 to V6, and DI, aVL, which suggested a typical AMI (Figure 3).
Figure 2 Chest radiograph revealing bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces.
Figure 3 A 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2–V6, and DI, aVL.
Transthoracic echocardiography showed the left ventricular ejection fraction of 50%, apical and septal hypokinaesia, with systolic pulmonary arterial pressure of 48 mmHg.
Due to suspected AMI, the patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections (Figures 4–6). Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Figure 4 Left caudal angiographic view showing mid-circumflex dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 5 Left cranial angiographic view showing mid-descending artery dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 6 Contrast remained at the positions of dissections (arrows).
Discussion
To the best of our knowledge, this is first report on multiple SCAD associated with daunorubicin intravenous infusion for AML. According to the American Heart Association scientific statement on SCAD, predisposing conditions for SCAD include FMD, pregnancy, multiparity, hereditary arteriopathy, connective tissue disorders, exogenous hormonal therapy, systemic inflammatory diseases, migraine headaches, and coronary spasms.7 However, a paucity of case reports exists regarding the usage of intravenous daunorubicin in AML treatment.
Spontaneous coronary artery dissection is characterized by spontaneous IMH within the coronary artery wall, which is confirmed by intravascular ultrasound,8 histopathology, case reports, and case series.9–11 Clinical symptoms of SCAD are usually chest pain, typically consistent with acute coronary syndrome, while 26–87% and 13–69% patients present with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), respectively.12 Our case presented with typical chest pain and ST-elevation on electrocardiogram (ECG). Thereafter, the patient immediately experienced a cardiogenic shock, which primarily caused the collapse.
We performed an in-depth literature searches to uncover the pathological mechanism underlying this episode of cardiovascular complication of daunorubicin. However, we could not find any published literature pertaining to this condition. Daunorubicin is an anthracycline, antineoplastic, antibiotic drug. It exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication; DNA repair; and RNA and protein synthesis.13 Lawrence et al. reported a case of AML involving acute heart failure as a complication after intensified treatment with daunorubicin, with decrease in ejection fraction (EF) from 60% to 10%, which is recovered after few months of medical treatment. Additionally, Takotsubo cardiomyopathy was associated with the use of daunorubicin.14 Thus, these cases indicate the acute cardiotoxicity of daunorubicin.
Disseminated intravascular coagulation (DIC) or ‘late’ differentiate syndrome may contribute to the severity of the patient’s condition. According to the diagnostic scoring system for DIC, this patient had platelet count <50 (2 points) and D-dimer was five times above the upper limit of normal (3 points).15 Consequently, she got an overt DIC. However, changes in ECG tracing and coronary dissections cannot be explained by DIC. Disseminated intravascular coagulation maybe a contributory factor but not a cause of the patient’s collapse. Regarding ‘late’ differentiate syndrome, a chest X-ray at admission was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion. Moreover, clinical symptoms/signs that lead to high suspicion of DS include dyspnoea, oedema, unexplained fever, hypotension, weight gain more than 5 kg, and/or vascular leakage syndrome, were absent. Therefore, it was less likely that the patient had a ‘late’ differentiate syndrome.
We treated the patient according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML.16 However, the risk of cardiotoxicity, specifically that of spontaneous coronary dissection, has not yet been established. We believe that our report can create awareness regarding the adverse effects of daunorubicin among physicians who prescribe daunorubicin for the treatment of AML regardless of the drug’s dosage and timing.
We could not ascertain whether the treatment of the complication in our case was adequate. Initially, we intended to perform diagnostic angiography followed by coronary stenting or coronary artery bypass grafting (CABG) surgery. However, as the patient collapsed sooner, we were unable to perform percutaneous coronary intervention (PCI). We believe that PCI may not be a suitable treatment of SCAD because guidewires may enter the false lumen and occlude the true lumen. In our patient, there were multiple dissections of the mid-left descending coronary artery and left circumflex (LCX) that led to more complications. Meanwhile, we also found a paucity of evidence to support CABG in SCAD. Only one small study showed the initial success of CABG for treatment of SCAD.17
Conclusion
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections as illustrated in this case. Following the evaluation of the patient, immediate medical decision-making and accurate treatment are warranted in such cases as the risks of mortality is quite high.
Lead author biography
Dr Do Van Chien, MD, PhD, graduated from Volgograd Medical School, Russia with distinction in 2006 and currently works as Deputy Head, Department of Cardiology, 108 Central Military Hospital, Hanoi, Vietnam. He was also a fellow of interventional cardiology at Sydney Concord Repatriation, Australia in 2011 and National Heart Centre Singapore in 2014. His clinical and research interests include interventional cardiology, echocardiography, and cardiomyopathy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: This report is funded by 108 Central Military Hospital, Hanoi, Vietnam.
Supplementary Material
ytaa427_Supplementary_Data Click here for additional data file. | CYTARABINE, DAUNORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33644638 | 19,020,123 | 2021-01 |
What was the administration route of drug 'DAUNORUBICIN HYDROCHLORIDE'? | Multiple spontaneous coronary artery dissections associated with intravenous daunorubicin treatment for acute myelocytic leukaemia: a case report.
Multiple spontaneous coronary artery dissection (SCAD) is a rare condition which may lead to serious consequences such as sudden cardiac death, acute myocardial infarction (AMI), and acute heart failure.
In this paper, we report the case of a 57-year-old woman with acute myelocytic leukaemia who was undergoing her second phase of chemotherapy. After the first induction cycle of intravenous infusion of daunorubicin, the patient experienced chest pain, shortness of breath, and low blood pressure. The electrocardiograms revealed significant ST-elevation in the D1, aVL, and V2-V6 leads, which indicated AMI. Coronary catheterization showed spontaneous coronary dissection in the mid-left descending coronary artery and first obtuse marginal artery of the circumflex. The patient died immediately.
This is the first reported case of multiple SCAD associated with intravenous (IV) daunorubicin infusion. We also reviewed the literature and proposed the mechanism of this complication.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Multiple spontaneous coronary artery dissection is a rare condition. It can cause fatal consequences such as sudden cardiac death, acute myocardial infarction, and acute heart failure.
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of daunorubicin for 3 days and cytarabine for 7 days.
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections.
Introduction
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of 45 mg/m2 daunorubicin for 3 days with 100–200 mg/m2 cytarabine infusion for 7 days.1 Löwenberg et al.2 reported an early mortality rate of 12% after the first two cycles of conventional dose of daunorubicin. However, sudden cardiac death following spontaneous dissection has not been reported yet.
Spontaneous coronary artery dissection (SCAD) is defined as a non-iatrogenic, non-atherosclerotic, and non-traumatic spontaneous separation of the coronary artery wall.3 More than 90% of SCAD cases occurs in women with negligible cardiovascular risk factors.4 Moreover, SCAD is highly associated with fibromuscular dysplasia (FMD)5 and caused by other risk factors such as hormonal therapy, Marfan syndrome, vascular Ehlers–Danlos, Loyes–Dietz syndrome, and polycystic kidney.6 However, no study has indicated that daunorubicin could be associated with SCAD.
Herein, we report a case of multiple SCAD in a patient with AML type M3. During the second phase of chemotherapy with daunorubicin and cytarabine, she experienced acute myocardial infarction (AMI) with ST-elevation and died suddenly.
Timeline
Day 0 A 57-year-old woman presented with left lower arm purpura and several weeks old of left thigh intra-muscle haemorrhage in the left thigh.
Day 1 She was diagnosed with acute myeloid leukaemia type M3. Chemotherapy with cytarabine and tretinoin was administered.
Day 3 The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
Day 30 (1 month after discharge) The patient was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura.
Day 31 The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Day 31 Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain.
Day 31 The patient was intubated and transferred to the intensive care unit for mechanical ventilation.
Day 31 The patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections. Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Case presentation
A 57-year-old woman presented with left lower arm purpura and several weeks of left thigh intra-muscle haemorrhage (IMH) in the left thigh. She was diagnosed with AML type M3. Chemotherapy with cytarabine and tretinoin was administered. The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
One month later, she was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura. She had no history of hypertension, diabetes, smoking, heart failure, or other risk factors for coronary diseases. She had no complaint of fever, weight loss, or chest pain. She denied any occurrence of lung diseases in the past. On admission, a chest X-ray showed the lung was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion (Figure 1).
Figure 1 Chest X-ray on admission showed lung clear, no pulmonary infiltration or pleuro-pericardial effusion.
The complete blood count showed anaemia with Hb of 7.5 g/dL, significant leucocytosis with leucocyte count of 67.7 × 109/L, neutrophil concentration of 86.1%, and thrombocytopenia (42 G/L). The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain. Physical examination showed wheezing, respiratory coarse crackles, and a 100-150 b.p.m. heart rate. Blood pressure dropped from 130/70 to 100/60 mmHg. The SpO2 decreased from 95% to 73% with 15 L O2/min. D-dimer, prothrombin, and fibrinogen were 65.230 ng/mL, 61%, and 1.04 g/L, respectively.
Arterial blood gas analysis revealed a developed respiratory failure with 7.23 pH, PaCO2 of 52 mmHg, and a PaO2 of 54 mmHg. Therefore, she was intubated and transferred to the intensive care unit for mechanical ventilation. The chest radiograph revealed bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces (Figure 2). And the 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2 to V6, and DI, aVL, which suggested a typical AMI (Figure 3).
Figure 2 Chest radiograph revealing bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces.
Figure 3 A 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2–V6, and DI, aVL.
Transthoracic echocardiography showed the left ventricular ejection fraction of 50%, apical and septal hypokinaesia, with systolic pulmonary arterial pressure of 48 mmHg.
Due to suspected AMI, the patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections (Figures 4–6). Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Figure 4 Left caudal angiographic view showing mid-circumflex dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 5 Left cranial angiographic view showing mid-descending artery dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 6 Contrast remained at the positions of dissections (arrows).
Discussion
To the best of our knowledge, this is first report on multiple SCAD associated with daunorubicin intravenous infusion for AML. According to the American Heart Association scientific statement on SCAD, predisposing conditions for SCAD include FMD, pregnancy, multiparity, hereditary arteriopathy, connective tissue disorders, exogenous hormonal therapy, systemic inflammatory diseases, migraine headaches, and coronary spasms.7 However, a paucity of case reports exists regarding the usage of intravenous daunorubicin in AML treatment.
Spontaneous coronary artery dissection is characterized by spontaneous IMH within the coronary artery wall, which is confirmed by intravascular ultrasound,8 histopathology, case reports, and case series.9–11 Clinical symptoms of SCAD are usually chest pain, typically consistent with acute coronary syndrome, while 26–87% and 13–69% patients present with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), respectively.12 Our case presented with typical chest pain and ST-elevation on electrocardiogram (ECG). Thereafter, the patient immediately experienced a cardiogenic shock, which primarily caused the collapse.
We performed an in-depth literature searches to uncover the pathological mechanism underlying this episode of cardiovascular complication of daunorubicin. However, we could not find any published literature pertaining to this condition. Daunorubicin is an anthracycline, antineoplastic, antibiotic drug. It exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication; DNA repair; and RNA and protein synthesis.13 Lawrence et al. reported a case of AML involving acute heart failure as a complication after intensified treatment with daunorubicin, with decrease in ejection fraction (EF) from 60% to 10%, which is recovered after few months of medical treatment. Additionally, Takotsubo cardiomyopathy was associated with the use of daunorubicin.14 Thus, these cases indicate the acute cardiotoxicity of daunorubicin.
Disseminated intravascular coagulation (DIC) or ‘late’ differentiate syndrome may contribute to the severity of the patient’s condition. According to the diagnostic scoring system for DIC, this patient had platelet count <50 (2 points) and D-dimer was five times above the upper limit of normal (3 points).15 Consequently, she got an overt DIC. However, changes in ECG tracing and coronary dissections cannot be explained by DIC. Disseminated intravascular coagulation maybe a contributory factor but not a cause of the patient’s collapse. Regarding ‘late’ differentiate syndrome, a chest X-ray at admission was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion. Moreover, clinical symptoms/signs that lead to high suspicion of DS include dyspnoea, oedema, unexplained fever, hypotension, weight gain more than 5 kg, and/or vascular leakage syndrome, were absent. Therefore, it was less likely that the patient had a ‘late’ differentiate syndrome.
We treated the patient according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML.16 However, the risk of cardiotoxicity, specifically that of spontaneous coronary dissection, has not yet been established. We believe that our report can create awareness regarding the adverse effects of daunorubicin among physicians who prescribe daunorubicin for the treatment of AML regardless of the drug’s dosage and timing.
We could not ascertain whether the treatment of the complication in our case was adequate. Initially, we intended to perform diagnostic angiography followed by coronary stenting or coronary artery bypass grafting (CABG) surgery. However, as the patient collapsed sooner, we were unable to perform percutaneous coronary intervention (PCI). We believe that PCI may not be a suitable treatment of SCAD because guidewires may enter the false lumen and occlude the true lumen. In our patient, there were multiple dissections of the mid-left descending coronary artery and left circumflex (LCX) that led to more complications. Meanwhile, we also found a paucity of evidence to support CABG in SCAD. Only one small study showed the initial success of CABG for treatment of SCAD.17
Conclusion
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections as illustrated in this case. Following the evaluation of the patient, immediate medical decision-making and accurate treatment are warranted in such cases as the risks of mortality is quite high.
Lead author biography
Dr Do Van Chien, MD, PhD, graduated from Volgograd Medical School, Russia with distinction in 2006 and currently works as Deputy Head, Department of Cardiology, 108 Central Military Hospital, Hanoi, Vietnam. He was also a fellow of interventional cardiology at Sydney Concord Repatriation, Australia in 2011 and National Heart Centre Singapore in 2014. His clinical and research interests include interventional cardiology, echocardiography, and cardiomyopathy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: This report is funded by 108 Central Military Hospital, Hanoi, Vietnam.
Supplementary Material
ytaa427_Supplementary_Data Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33644638 | 19,020,123 | 2021-01 |
What was the outcome of reaction 'Acute myocardial infarction'? | Multiple spontaneous coronary artery dissections associated with intravenous daunorubicin treatment for acute myelocytic leukaemia: a case report.
Multiple spontaneous coronary artery dissection (SCAD) is a rare condition which may lead to serious consequences such as sudden cardiac death, acute myocardial infarction (AMI), and acute heart failure.
In this paper, we report the case of a 57-year-old woman with acute myelocytic leukaemia who was undergoing her second phase of chemotherapy. After the first induction cycle of intravenous infusion of daunorubicin, the patient experienced chest pain, shortness of breath, and low blood pressure. The electrocardiograms revealed significant ST-elevation in the D1, aVL, and V2-V6 leads, which indicated AMI. Coronary catheterization showed spontaneous coronary dissection in the mid-left descending coronary artery and first obtuse marginal artery of the circumflex. The patient died immediately.
This is the first reported case of multiple SCAD associated with intravenous (IV) daunorubicin infusion. We also reviewed the literature and proposed the mechanism of this complication.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Multiple spontaneous coronary artery dissection is a rare condition. It can cause fatal consequences such as sudden cardiac death, acute myocardial infarction, and acute heart failure.
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of daunorubicin for 3 days and cytarabine for 7 days.
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections.
Introduction
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of 45 mg/m2 daunorubicin for 3 days with 100–200 mg/m2 cytarabine infusion for 7 days.1 Löwenberg et al.2 reported an early mortality rate of 12% after the first two cycles of conventional dose of daunorubicin. However, sudden cardiac death following spontaneous dissection has not been reported yet.
Spontaneous coronary artery dissection (SCAD) is defined as a non-iatrogenic, non-atherosclerotic, and non-traumatic spontaneous separation of the coronary artery wall.3 More than 90% of SCAD cases occurs in women with negligible cardiovascular risk factors.4 Moreover, SCAD is highly associated with fibromuscular dysplasia (FMD)5 and caused by other risk factors such as hormonal therapy, Marfan syndrome, vascular Ehlers–Danlos, Loyes–Dietz syndrome, and polycystic kidney.6 However, no study has indicated that daunorubicin could be associated with SCAD.
Herein, we report a case of multiple SCAD in a patient with AML type M3. During the second phase of chemotherapy with daunorubicin and cytarabine, she experienced acute myocardial infarction (AMI) with ST-elevation and died suddenly.
Timeline
Day 0 A 57-year-old woman presented with left lower arm purpura and several weeks old of left thigh intra-muscle haemorrhage in the left thigh.
Day 1 She was diagnosed with acute myeloid leukaemia type M3. Chemotherapy with cytarabine and tretinoin was administered.
Day 3 The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
Day 30 (1 month after discharge) The patient was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura.
Day 31 The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Day 31 Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain.
Day 31 The patient was intubated and transferred to the intensive care unit for mechanical ventilation.
Day 31 The patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections. Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Case presentation
A 57-year-old woman presented with left lower arm purpura and several weeks of left thigh intra-muscle haemorrhage (IMH) in the left thigh. She was diagnosed with AML type M3. Chemotherapy with cytarabine and tretinoin was administered. The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
One month later, she was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura. She had no history of hypertension, diabetes, smoking, heart failure, or other risk factors for coronary diseases. She had no complaint of fever, weight loss, or chest pain. She denied any occurrence of lung diseases in the past. On admission, a chest X-ray showed the lung was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion (Figure 1).
Figure 1 Chest X-ray on admission showed lung clear, no pulmonary infiltration or pleuro-pericardial effusion.
The complete blood count showed anaemia with Hb of 7.5 g/dL, significant leucocytosis with leucocyte count of 67.7 × 109/L, neutrophil concentration of 86.1%, and thrombocytopenia (42 G/L). The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain. Physical examination showed wheezing, respiratory coarse crackles, and a 100-150 b.p.m. heart rate. Blood pressure dropped from 130/70 to 100/60 mmHg. The SpO2 decreased from 95% to 73% with 15 L O2/min. D-dimer, prothrombin, and fibrinogen were 65.230 ng/mL, 61%, and 1.04 g/L, respectively.
Arterial blood gas analysis revealed a developed respiratory failure with 7.23 pH, PaCO2 of 52 mmHg, and a PaO2 of 54 mmHg. Therefore, she was intubated and transferred to the intensive care unit for mechanical ventilation. The chest radiograph revealed bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces (Figure 2). And the 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2 to V6, and DI, aVL, which suggested a typical AMI (Figure 3).
Figure 2 Chest radiograph revealing bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces.
Figure 3 A 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2–V6, and DI, aVL.
Transthoracic echocardiography showed the left ventricular ejection fraction of 50%, apical and septal hypokinaesia, with systolic pulmonary arterial pressure of 48 mmHg.
Due to suspected AMI, the patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections (Figures 4–6). Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Figure 4 Left caudal angiographic view showing mid-circumflex dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 5 Left cranial angiographic view showing mid-descending artery dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 6 Contrast remained at the positions of dissections (arrows).
Discussion
To the best of our knowledge, this is first report on multiple SCAD associated with daunorubicin intravenous infusion for AML. According to the American Heart Association scientific statement on SCAD, predisposing conditions for SCAD include FMD, pregnancy, multiparity, hereditary arteriopathy, connective tissue disorders, exogenous hormonal therapy, systemic inflammatory diseases, migraine headaches, and coronary spasms.7 However, a paucity of case reports exists regarding the usage of intravenous daunorubicin in AML treatment.
Spontaneous coronary artery dissection is characterized by spontaneous IMH within the coronary artery wall, which is confirmed by intravascular ultrasound,8 histopathology, case reports, and case series.9–11 Clinical symptoms of SCAD are usually chest pain, typically consistent with acute coronary syndrome, while 26–87% and 13–69% patients present with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), respectively.12 Our case presented with typical chest pain and ST-elevation on electrocardiogram (ECG). Thereafter, the patient immediately experienced a cardiogenic shock, which primarily caused the collapse.
We performed an in-depth literature searches to uncover the pathological mechanism underlying this episode of cardiovascular complication of daunorubicin. However, we could not find any published literature pertaining to this condition. Daunorubicin is an anthracycline, antineoplastic, antibiotic drug. It exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication; DNA repair; and RNA and protein synthesis.13 Lawrence et al. reported a case of AML involving acute heart failure as a complication after intensified treatment with daunorubicin, with decrease in ejection fraction (EF) from 60% to 10%, which is recovered after few months of medical treatment. Additionally, Takotsubo cardiomyopathy was associated with the use of daunorubicin.14 Thus, these cases indicate the acute cardiotoxicity of daunorubicin.
Disseminated intravascular coagulation (DIC) or ‘late’ differentiate syndrome may contribute to the severity of the patient’s condition. According to the diagnostic scoring system for DIC, this patient had platelet count <50 (2 points) and D-dimer was five times above the upper limit of normal (3 points).15 Consequently, she got an overt DIC. However, changes in ECG tracing and coronary dissections cannot be explained by DIC. Disseminated intravascular coagulation maybe a contributory factor but not a cause of the patient’s collapse. Regarding ‘late’ differentiate syndrome, a chest X-ray at admission was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion. Moreover, clinical symptoms/signs that lead to high suspicion of DS include dyspnoea, oedema, unexplained fever, hypotension, weight gain more than 5 kg, and/or vascular leakage syndrome, were absent. Therefore, it was less likely that the patient had a ‘late’ differentiate syndrome.
We treated the patient according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML.16 However, the risk of cardiotoxicity, specifically that of spontaneous coronary dissection, has not yet been established. We believe that our report can create awareness regarding the adverse effects of daunorubicin among physicians who prescribe daunorubicin for the treatment of AML regardless of the drug’s dosage and timing.
We could not ascertain whether the treatment of the complication in our case was adequate. Initially, we intended to perform diagnostic angiography followed by coronary stenting or coronary artery bypass grafting (CABG) surgery. However, as the patient collapsed sooner, we were unable to perform percutaneous coronary intervention (PCI). We believe that PCI may not be a suitable treatment of SCAD because guidewires may enter the false lumen and occlude the true lumen. In our patient, there were multiple dissections of the mid-left descending coronary artery and left circumflex (LCX) that led to more complications. Meanwhile, we also found a paucity of evidence to support CABG in SCAD. Only one small study showed the initial success of CABG for treatment of SCAD.17
Conclusion
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections as illustrated in this case. Following the evaluation of the patient, immediate medical decision-making and accurate treatment are warranted in such cases as the risks of mortality is quite high.
Lead author biography
Dr Do Van Chien, MD, PhD, graduated from Volgograd Medical School, Russia with distinction in 2006 and currently works as Deputy Head, Department of Cardiology, 108 Central Military Hospital, Hanoi, Vietnam. He was also a fellow of interventional cardiology at Sydney Concord Repatriation, Australia in 2011 and National Heart Centre Singapore in 2014. His clinical and research interests include interventional cardiology, echocardiography, and cardiomyopathy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: This report is funded by 108 Central Military Hospital, Hanoi, Vietnam.
Supplementary Material
ytaa427_Supplementary_Data Click here for additional data file. | Fatal | ReactionOutcome | CC BY-NC | 33644638 | 19,020,123 | 2021-01 |
What was the outcome of reaction 'Cardiogenic shock'? | Multiple spontaneous coronary artery dissections associated with intravenous daunorubicin treatment for acute myelocytic leukaemia: a case report.
Multiple spontaneous coronary artery dissection (SCAD) is a rare condition which may lead to serious consequences such as sudden cardiac death, acute myocardial infarction (AMI), and acute heart failure.
In this paper, we report the case of a 57-year-old woman with acute myelocytic leukaemia who was undergoing her second phase of chemotherapy. After the first induction cycle of intravenous infusion of daunorubicin, the patient experienced chest pain, shortness of breath, and low blood pressure. The electrocardiograms revealed significant ST-elevation in the D1, aVL, and V2-V6 leads, which indicated AMI. Coronary catheterization showed spontaneous coronary dissection in the mid-left descending coronary artery and first obtuse marginal artery of the circumflex. The patient died immediately.
This is the first reported case of multiple SCAD associated with intravenous (IV) daunorubicin infusion. We also reviewed the literature and proposed the mechanism of this complication.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Multiple spontaneous coronary artery dissection is a rare condition. It can cause fatal consequences such as sudden cardiac death, acute myocardial infarction, and acute heart failure.
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of daunorubicin for 3 days and cytarabine for 7 days.
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections.
Introduction
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of 45 mg/m2 daunorubicin for 3 days with 100–200 mg/m2 cytarabine infusion for 7 days.1 Löwenberg et al.2 reported an early mortality rate of 12% after the first two cycles of conventional dose of daunorubicin. However, sudden cardiac death following spontaneous dissection has not been reported yet.
Spontaneous coronary artery dissection (SCAD) is defined as a non-iatrogenic, non-atherosclerotic, and non-traumatic spontaneous separation of the coronary artery wall.3 More than 90% of SCAD cases occurs in women with negligible cardiovascular risk factors.4 Moreover, SCAD is highly associated with fibromuscular dysplasia (FMD)5 and caused by other risk factors such as hormonal therapy, Marfan syndrome, vascular Ehlers–Danlos, Loyes–Dietz syndrome, and polycystic kidney.6 However, no study has indicated that daunorubicin could be associated with SCAD.
Herein, we report a case of multiple SCAD in a patient with AML type M3. During the second phase of chemotherapy with daunorubicin and cytarabine, she experienced acute myocardial infarction (AMI) with ST-elevation and died suddenly.
Timeline
Day 0 A 57-year-old woman presented with left lower arm purpura and several weeks old of left thigh intra-muscle haemorrhage in the left thigh.
Day 1 She was diagnosed with acute myeloid leukaemia type M3. Chemotherapy with cytarabine and tretinoin was administered.
Day 3 The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
Day 30 (1 month after discharge) The patient was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura.
Day 31 The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Day 31 Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain.
Day 31 The patient was intubated and transferred to the intensive care unit for mechanical ventilation.
Day 31 The patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections. Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Case presentation
A 57-year-old woman presented with left lower arm purpura and several weeks of left thigh intra-muscle haemorrhage (IMH) in the left thigh. She was diagnosed with AML type M3. Chemotherapy with cytarabine and tretinoin was administered. The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
One month later, she was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura. She had no history of hypertension, diabetes, smoking, heart failure, or other risk factors for coronary diseases. She had no complaint of fever, weight loss, or chest pain. She denied any occurrence of lung diseases in the past. On admission, a chest X-ray showed the lung was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion (Figure 1).
Figure 1 Chest X-ray on admission showed lung clear, no pulmonary infiltration or pleuro-pericardial effusion.
The complete blood count showed anaemia with Hb of 7.5 g/dL, significant leucocytosis with leucocyte count of 67.7 × 109/L, neutrophil concentration of 86.1%, and thrombocytopenia (42 G/L). The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain. Physical examination showed wheezing, respiratory coarse crackles, and a 100-150 b.p.m. heart rate. Blood pressure dropped from 130/70 to 100/60 mmHg. The SpO2 decreased from 95% to 73% with 15 L O2/min. D-dimer, prothrombin, and fibrinogen were 65.230 ng/mL, 61%, and 1.04 g/L, respectively.
Arterial blood gas analysis revealed a developed respiratory failure with 7.23 pH, PaCO2 of 52 mmHg, and a PaO2 of 54 mmHg. Therefore, she was intubated and transferred to the intensive care unit for mechanical ventilation. The chest radiograph revealed bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces (Figure 2). And the 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2 to V6, and DI, aVL, which suggested a typical AMI (Figure 3).
Figure 2 Chest radiograph revealing bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces.
Figure 3 A 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2–V6, and DI, aVL.
Transthoracic echocardiography showed the left ventricular ejection fraction of 50%, apical and septal hypokinaesia, with systolic pulmonary arterial pressure of 48 mmHg.
Due to suspected AMI, the patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections (Figures 4–6). Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Figure 4 Left caudal angiographic view showing mid-circumflex dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 5 Left cranial angiographic view showing mid-descending artery dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 6 Contrast remained at the positions of dissections (arrows).
Discussion
To the best of our knowledge, this is first report on multiple SCAD associated with daunorubicin intravenous infusion for AML. According to the American Heart Association scientific statement on SCAD, predisposing conditions for SCAD include FMD, pregnancy, multiparity, hereditary arteriopathy, connective tissue disorders, exogenous hormonal therapy, systemic inflammatory diseases, migraine headaches, and coronary spasms.7 However, a paucity of case reports exists regarding the usage of intravenous daunorubicin in AML treatment.
Spontaneous coronary artery dissection is characterized by spontaneous IMH within the coronary artery wall, which is confirmed by intravascular ultrasound,8 histopathology, case reports, and case series.9–11 Clinical symptoms of SCAD are usually chest pain, typically consistent with acute coronary syndrome, while 26–87% and 13–69% patients present with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), respectively.12 Our case presented with typical chest pain and ST-elevation on electrocardiogram (ECG). Thereafter, the patient immediately experienced a cardiogenic shock, which primarily caused the collapse.
We performed an in-depth literature searches to uncover the pathological mechanism underlying this episode of cardiovascular complication of daunorubicin. However, we could not find any published literature pertaining to this condition. Daunorubicin is an anthracycline, antineoplastic, antibiotic drug. It exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication; DNA repair; and RNA and protein synthesis.13 Lawrence et al. reported a case of AML involving acute heart failure as a complication after intensified treatment with daunorubicin, with decrease in ejection fraction (EF) from 60% to 10%, which is recovered after few months of medical treatment. Additionally, Takotsubo cardiomyopathy was associated with the use of daunorubicin.14 Thus, these cases indicate the acute cardiotoxicity of daunorubicin.
Disseminated intravascular coagulation (DIC) or ‘late’ differentiate syndrome may contribute to the severity of the patient’s condition. According to the diagnostic scoring system for DIC, this patient had platelet count <50 (2 points) and D-dimer was five times above the upper limit of normal (3 points).15 Consequently, she got an overt DIC. However, changes in ECG tracing and coronary dissections cannot be explained by DIC. Disseminated intravascular coagulation maybe a contributory factor but not a cause of the patient’s collapse. Regarding ‘late’ differentiate syndrome, a chest X-ray at admission was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion. Moreover, clinical symptoms/signs that lead to high suspicion of DS include dyspnoea, oedema, unexplained fever, hypotension, weight gain more than 5 kg, and/or vascular leakage syndrome, were absent. Therefore, it was less likely that the patient had a ‘late’ differentiate syndrome.
We treated the patient according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML.16 However, the risk of cardiotoxicity, specifically that of spontaneous coronary dissection, has not yet been established. We believe that our report can create awareness regarding the adverse effects of daunorubicin among physicians who prescribe daunorubicin for the treatment of AML regardless of the drug’s dosage and timing.
We could not ascertain whether the treatment of the complication in our case was adequate. Initially, we intended to perform diagnostic angiography followed by coronary stenting or coronary artery bypass grafting (CABG) surgery. However, as the patient collapsed sooner, we were unable to perform percutaneous coronary intervention (PCI). We believe that PCI may not be a suitable treatment of SCAD because guidewires may enter the false lumen and occlude the true lumen. In our patient, there were multiple dissections of the mid-left descending coronary artery and left circumflex (LCX) that led to more complications. Meanwhile, we also found a paucity of evidence to support CABG in SCAD. Only one small study showed the initial success of CABG for treatment of SCAD.17
Conclusion
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections as illustrated in this case. Following the evaluation of the patient, immediate medical decision-making and accurate treatment are warranted in such cases as the risks of mortality is quite high.
Lead author biography
Dr Do Van Chien, MD, PhD, graduated from Volgograd Medical School, Russia with distinction in 2006 and currently works as Deputy Head, Department of Cardiology, 108 Central Military Hospital, Hanoi, Vietnam. He was also a fellow of interventional cardiology at Sydney Concord Repatriation, Australia in 2011 and National Heart Centre Singapore in 2014. His clinical and research interests include interventional cardiology, echocardiography, and cardiomyopathy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: This report is funded by 108 Central Military Hospital, Hanoi, Vietnam.
Supplementary Material
ytaa427_Supplementary_Data Click here for additional data file. | Fatal | ReactionOutcome | CC BY-NC | 33644638 | 19,020,123 | 2021-01 |
What was the outcome of reaction 'Coronary artery dissection'? | Multiple spontaneous coronary artery dissections associated with intravenous daunorubicin treatment for acute myelocytic leukaemia: a case report.
Multiple spontaneous coronary artery dissection (SCAD) is a rare condition which may lead to serious consequences such as sudden cardiac death, acute myocardial infarction (AMI), and acute heart failure.
In this paper, we report the case of a 57-year-old woman with acute myelocytic leukaemia who was undergoing her second phase of chemotherapy. After the first induction cycle of intravenous infusion of daunorubicin, the patient experienced chest pain, shortness of breath, and low blood pressure. The electrocardiograms revealed significant ST-elevation in the D1, aVL, and V2-V6 leads, which indicated AMI. Coronary catheterization showed spontaneous coronary dissection in the mid-left descending coronary artery and first obtuse marginal artery of the circumflex. The patient died immediately.
This is the first reported case of multiple SCAD associated with intravenous (IV) daunorubicin infusion. We also reviewed the literature and proposed the mechanism of this complication.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Multiple spontaneous coronary artery dissection is a rare condition. It can cause fatal consequences such as sudden cardiac death, acute myocardial infarction, and acute heart failure.
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of daunorubicin for 3 days and cytarabine for 7 days.
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections.
Introduction
Acute myeloid leukaemia (AML) is the most prevalent malignancy of the bone marrow in adults. Its conventional treatment regimen includes intravenous infusion of 45 mg/m2 daunorubicin for 3 days with 100–200 mg/m2 cytarabine infusion for 7 days.1 Löwenberg et al.2 reported an early mortality rate of 12% after the first two cycles of conventional dose of daunorubicin. However, sudden cardiac death following spontaneous dissection has not been reported yet.
Spontaneous coronary artery dissection (SCAD) is defined as a non-iatrogenic, non-atherosclerotic, and non-traumatic spontaneous separation of the coronary artery wall.3 More than 90% of SCAD cases occurs in women with negligible cardiovascular risk factors.4 Moreover, SCAD is highly associated with fibromuscular dysplasia (FMD)5 and caused by other risk factors such as hormonal therapy, Marfan syndrome, vascular Ehlers–Danlos, Loyes–Dietz syndrome, and polycystic kidney.6 However, no study has indicated that daunorubicin could be associated with SCAD.
Herein, we report a case of multiple SCAD in a patient with AML type M3. During the second phase of chemotherapy with daunorubicin and cytarabine, she experienced acute myocardial infarction (AMI) with ST-elevation and died suddenly.
Timeline
Day 0 A 57-year-old woman presented with left lower arm purpura and several weeks old of left thigh intra-muscle haemorrhage in the left thigh.
Day 1 She was diagnosed with acute myeloid leukaemia type M3. Chemotherapy with cytarabine and tretinoin was administered.
Day 3 The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
Day 30 (1 month after discharge) The patient was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura.
Day 31 The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Day 31 Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain.
Day 31 The patient was intubated and transferred to the intensive care unit for mechanical ventilation.
Day 31 The patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections. Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Case presentation
A 57-year-old woman presented with left lower arm purpura and several weeks of left thigh intra-muscle haemorrhage (IMH) in the left thigh. She was diagnosed with AML type M3. Chemotherapy with cytarabine and tretinoin was administered. The first chemotherapy cycle with cytarabine and tretinoin was successful without complications and the patient was discharged in stable condition.
One month later, she was re-hospitalized with cough, exertional dyspnoea, and tooth bleeding. Physical examination revealed scattered subcutaneous purpura. She had no history of hypertension, diabetes, smoking, heart failure, or other risk factors for coronary diseases. She had no complaint of fever, weight loss, or chest pain. She denied any occurrence of lung diseases in the past. On admission, a chest X-ray showed the lung was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion (Figure 1).
Figure 1 Chest X-ray on admission showed lung clear, no pulmonary infiltration or pleuro-pericardial effusion.
The complete blood count showed anaemia with Hb of 7.5 g/dL, significant leucocytosis with leucocyte count of 67.7 × 109/L, neutrophil concentration of 86.1%, and thrombocytopenia (42 G/L). The second cycle of chemotherapy with daunorubicin 45 mg/m2 of body mass diluted by 200 mL of 0.9% sodium chloride followed by cytarabine 100 mg/m2 was administered.
Immediately after the intravenous infusion of daunorubicin and cytarabine infusion, the patient suddenly complained of fatigue, acute dyspnoea, and heavy chest pain. Physical examination showed wheezing, respiratory coarse crackles, and a 100-150 b.p.m. heart rate. Blood pressure dropped from 130/70 to 100/60 mmHg. The SpO2 decreased from 95% to 73% with 15 L O2/min. D-dimer, prothrombin, and fibrinogen were 65.230 ng/mL, 61%, and 1.04 g/L, respectively.
Arterial blood gas analysis revealed a developed respiratory failure with 7.23 pH, PaCO2 of 52 mmHg, and a PaO2 of 54 mmHg. Therefore, she was intubated and transferred to the intensive care unit for mechanical ventilation. The chest radiograph revealed bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces (Figure 2). And the 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2 to V6, and DI, aVL, which suggested a typical AMI (Figure 3).
Figure 2 Chest radiograph revealing bilateral ground-glass opacity reflecting fluid filling of the alveolar spaces.
Figure 3 A 12-lead electrocardiogram showed a normal axis, 2–4 mm elevated ST-segment at V2–V6, and DI, aVL.
Transthoracic echocardiography showed the left ventricular ejection fraction of 50%, apical and septal hypokinaesia, with systolic pulmonary arterial pressure of 48 mmHg.
Due to suspected AMI, the patient was transferred to the catheterization laboratory. Diagnostic angiograms showed multiple coronary dissections (Figures 4–6). Suddenly, she collapsed and after unsuccessful resuscitation, she died.
Figure 4 Left caudal angiographic view showing mid-circumflex dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 5 Left cranial angiographic view showing mid-descending artery dissection (LAD, left anterior descending; LCX, left circumflex; LM, left main; OM, obtuse marginal, place of dissection indicated by an arrow).
Figure 6 Contrast remained at the positions of dissections (arrows).
Discussion
To the best of our knowledge, this is first report on multiple SCAD associated with daunorubicin intravenous infusion for AML. According to the American Heart Association scientific statement on SCAD, predisposing conditions for SCAD include FMD, pregnancy, multiparity, hereditary arteriopathy, connective tissue disorders, exogenous hormonal therapy, systemic inflammatory diseases, migraine headaches, and coronary spasms.7 However, a paucity of case reports exists regarding the usage of intravenous daunorubicin in AML treatment.
Spontaneous coronary artery dissection is characterized by spontaneous IMH within the coronary artery wall, which is confirmed by intravascular ultrasound,8 histopathology, case reports, and case series.9–11 Clinical symptoms of SCAD are usually chest pain, typically consistent with acute coronary syndrome, while 26–87% and 13–69% patients present with ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), respectively.12 Our case presented with typical chest pain and ST-elevation on electrocardiogram (ECG). Thereafter, the patient immediately experienced a cardiogenic shock, which primarily caused the collapse.
We performed an in-depth literature searches to uncover the pathological mechanism underlying this episode of cardiovascular complication of daunorubicin. However, we could not find any published literature pertaining to this condition. Daunorubicin is an anthracycline, antineoplastic, antibiotic drug. It exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication; DNA repair; and RNA and protein synthesis.13 Lawrence et al. reported a case of AML involving acute heart failure as a complication after intensified treatment with daunorubicin, with decrease in ejection fraction (EF) from 60% to 10%, which is recovered after few months of medical treatment. Additionally, Takotsubo cardiomyopathy was associated with the use of daunorubicin.14 Thus, these cases indicate the acute cardiotoxicity of daunorubicin.
Disseminated intravascular coagulation (DIC) or ‘late’ differentiate syndrome may contribute to the severity of the patient’s condition. According to the diagnostic scoring system for DIC, this patient had platelet count <50 (2 points) and D-dimer was five times above the upper limit of normal (3 points).15 Consequently, she got an overt DIC. However, changes in ECG tracing and coronary dissections cannot be explained by DIC. Disseminated intravascular coagulation maybe a contributory factor but not a cause of the patient’s collapse. Regarding ‘late’ differentiate syndrome, a chest X-ray at admission was clear without any evidence of pulmonary infiltration or pleuro-pericardial effusion. Moreover, clinical symptoms/signs that lead to high suspicion of DS include dyspnoea, oedema, unexplained fever, hypotension, weight gain more than 5 kg, and/or vascular leakage syndrome, were absent. Therefore, it was less likely that the patient had a ‘late’ differentiate syndrome.
We treated the patient according to the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML.16 However, the risk of cardiotoxicity, specifically that of spontaneous coronary dissection, has not yet been established. We believe that our report can create awareness regarding the adverse effects of daunorubicin among physicians who prescribe daunorubicin for the treatment of AML regardless of the drug’s dosage and timing.
We could not ascertain whether the treatment of the complication in our case was adequate. Initially, we intended to perform diagnostic angiography followed by coronary stenting or coronary artery bypass grafting (CABG) surgery. However, as the patient collapsed sooner, we were unable to perform percutaneous coronary intervention (PCI). We believe that PCI may not be a suitable treatment of SCAD because guidewires may enter the false lumen and occlude the true lumen. In our patient, there were multiple dissections of the mid-left descending coronary artery and left circumflex (LCX) that led to more complications. Meanwhile, we also found a paucity of evidence to support CABG in SCAD. Only one small study showed the initial success of CABG for treatment of SCAD.17
Conclusion
It is essential to recognize the cardiac complications following daunorubicin intravenous administration for AML, such as multiple coronary dissections as illustrated in this case. Following the evaluation of the patient, immediate medical decision-making and accurate treatment are warranted in such cases as the risks of mortality is quite high.
Lead author biography
Dr Do Van Chien, MD, PhD, graduated from Volgograd Medical School, Russia with distinction in 2006 and currently works as Deputy Head, Department of Cardiology, 108 Central Military Hospital, Hanoi, Vietnam. He was also a fellow of interventional cardiology at Sydney Concord Repatriation, Australia in 2011 and National Heart Centre Singapore in 2014. His clinical and research interests include interventional cardiology, echocardiography, and cardiomyopathy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: This report is funded by 108 Central Military Hospital, Hanoi, Vietnam.
Supplementary Material
ytaa427_Supplementary_Data Click here for additional data file. | Fatal | ReactionOutcome | CC BY-NC | 33644638 | 19,020,123 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | AZITHROMYCIN ANHYDROUS, HUMAN IMMUNOGLOBULIN G, HYDROXYCHLOROQUINE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxia'. | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | AZITHROMYCIN ANHYDROUS, HUMAN IMMUNOGLOBULIN G, HYDROXYCHLOROQUINE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple organ dysfunction syndrome'. | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | AZITHROMYCIN ANHYDROUS, HUMAN IMMUNOGLOBULIN G, HYDROXYCHLOROQUINE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | AZITHROMYCIN ANHYDROUS, HUMAN IMMUNOGLOBULIN G, HYDROXYCHLOROQUINE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Shock'. | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | AZITHROMYCIN ANHYDROUS, HUMAN IMMUNOGLOBULIN G, HYDROXYCHLOROQUINE, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What is the weight of the patient? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | 7.1 kg. | Weight | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What was the dosage of drug 'HUMAN IMMUNOGLOBULIN G'? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | UNK (TOTAL DOSE OF 2 G/KG) | DrugDosageText | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What was the dosage of drug 'TOCILIZUMAB'? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | 12 MG/KG (REPEATED WITHIN 12 H) | DrugDosageText | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What was the outcome of reaction 'Cardiac arrest'? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | Fatal | ReactionOutcome | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What was the outcome of reaction 'Hypoxia'? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | Fatal | ReactionOutcome | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What was the outcome of reaction 'Multiple organ dysfunction syndrome'? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | Fatal | ReactionOutcome | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
What was the outcome of reaction 'Shock'? | Impact of coronavirus disease 2019 in a child who underwent ventricular septal defect device closure: a case report.
Studies about the incidence and severity of coronavirus disease 2019 (COVID-19) in children are still significantly lower than those in adults. Moreover, data on the effect of COVID-19 in children with congenital heart disease (CHD) are limited. To the best of our knowledge, this study first reported mortality in a child with CHD who acquired COVID-19.
A 16-month-old boy presented to the emergency department due to shortness of breath, fever, cough, and poor oral intake. He tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He required mechanical ventilation for rapidly progressing respiratory failure. The patient had a large mid-muscular ventricular septal defect (VSD) that was closed percutaneously at the age of 13 months. Moreover, we followed his hospital sequelae from admission to death.
This child had multiple risk factors, including malnutrition and persistent pulmonary hypertension (PH) after late closure of the VSD. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19 and the respiratory failure triggered by SARS-CoV-2 infection. The patient presented with ventricular systolic dysfunction, elevated troponin serum levels and newly developed trifascicular block, which were indicative of myocardial injury. The elevated inflammatory markers and multi-organ dysfunction seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.
Learning points
Persistent pulmonary hypertension after late ventricular septal defect closure and malnutrition could be risk factors for critical illness in children with severe acute respiratory syndrome coronavirus 2 infection.
Myocardial injury can be observed in paediatric patients with coronavirus disease 2019.
Introduction
The world has been experiencing the greatest healthcare challenge since December 2019 when coronavirus disease 2019 (COVID-19) was first detected in Wuhan, China.1 The first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a child was reported in Shenzhen on 20 January 2020.2 Thereafter, several paediatric case reports and case series have been published.
The SARS-CoV-2 infection rate in children is significantly lower than that in adults. Data from China and the USA showed that only about 2% of all reported COVID-19 cases involved individuals aged below 18 years.3,4 Data on children with congenital heart disease (CHD) who acquire COVID-19 are limited. Moreover, comorbidities are associated with severe illness in children.5
Timeline
Time Events
3 February 2020 Percutaneous ventricular septal defect closure
25 March 2020 Hospital admission due to bronchiolitis
29 March 2020 Discharged home
13 May 2020 The patient had shortness of breath, fever, cough, vomiting, and poor oral intake
15 May 2020
4:00 Presentation to the emergency department due to respiratory failure.
The patient was suspected of coronavirus disease 2019. A swab test was performed to confirm the diagnosis. He had anaemia, elevated inflammatory markers, and high cardiac enzyme levels. Chest radiography revealed bilateral ground-glass opacities.
15 May 2020
7:00 The patient required mechanical ventilation for rapidly progressing respiratory failure. He was transferred to the paediatric intensive care unit. Inotropic support was started.
16 May 2020 Reverse transcription polymerase chain reaction confirmed the diagnosis of coronavirus disease 2019. Treatment with hydroxychloroquine, azithromycin, and tocilizumab was initiated. Intravenous immunoglobulin was also administered.
16–19 May 2020 The patient presented with multi-organ dysfunction. High-frequency oscillatory ventilation and vasopressors were continuously administered.
20 May 2020 The patient experienced worsening shock, refractory hypoxaemia, and cardiac arrest, and eventually died.
Case presentation
A 16-month-old Saudi Arabian boy presented to the emergency department due to shortness of breath. The patient experienced fever, poor oral intake, vomiting 1–2 times per day, and dry cough for 2 days. The patient had a large mid-muscular ventricular septal defect (VSD), with a previous history of percutaneous closure of VSD 3 months before the current presentation. The child had been in contact with his mother who tested positive for COVID-19. The mother’s manifestations started 8 days before the child developed symptoms. Upon presentation, the patient’s oxygen saturation was 70%. Hence, he required oxygen supplementation. COVID-19 test, other blood examinations, and chest radiography were performed. In the emergency room (ER), the condition of the child deteriorated. Therefore, he required mechanical ventilation for rapidly progressing respiratory failure. Premedication for endotracheal intubation was administered including atropine 0.02 mg/kg, ketamine 1 mg/kg, and rocuronium 1 mg/kg. During intubation, he developed bradycardia and asystole that required cardiopulmonary resuscitation (CPR) for 6 min and two doses of epinephrine (0.01 mg/kg/dose). Then, a successful return of spontaneous circulation was achieved, and the patient was transferred to the paediatric intensive care unit (PICU).
The following examination results were obtained. Assessment in the ER: weight, 7.1 kg; height, 71.5 cm (both below the 3rd percentile); temperature, 38.3°C; heart rate, 180 beats/min; respiratory rate, 70 cycles/min; blood pressure, 73/43 mmHg; and capillary refill time, >3 s. Chest examination: severe subcostal and intercostal recessions and bilateral fine crackles. Cardiac examination: grade I–II soft systolic murmur at the lower left sternal border. Abdominal examination: enlarged liver located 4 cm below the costal margin. Examination of the other systems: unremarkable results.
The patient tested positive for SARS-CoV-2 based on reverse transcription polymerase chain reaction. Initial laboratory testing revealed anaemia (haemoglobin 7.6 g/dL, normal range 9.6–15.6 g/dL), elevated D-dimer levels (40.56 mg/L, normal <0.5 mg/L), prolonged prothrombin time (23 sec, normal <12.5 s), increased aspartate transaminase enzyme levels (79 U/L, normal <37 U/L), lactic acidosis (7.7 mmol/L, normal <2 mmol/L), and elevated lactate dehydrogenase (LDH) levels (1284 U/L, normal <240 U/L) and high cardiac enzyme levels (troponin-I 2.07 µg/L, normal <0.04 µg/L). While in the PICU, the patient had thrombocytopenia (72–92 K/µL, normal >150 K/µL), lymphopenia (1.27–3.62 K/µL, normal range 4–10.5 K/µL), increased C-reactive protein (CRP) level (19 mg/L, normal <3 mg/L), and impaired liver and kidney functions (alanine transaminase 110–146 U/L, normal <78 U/L; urea 11.3–19.5 mmol/L, normal <6.4 mmol/L) (Table 1). The bacterial culture and respiratory and blood examination results were negative. Chest radiography revealed bilateral ground-glass opacities and cardiomegaly (Figure 1). Electrocardiogram upon admission showed sinus rhythm with trifascicular block and precordial T-wave inversion (Figure 2).
Figure 1 Chest radiography was conducted before ventricular septal defect closure (A), during the last admission in the emergency department (B), and immediately after mechanical ventilation (C). Results reveal bilateral ground-glass opacities and cardiomegaly. The ventricular septal defect device (yellow arrows).
Figure 2 (A) Electrocardiogram was conducted after percutaneous ventricular septal defect closure. Results reveal sinus rhythm with incomplete right bundle branch block. (B) Electrocardiogram upon admission showing sinus rhythm with trifasicular block and precordial T-wave inversion.
Table 1 Serial laboratory results during hospital admission
Normal reference range Baseline levela Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
CBC
WBC (K/µL) 5.5–17.5 8.8 8.7 11.35 8.39 7.19 7.23 10.8
Lymphocytes (K/µL) 4–10.5 6.16 5.49 1.47 1.27 1.28 3.11 3.62
Platelets (K/µL) 150–450 347 160 88 92 83 75 72
Haemoglobin (g/dL) 9.6–15.6 9.9 7.6 8.6 8.9 8 8.3 8.5
Coagulation profile
Prothrombin time (s) 9.4–12.5 13 23 23.2 20.8 13.9
INR 0.85–1.3 1.16 1.5 2.04 1.83 1.24
APTT (s) 25.1–36.5 34.4 27.1 27.6 25.4 27.5
D-dimer (mg/L) 0–0.5 40.56 28.27 4.15
Fibrinogen (mg/dL) 200–393 118 385 297
CRP (mg/L) 0–3 <3 <3 19
Ferritin (ng/ml) 30–400 273 157
KFTs and electrolytes
Na (mmol/L) 136–145 140 140 148 149 153 154 155
K (mmol/L) 3.5–5.1 4.3 5 3.8 3.9 3.3 3 4
Urea (mmol/L) 2.5–6.4 5.8 4.3 11.3 19.5 13.6 14.2 19.5
Creatinine (µmol/L) 53–115 20 31 86 68.7 78 68 65.3
Calcium (mmol/L) 2.12–2.52 2.2 2.2 1.67 2.09 2.05 2.12 2.01
Magnesium (mmol/L) 0.70–1.0 0.82 0.81 0.66 1.07 0.86 0.76 1.02
Liver function tests
AST (U/L) 15–37 47 79 367 510
ALT (U/L) 12–78 34 38 110 146
GGT (U/L) 5–85 12 13 33 22
Bilirubin total (µmol/L) 0–17 14 15 5.5 13.5
Albumin (g/L) 40.2–47.6 41 32.4 29.2 30.5 28.2
Lactic acid, mmol/L 0.4–2 7.7 1.3 0.9 1.1 1.4 1.7
Cardiac enzymes
Troponin-I (µg/L) 0.02–0.04 2.07
Creatine kinase (IU/L) 26–308 398
Mass CK MB (µg/L) 0–3.6 11.0
LDH (U/L) 100–240 1284
Blood group O positive
ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; GGT, γ-glutamyl transferase; INR, international normalized ratio; KFTs, kidney function tests; LDH, lactate dehydrogenase; WBC, white blood count.
a The values obtained before cardiac catheterization.
Echocardiography was performed after PICU admission. Results showed that the VSD device was in place, with a small residual leak across the device, mild tricuspid valve regurgitation, with an estimated systolic pulmonary pressure of 60 mmHg, moderate biventricular systolic dysfunction with a left ventricular ejection fraction of 40% (Video1), normal coronary arteries (Video2), and no pericardial effusion or vegetations. Two days after PICU admission, a follow-up echocardiography demonstrated unchanged ventricular systolic dysfunction and pulmonary hypertension (PH) (Figure 3).
Figure 3 Echocardiography before and after ventricular septal defect device closure. (A) Apical four-chamber view showing a large mid-muscular ventricular septal defect (yellow arrow). (B) Apical four-chamber view with colour Doppler after device closure showing a small residual leak across the ventricular septal defect device (yellow arrow). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
After a successful CPR, the patient was conscious with bilateral equal and reactive pupils. Fentanyl, epinephrine, and milrinone infusions were initiated in PICU. Then, norepinephrine infusion for vasodilatory shock was initiated. Six hours after PICU admission, oxygenation and ventilation were not maintained even with conventional mechanical ventilation. Thus, the patient was connected to high-frequency oscillatory ventilation (HFOV). Based on our protocol, he received the following medical therapy: hydroxychloroquine 6.5 mg/kg twice daily for Day 1; followed by 3.25 mg/kg twice daily for 5 days, azithromycin 10 mg/kg on Day 1; followed by 5 mg/kg once daily on Days 2–5, and tocilizumab 12 mg/kg repeated within 12 h. Intravenous immunoglobulin (total dose of 2 g/kg) was administered for suspected myocarditis.
Despite the provision of aggressive supportive care, the patient developed multiple organ dysfunction syndrome (MODS). HFOV and vasopressors were continuously administered for 5 days. Ultimately, he presented with worsening shock, refractory hypoxaemia, and cardiac arrest. The patient died on Day 6 of hospitalization.
At the age of 2 weeks, he developed shortness of breath and was diagnosed with a large mid-muscular VSD. He was referred for cardiac surgery but was never followed-up due to family living in a remote area. He returned to our institution at the age of 13 months. He was malnourished because of poor oral intake. Echocardiography was performed and revealed a large mid-muscular VSD (16 mm) with severe PH (70 mmHg).
Cardiac catheterization showed a baseline indexed pulmonary vascular resistance (PVRI) of 5.8 Wood units (WU)⋅m2, but it dropped to 2.6 WU⋅m2 on 100% oxygen. The baseline systolic pulmonary artery pressure was 71 mmHg; systemic blood pressure was 76/40 mmHg; QP/QS was 2.5 and the pulmonary vascular resistance/systemic vascular resistance (SVR) was 0.26. After a multidisciplinary consensus meeting and discussion with the family, percutaneous VSD closure was performed successfully without complications using a 19 mm Amplatzer septal occluder (St. Jude Medical, Plymouth, MN, USA).
One month before the current presentation, he had bronchiolitis that required hospitalization for 5 days. Echocardiography was repeated and revealed haemodynamically insignificant small residual VSD, PH (60 mmHg), and normal ventricular function (Video3). He was scheduled for a re-evaluation of PH after 6 weeks to allow complete lung recovery, but he presented earlier with COVID-19.
Discussion
There are only a few reported cases of COVID-19 in children with CHD worldwide. These cases included three patients from China6 and three patients from North America.5 Although these patients had a severe illness, they all survived. To the best of our knowledge, this study first reported mortality among children with CHD who acquired SARS-CoV-2 infection.
Consistent with previous reports,5 our patient had underlying CHD and malnutrition. These disorders likely contributed to the severity of the condition that required mechanical ventilation and resulted in MODS.
Our patient presented with fever, dyspnoea, and respiratory failure complicated by cardiac arrest and MODS. Chest radiography revealed bilateral lung infiltrations, which is consistent with previous reports.4,7 A chest computed tomography scan was not performed to limit the spread of infection. Similar to other studies,6 there were evident laboratory abnormalities throughout the disease course (Table 1), including elevated D-dimer, CRP, LDH, and cardiac enzyme levels. The lymphocytic and platelet counts were low as well.
The American Heart Association guidelines recommend the repair of CHD in patients with PH if the PVRI is <6 WU⋅m2 or the PVR/SVR is <0.3 at baseline.8 Accordingly, our patient underwent VSD device closure. The pre-existing PH could have been aggravated by the lung condition associated with COVID-19. Respiratory failure triggered by SARS-CoV-2 infection and MODS could have been correlated with COVID-19 and/or cardiac arrest.
SARS-CoV-2 infection can cause an exacerbated immune reaction that causes a surge in pro-inflammatory cytokines, which is known as a cytokine storm. The biomarkers of cytokine storm include D-dimer, CRP, LDH, troponin, and lymphopenia.9 All of these were observed in the current case.
The patient presented with ventricular dysfunction, elevated troponin serum levels, and newly developed trifascicular block, which were indicative of myocardial injury. The cause of myocardial damage might have been a multifactorial process, which includes viral myocarditis, MODS, and sequelae of cardiac arrest. The previous findings seem to corroborate multisystem inflammatory syndrome in children, which was described recently among paediatric patients with COVID-19.10
Conclusion
COVID-19 may cause life-threatening symptoms in children with underlying CHD.
Lead author biography
Jameel Al-Ata, FRCPC, is an associate professor of Pediatrics and Pediatric Cardiology at King Abdulaziz University, Jeddah, Saudi Arabia. After completing the American Board of Pediatrics, he performed a paediatric cardiology fellowship in Montreal Children’s Hospital (MCH), McGill University, Canada. He is an interventional paediatric cardiologist. He is also very involved in teaching students, residents, and fellows at King Abdulaziz University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient’s parents in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa478_Supplementary_Data Click here for additional data file. | Fatal | ReactionOutcome | CC BY-NC | 33644647 | 19,609,750 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac tamponade'. | Hemopericardium with subsequent cardiac tamponade secondary to rivaroxaban treatment: a case report.
The use and utility of novel oral anticoagulants has been increasing in clinical practice due to their relatively lower incidence of side effects such as intracranial haemorrhage, particularly in the elderly, when compared with vitamin K antagonists. Rivaroxaban is a factor Xa and prothrombinase inhibitor indicated for stroke and venous thromboembolism prophylaxis in non-valvular atrial fibrillation as well as treatment of venous thromboembolism.
A patient with history of paroxysmal atrial fibrillation on Rivaroxaban presented with generalized malaise, lightheadedness, and dizziness. The patient was found to be in profound cardiogenic shock despite unremarkable cardiac enzymes. Electrocardiogram revealed rate controlled atrial fibrillation and T-wave inversions in the inferolateral leads without associated electrical alternans. Bedside echocardiogram revealed a large pericardial effusion consistent with cardiac tamponade physiology. Following anticoagulation reversal, the patient underwent urgent pericardiocentesis yielding haemorrhagic fluid, with subsequent improvement in haemodynamic status. Despite the presence of retroperitoneal lymphadenopathy on previous computed tomography of the abdomen and concern for underlying malignant effusion secondary to lymphoma, cytology of the fluid revealed no evidence of malignant cells and follow-up flow cytometry and bone marrow biopsy were unremarkable.
While hemopericardium is not listed as a known side effect of Rivaroxaban, previous cases of hemopericardium secondary to Rivaroxaban have been described in the literature secondary to pre-disposing risk factors including CYP450 drug interactions or cardiac device implantations. In this case, the patient experienced a spontaneous hemopericardium on Rivaroxaban without any previously elucidated risk factors or evidence of malignancy.
Learning points
Consider Rivaroxaban as the potential offending agent for patients presenting with hemopericardium and subsequent cardiac tamponade secondary to an unclear aetiology.
Previous cases of hemopericardium due to Rivaroxaban have been attributed to drug interactions from CYP3A4 inhibition or recent elective cardiac device implantations.
Concurrent medications known to interact with cytochrome P450 should considered and stratified appropriately, particularly in patients with known underlying renal or hepatic dysfunction, and on azole antifungals or protease inhibitors.
Introduction
The use and utility of novel oral anticoagulants (NOACs) has been increasing in clinical practice due to their relatively lower incidence of side effects such as intracranial haemorrhage, particularly in the elderly, when compared with vitamin K antagonists.1 NOACs are associated with an overall lower risk of major bleeding and lower incidence of thromboembolic events as compared to warfarin. In addition, a predictable clinical profile along with a lack of need for periodic monitoring makes them a convenient option for patients with baseline debility or dementia. Rivaroxaban is a factor Xa and prothrombinase inhibitor indicated for stroke and venous thromboembolism prophylaxis in non-valvular atrial fibrillation as well as treatment of venous thromboembolism based on the ROCKET AF, EINSTEIN DVT, and EINSTEIN PE studies.2–4 While hemopericardium is not listed as a known side effect of Rivaroxaban, previous cases of hemopericardium secondary to Rivaroxaban have been described in the literature secondary to pre-disposing risk factors including CYP450 drug interactions or cardiac device implantations.5–9
Timeline
10 days prior Patient presents with atypical chest pain. Diagnostic workup including troponins, electrocardiogram, and echocardiogram was unremarkable. Computed tomography (CT) angiogram of chest, abdomen, and pelvis was obtained to assess the aorta, which revealed no acute pathology but did note the presence of retroperitoneal lymphadenopathy. The patient was discharged with outpatient follow-up.
3 days prior Patient holds Rivaroxaban in anticipation of gastrointestinal endoscopy for evaluation of chronic anaemia.
1 day prior Patient undergoes upper and lower gastrointestinal endoscopy which reveals no overt bleeding or evidence of malignancy.
Hour 1 Patient presents with generalized malaise, lightheadedness, and dizziness. Found to be hypotensive with a narrow pulse pressure and blood pressure of 80/60 mmHg and tachycardic with a heart rate over 110 b.p.m. On exam, patient is intermittently somnolent with evidence of jugular venous distension, distant heart sounds, prolonged capillary refill, and cool extremities.
Hour 3 Intravenous crystalloids administered and right internal jugular central venous catheter placed for profound hypotension.
Hour 4 Vasopressors initiated with norepinephrine and vasopressin. Admitted to cardiac critical care unit.
Hour 6 Bedside echocardiogram reveals a large global pericardial effusion with concern for cardiac tamponade physiology.
Hour 9 Urgent prothrombin complex concentrate administered to reverse elevated international normalized ratio.
Hour 10 Urgent pericardial drain placed with 1.5 L of haemorrhagic fluid output.
Day 2 Improvement in tamponade physiology on transthoracic echocardiogram.
Day 3 Vasopressors discontinued and pericardial drain removed.
Day 7 Bone marrow biopsy performed. CT-guided biopsy of retroperitoneal lymph node biopsy not performed as the lymph nodes are too small to be biopsied per interventional radiology.
Day 11 Discharged successfully without further complications.
Month 1 Follow-up with haematology outpatient noted unremarkable malignancy workup including pericardial fluid cytology, bone marrow biopsy, flow cytometry of marrow, and chromosome studies of marrow.
Month 3 Evaluated by haematology at another quaternary centre, further testing and bone marrow biopsy were reviewed with no new conclusions.
Month 4 Follow-up CT with contrast of chest, abdomen and pelvis demonstrated no progression of lymphadenopathy or ascending aorta dilation.
Month 5 Follow-up with haematology outpatient with no new developments. Plan for observation and active surveillance.
Case presentation
An 84-year-old man with a past medical history of paroxysmal atrial fibrillation on Rivaroxaban, chronic pancytopenia, coronary artery disease status post remote percutaneous coronary intervention, asymptomatic dilated ascending aorta (5.0 cm in diameter, followed serially, stable for 8 years), essential hypertension and hypothyroidism was admitted for general malaise, lightheadedness, and dizziness. The last dose of Rivaroxaban was 72 h prior to presentation as the patient underwent upper and lower gastrointestinal endoscopy 24 h prior to presentation, for evaluation of chronic anaemia, which revealed non-obstructive schatzki’s ring, mild diverticulosis, three small polyps in ascending colon which were resected with follow-up pathology showing tubular adenoma, and non-bleeding internal haemorrhoids. The patient was not taking any medications known to interact with Rivaroxaban. Upon presentation to the emergency department, the patient was noted to be hypotensive with a narrow pulse pressure and blood pressure of 80/60 mmHg and tachycardic with a heart rate over 110 b.p.m. On exam, patient was intermittently somnolent with evidence of jugular venous distension, distant heart sounds, prolonged capillary refill, and cool extremities. The platelet count on arrival was 219 × 109/L (150–450 × 109/L). There was no significant troponin elevation. Electrocardiogram revealed atrial fibrillation with a rate of 87 and T-wave inversions in the inferolateral leads without associated electrical alternans (Figure 1). Chest radiograph showed a right pleural effusion with an enlarged cardiac silhouette increased in size from a previous radiograph (Figure 2). Following inadequate response to 2.5 L of isotonic crystalloid, the patient was transferred to the intensive care unit and started on high doses of multiple vasopressors. He was noted to have an elevated lactate of 4.3 mmol/L (0.4–2.0 mmol/L), creatinine of 0.225 mmol/L (0.0530–0.1149 mmol/L), aspartate transaminase (AST) of 1499 U/L (0–41 U/L), alanine transaminase (ALT) of 1813 U/L (0–40 U/L), and international normalized ratio (INR) of 3.7 (0.9–1.2) concerning for renal and hepatic hypoperfusion. Bedside echocardiogram was performed which revealed a large global pericardial effusion with a maximal depth of 30 mm with respiratory collapse of the right ventricle consistent with cardiac tamponade physiology (Video 1). Due to worsening hypoxia and haemodynamic instability, the patient underwent immediate INR reversal with prothrombin complex concentrate and then urgent pericardiocentesis via subxiphoid approach, while on non-invasive positive pressure ventilation, which yielded 1.5 L of grossly bloody fluid (Table 1). A pericardial drain was inserted to prevent further fluid accumulation. Repeat INR was 2.2 (0.9–1.2). Post-procedure echocardiogram revealed resolution of tamponade physiology with newly reduced ejection fraction of 35% and severe mitral regurgitation (Video 2). The patient’s oxygenation and haemodynamic parameters improved following the procedure and he was successfully discharged without further complications. The patient was discharged without anticoagulation due to concern for significant bleeding risk and potential for recurrent haemorrhagic pericardial effusion.
Figure 1 Initial electrocardiogram demonstrating atrial fibrillation and T-wave inversions in inferolateral leads.
Figure 2 Chest X-ray from 8 days prior (A) compared to chest X-ray on admission (B) demonstrating enlarged cardiac silhouette.
Table 1 Biochemical and histological examination of the pericardial fluid
Specimen type Pericardial fluid
Colour Red
Clarity Grossly bloody
Red blood cell count 2 617 534/µL
Nucleated cell count 1553/µL
Neutrophils 92%
Lymphocyte 4%
Macrophages 4%
Amylase 47 U/L
Glucose 10 mg/dL
LDH 779 U/L
Total protein 6 g/dL
Culture No growth after 5 days
Gram stain WBC present on direct smear, no organisms seen
Anaerobic culture No growth after 5 days
Fungal smear No fungal elements seen on concentrated smear
Fungal culture No fungus isolated after 4 weeks
AFB smear No acid fast bacilli (concentrated smear)
AFB culture No acid fast bacilli isolated in 8 weeks
Cytology No malignant cells identified
Notably, 10 days prior, patient had presented to the hospital with atypical chest pain. Diagnostic workup including troponins, electrocardiogram, and echocardiogram was unremarkable. Computed tomography (CT) angiogram of chest, abdomen, and pelvis was obtained to assess the aorta, which revealed no acute pathology but did note the presence of retroperitoneal lymphadenopathy (Figure 3). The patient was discharged as the chest pain was deemed to be pleuritic in nature, of non-cardiac aetiology and resolved spontaneously. Given subsequent presentation for hemopericardium, there was concern for underlying malignant effusion, but cytology of the pericardial fluid revealed no evidence of malignant cells. Bone marrow biopsy revealed no overt dysplasia, only normal cellularity with trilineage haematopoiesis. Flow cytometry and chromosome studies of marrow were also unremarkable. A retroperitoneal lymph node biopsy was not performed as the lymph nodes were not deemed pathological by size criteria and were too small to be biopsied per interventional radiology. Haematology recommended long-term follow-up with repeat imaging. Follow-up CT with contrast of chest, abdomen and pelvis 4 months later demonstrated no progression of lymphadenopathy or ascending aorta dilation. Evaluation by two independent haematologists at major quaternary centres including a repeat reading of the bone marrow biopsy, found no evidence of malignancy, recommending observation and active surveillance.
Figure 3 Retroperitoneal lymphadenopathy demonstrated on computed tomography angiogram abdomen with axial view (A) and coronal view (B).
Discussion
Previous cases of hemopericardium due to Rivaroxaban have been attributed to interactions with CYP3A4 via inhibitors such as saw palmetto or amiodarone leading to increased haemorrhagic risk.7,10 In addition, two reported cases detail patients who underwent elective pacemaker or cardiac device implantation 3–6 months prior.8,9 Typically, grossly haemorrhagic pericardial fluid raises suspicion for underlying malignancy, and given our patient’s history of chronic pancytopenia, a thorough workup was conducted which ruled out this possibility. Another aetiology includes myocardial infarction, but this was less likely based on electrocardiographic and laboratory evidence. While this appears to be a spontaneous event in the setting of Rivaroxaban use, the patient’s underlying pancytopenia may have increased the risk of hemopericardium.
Rivaroxaban is primarily metabolized via hepatic cytochrome P450 enzymes including CYP3A4/5 and CYP2J2 but approximately one-third of the dose is unmetabolized and eliminated via renal excretion via P-glycoprotein transporters.11 The remainder is via breast cancer resistance proteins and oxidative biotransformation and non-CYP mediated hydrolysis of amide bonds.12 Cases of hemopericardium are sporadic overall but given the possibility of severe complications, changes to guidelines and protocols for monitoring levels of these NOACs may be indicated. A higher level of clinical suspicion may be appropriate in patients currently taking NOACs who present with non-specific symptoms similar to our gentleman with anaemia of unknown aetiology. While significant renal dysfunction is a contraindication for the administration of Rivaroxaban, reduced doses can be utilized in patients with up to stage 4 chronic kidney disease. Subsequently, concurrent medications known to interact with cytochrome P450 must be considered and stratified appropriately, particularly in patients with known underlying renal or hepatic dysfunction. The significance of the interaction must also be considered as many medications may not produce a clinically relevant effect while strong inhibitors such as azole antifungals and protease inhibitors lead to significantly elevated serum levels of Rivaroxaban.12
Typically, anti-Factor Xa chromogenic assays are used to measure the drug concentration of Rivaroxaban but these levels reportedly do not have any direct correlation with anticoagulant activity13 further emphasizing the need for careful assessment of concurrent medications and supplements for potential interactions. For our patient, urgent reversal with recombinant factor Xa was considered but due to the urgent nature of the situation and concurrent hepatic dysfunction, prothrombin concentrate was utilized instead. A previous randomized, double-blind study demonstrated efficacy in reversing elongated prothrombin time induced by Rivaroxaban with prothrombin complex concentrate albeit with a limited sample size.14 However, our patient was felt to be outside the window period for recombinant factor Xa administration as he had not taken his dose of Rivaroxaban prior to presentation. Administration of recombinant factor Xa demonstrated significant haemostasis in a majority of patients within 12 h of major bleeding but currently, data for bleeding outside of intracranial and gastrointestinal sources available based on the ANEXXA-4 study is limited.15 Larger scale trials in the future would be helpful to obtain more information regarding pharmacokinetics and potential reversal agents in order to guide proper clinical use.
Lead author biography
Pinang Shastri, D.O. is a resident physician at the University of Toledo College of Medicine and Life Sciences. His research interests include cardiac imaging, novel anticoagulation therapies, and cardiac critical care.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa482_Supplementary_Data Click here for additional data file. | RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33644649 | 18,987,635 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pericardial haemorrhage'. | Hemopericardium with subsequent cardiac tamponade secondary to rivaroxaban treatment: a case report.
The use and utility of novel oral anticoagulants has been increasing in clinical practice due to their relatively lower incidence of side effects such as intracranial haemorrhage, particularly in the elderly, when compared with vitamin K antagonists. Rivaroxaban is a factor Xa and prothrombinase inhibitor indicated for stroke and venous thromboembolism prophylaxis in non-valvular atrial fibrillation as well as treatment of venous thromboembolism.
A patient with history of paroxysmal atrial fibrillation on Rivaroxaban presented with generalized malaise, lightheadedness, and dizziness. The patient was found to be in profound cardiogenic shock despite unremarkable cardiac enzymes. Electrocardiogram revealed rate controlled atrial fibrillation and T-wave inversions in the inferolateral leads without associated electrical alternans. Bedside echocardiogram revealed a large pericardial effusion consistent with cardiac tamponade physiology. Following anticoagulation reversal, the patient underwent urgent pericardiocentesis yielding haemorrhagic fluid, with subsequent improvement in haemodynamic status. Despite the presence of retroperitoneal lymphadenopathy on previous computed tomography of the abdomen and concern for underlying malignant effusion secondary to lymphoma, cytology of the fluid revealed no evidence of malignant cells and follow-up flow cytometry and bone marrow biopsy were unremarkable.
While hemopericardium is not listed as a known side effect of Rivaroxaban, previous cases of hemopericardium secondary to Rivaroxaban have been described in the literature secondary to pre-disposing risk factors including CYP450 drug interactions or cardiac device implantations. In this case, the patient experienced a spontaneous hemopericardium on Rivaroxaban without any previously elucidated risk factors or evidence of malignancy.
Learning points
Consider Rivaroxaban as the potential offending agent for patients presenting with hemopericardium and subsequent cardiac tamponade secondary to an unclear aetiology.
Previous cases of hemopericardium due to Rivaroxaban have been attributed to drug interactions from CYP3A4 inhibition or recent elective cardiac device implantations.
Concurrent medications known to interact with cytochrome P450 should considered and stratified appropriately, particularly in patients with known underlying renal or hepatic dysfunction, and on azole antifungals or protease inhibitors.
Introduction
The use and utility of novel oral anticoagulants (NOACs) has been increasing in clinical practice due to their relatively lower incidence of side effects such as intracranial haemorrhage, particularly in the elderly, when compared with vitamin K antagonists.1 NOACs are associated with an overall lower risk of major bleeding and lower incidence of thromboembolic events as compared to warfarin. In addition, a predictable clinical profile along with a lack of need for periodic monitoring makes them a convenient option for patients with baseline debility or dementia. Rivaroxaban is a factor Xa and prothrombinase inhibitor indicated for stroke and venous thromboembolism prophylaxis in non-valvular atrial fibrillation as well as treatment of venous thromboembolism based on the ROCKET AF, EINSTEIN DVT, and EINSTEIN PE studies.2–4 While hemopericardium is not listed as a known side effect of Rivaroxaban, previous cases of hemopericardium secondary to Rivaroxaban have been described in the literature secondary to pre-disposing risk factors including CYP450 drug interactions or cardiac device implantations.5–9
Timeline
10 days prior Patient presents with atypical chest pain. Diagnostic workup including troponins, electrocardiogram, and echocardiogram was unremarkable. Computed tomography (CT) angiogram of chest, abdomen, and pelvis was obtained to assess the aorta, which revealed no acute pathology but did note the presence of retroperitoneal lymphadenopathy. The patient was discharged with outpatient follow-up.
3 days prior Patient holds Rivaroxaban in anticipation of gastrointestinal endoscopy for evaluation of chronic anaemia.
1 day prior Patient undergoes upper and lower gastrointestinal endoscopy which reveals no overt bleeding or evidence of malignancy.
Hour 1 Patient presents with generalized malaise, lightheadedness, and dizziness. Found to be hypotensive with a narrow pulse pressure and blood pressure of 80/60 mmHg and tachycardic with a heart rate over 110 b.p.m. On exam, patient is intermittently somnolent with evidence of jugular venous distension, distant heart sounds, prolonged capillary refill, and cool extremities.
Hour 3 Intravenous crystalloids administered and right internal jugular central venous catheter placed for profound hypotension.
Hour 4 Vasopressors initiated with norepinephrine and vasopressin. Admitted to cardiac critical care unit.
Hour 6 Bedside echocardiogram reveals a large global pericardial effusion with concern for cardiac tamponade physiology.
Hour 9 Urgent prothrombin complex concentrate administered to reverse elevated international normalized ratio.
Hour 10 Urgent pericardial drain placed with 1.5 L of haemorrhagic fluid output.
Day 2 Improvement in tamponade physiology on transthoracic echocardiogram.
Day 3 Vasopressors discontinued and pericardial drain removed.
Day 7 Bone marrow biopsy performed. CT-guided biopsy of retroperitoneal lymph node biopsy not performed as the lymph nodes are too small to be biopsied per interventional radiology.
Day 11 Discharged successfully without further complications.
Month 1 Follow-up with haematology outpatient noted unremarkable malignancy workup including pericardial fluid cytology, bone marrow biopsy, flow cytometry of marrow, and chromosome studies of marrow.
Month 3 Evaluated by haematology at another quaternary centre, further testing and bone marrow biopsy were reviewed with no new conclusions.
Month 4 Follow-up CT with contrast of chest, abdomen and pelvis demonstrated no progression of lymphadenopathy or ascending aorta dilation.
Month 5 Follow-up with haematology outpatient with no new developments. Plan for observation and active surveillance.
Case presentation
An 84-year-old man with a past medical history of paroxysmal atrial fibrillation on Rivaroxaban, chronic pancytopenia, coronary artery disease status post remote percutaneous coronary intervention, asymptomatic dilated ascending aorta (5.0 cm in diameter, followed serially, stable for 8 years), essential hypertension and hypothyroidism was admitted for general malaise, lightheadedness, and dizziness. The last dose of Rivaroxaban was 72 h prior to presentation as the patient underwent upper and lower gastrointestinal endoscopy 24 h prior to presentation, for evaluation of chronic anaemia, which revealed non-obstructive schatzki’s ring, mild diverticulosis, three small polyps in ascending colon which were resected with follow-up pathology showing tubular adenoma, and non-bleeding internal haemorrhoids. The patient was not taking any medications known to interact with Rivaroxaban. Upon presentation to the emergency department, the patient was noted to be hypotensive with a narrow pulse pressure and blood pressure of 80/60 mmHg and tachycardic with a heart rate over 110 b.p.m. On exam, patient was intermittently somnolent with evidence of jugular venous distension, distant heart sounds, prolonged capillary refill, and cool extremities. The platelet count on arrival was 219 × 109/L (150–450 × 109/L). There was no significant troponin elevation. Electrocardiogram revealed atrial fibrillation with a rate of 87 and T-wave inversions in the inferolateral leads without associated electrical alternans (Figure 1). Chest radiograph showed a right pleural effusion with an enlarged cardiac silhouette increased in size from a previous radiograph (Figure 2). Following inadequate response to 2.5 L of isotonic crystalloid, the patient was transferred to the intensive care unit and started on high doses of multiple vasopressors. He was noted to have an elevated lactate of 4.3 mmol/L (0.4–2.0 mmol/L), creatinine of 0.225 mmol/L (0.0530–0.1149 mmol/L), aspartate transaminase (AST) of 1499 U/L (0–41 U/L), alanine transaminase (ALT) of 1813 U/L (0–40 U/L), and international normalized ratio (INR) of 3.7 (0.9–1.2) concerning for renal and hepatic hypoperfusion. Bedside echocardiogram was performed which revealed a large global pericardial effusion with a maximal depth of 30 mm with respiratory collapse of the right ventricle consistent with cardiac tamponade physiology (Video 1). Due to worsening hypoxia and haemodynamic instability, the patient underwent immediate INR reversal with prothrombin complex concentrate and then urgent pericardiocentesis via subxiphoid approach, while on non-invasive positive pressure ventilation, which yielded 1.5 L of grossly bloody fluid (Table 1). A pericardial drain was inserted to prevent further fluid accumulation. Repeat INR was 2.2 (0.9–1.2). Post-procedure echocardiogram revealed resolution of tamponade physiology with newly reduced ejection fraction of 35% and severe mitral regurgitation (Video 2). The patient’s oxygenation and haemodynamic parameters improved following the procedure and he was successfully discharged without further complications. The patient was discharged without anticoagulation due to concern for significant bleeding risk and potential for recurrent haemorrhagic pericardial effusion.
Figure 1 Initial electrocardiogram demonstrating atrial fibrillation and T-wave inversions in inferolateral leads.
Figure 2 Chest X-ray from 8 days prior (A) compared to chest X-ray on admission (B) demonstrating enlarged cardiac silhouette.
Table 1 Biochemical and histological examination of the pericardial fluid
Specimen type Pericardial fluid
Colour Red
Clarity Grossly bloody
Red blood cell count 2 617 534/µL
Nucleated cell count 1553/µL
Neutrophils 92%
Lymphocyte 4%
Macrophages 4%
Amylase 47 U/L
Glucose 10 mg/dL
LDH 779 U/L
Total protein 6 g/dL
Culture No growth after 5 days
Gram stain WBC present on direct smear, no organisms seen
Anaerobic culture No growth after 5 days
Fungal smear No fungal elements seen on concentrated smear
Fungal culture No fungus isolated after 4 weeks
AFB smear No acid fast bacilli (concentrated smear)
AFB culture No acid fast bacilli isolated in 8 weeks
Cytology No malignant cells identified
Notably, 10 days prior, patient had presented to the hospital with atypical chest pain. Diagnostic workup including troponins, electrocardiogram, and echocardiogram was unremarkable. Computed tomography (CT) angiogram of chest, abdomen, and pelvis was obtained to assess the aorta, which revealed no acute pathology but did note the presence of retroperitoneal lymphadenopathy (Figure 3). The patient was discharged as the chest pain was deemed to be pleuritic in nature, of non-cardiac aetiology and resolved spontaneously. Given subsequent presentation for hemopericardium, there was concern for underlying malignant effusion, but cytology of the pericardial fluid revealed no evidence of malignant cells. Bone marrow biopsy revealed no overt dysplasia, only normal cellularity with trilineage haematopoiesis. Flow cytometry and chromosome studies of marrow were also unremarkable. A retroperitoneal lymph node biopsy was not performed as the lymph nodes were not deemed pathological by size criteria and were too small to be biopsied per interventional radiology. Haematology recommended long-term follow-up with repeat imaging. Follow-up CT with contrast of chest, abdomen and pelvis 4 months later demonstrated no progression of lymphadenopathy or ascending aorta dilation. Evaluation by two independent haematologists at major quaternary centres including a repeat reading of the bone marrow biopsy, found no evidence of malignancy, recommending observation and active surveillance.
Figure 3 Retroperitoneal lymphadenopathy demonstrated on computed tomography angiogram abdomen with axial view (A) and coronal view (B).
Discussion
Previous cases of hemopericardium due to Rivaroxaban have been attributed to interactions with CYP3A4 via inhibitors such as saw palmetto or amiodarone leading to increased haemorrhagic risk.7,10 In addition, two reported cases detail patients who underwent elective pacemaker or cardiac device implantation 3–6 months prior.8,9 Typically, grossly haemorrhagic pericardial fluid raises suspicion for underlying malignancy, and given our patient’s history of chronic pancytopenia, a thorough workup was conducted which ruled out this possibility. Another aetiology includes myocardial infarction, but this was less likely based on electrocardiographic and laboratory evidence. While this appears to be a spontaneous event in the setting of Rivaroxaban use, the patient’s underlying pancytopenia may have increased the risk of hemopericardium.
Rivaroxaban is primarily metabolized via hepatic cytochrome P450 enzymes including CYP3A4/5 and CYP2J2 but approximately one-third of the dose is unmetabolized and eliminated via renal excretion via P-glycoprotein transporters.11 The remainder is via breast cancer resistance proteins and oxidative biotransformation and non-CYP mediated hydrolysis of amide bonds.12 Cases of hemopericardium are sporadic overall but given the possibility of severe complications, changes to guidelines and protocols for monitoring levels of these NOACs may be indicated. A higher level of clinical suspicion may be appropriate in patients currently taking NOACs who present with non-specific symptoms similar to our gentleman with anaemia of unknown aetiology. While significant renal dysfunction is a contraindication for the administration of Rivaroxaban, reduced doses can be utilized in patients with up to stage 4 chronic kidney disease. Subsequently, concurrent medications known to interact with cytochrome P450 must be considered and stratified appropriately, particularly in patients with known underlying renal or hepatic dysfunction. The significance of the interaction must also be considered as many medications may not produce a clinically relevant effect while strong inhibitors such as azole antifungals and protease inhibitors lead to significantly elevated serum levels of Rivaroxaban.12
Typically, anti-Factor Xa chromogenic assays are used to measure the drug concentration of Rivaroxaban but these levels reportedly do not have any direct correlation with anticoagulant activity13 further emphasizing the need for careful assessment of concurrent medications and supplements for potential interactions. For our patient, urgent reversal with recombinant factor Xa was considered but due to the urgent nature of the situation and concurrent hepatic dysfunction, prothrombin concentrate was utilized instead. A previous randomized, double-blind study demonstrated efficacy in reversing elongated prothrombin time induced by Rivaroxaban with prothrombin complex concentrate albeit with a limited sample size.14 However, our patient was felt to be outside the window period for recombinant factor Xa administration as he had not taken his dose of Rivaroxaban prior to presentation. Administration of recombinant factor Xa demonstrated significant haemostasis in a majority of patients within 12 h of major bleeding but currently, data for bleeding outside of intracranial and gastrointestinal sources available based on the ANEXXA-4 study is limited.15 Larger scale trials in the future would be helpful to obtain more information regarding pharmacokinetics and potential reversal agents in order to guide proper clinical use.
Lead author biography
Pinang Shastri, D.O. is a resident physician at the University of Toledo College of Medicine and Life Sciences. His research interests include cardiac imaging, novel anticoagulation therapies, and cardiac critical care.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa482_Supplementary_Data Click here for additional data file. | RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33644649 | 18,987,635 | 2021-01 |
What was the administration route of drug 'RIVAROXABAN'? | Hemopericardium with subsequent cardiac tamponade secondary to rivaroxaban treatment: a case report.
The use and utility of novel oral anticoagulants has been increasing in clinical practice due to their relatively lower incidence of side effects such as intracranial haemorrhage, particularly in the elderly, when compared with vitamin K antagonists. Rivaroxaban is a factor Xa and prothrombinase inhibitor indicated for stroke and venous thromboembolism prophylaxis in non-valvular atrial fibrillation as well as treatment of venous thromboembolism.
A patient with history of paroxysmal atrial fibrillation on Rivaroxaban presented with generalized malaise, lightheadedness, and dizziness. The patient was found to be in profound cardiogenic shock despite unremarkable cardiac enzymes. Electrocardiogram revealed rate controlled atrial fibrillation and T-wave inversions in the inferolateral leads without associated electrical alternans. Bedside echocardiogram revealed a large pericardial effusion consistent with cardiac tamponade physiology. Following anticoagulation reversal, the patient underwent urgent pericardiocentesis yielding haemorrhagic fluid, with subsequent improvement in haemodynamic status. Despite the presence of retroperitoneal lymphadenopathy on previous computed tomography of the abdomen and concern for underlying malignant effusion secondary to lymphoma, cytology of the fluid revealed no evidence of malignant cells and follow-up flow cytometry and bone marrow biopsy were unremarkable.
While hemopericardium is not listed as a known side effect of Rivaroxaban, previous cases of hemopericardium secondary to Rivaroxaban have been described in the literature secondary to pre-disposing risk factors including CYP450 drug interactions or cardiac device implantations. In this case, the patient experienced a spontaneous hemopericardium on Rivaroxaban without any previously elucidated risk factors or evidence of malignancy.
Learning points
Consider Rivaroxaban as the potential offending agent for patients presenting with hemopericardium and subsequent cardiac tamponade secondary to an unclear aetiology.
Previous cases of hemopericardium due to Rivaroxaban have been attributed to drug interactions from CYP3A4 inhibition or recent elective cardiac device implantations.
Concurrent medications known to interact with cytochrome P450 should considered and stratified appropriately, particularly in patients with known underlying renal or hepatic dysfunction, and on azole antifungals or protease inhibitors.
Introduction
The use and utility of novel oral anticoagulants (NOACs) has been increasing in clinical practice due to their relatively lower incidence of side effects such as intracranial haemorrhage, particularly in the elderly, when compared with vitamin K antagonists.1 NOACs are associated with an overall lower risk of major bleeding and lower incidence of thromboembolic events as compared to warfarin. In addition, a predictable clinical profile along with a lack of need for periodic monitoring makes them a convenient option for patients with baseline debility or dementia. Rivaroxaban is a factor Xa and prothrombinase inhibitor indicated for stroke and venous thromboembolism prophylaxis in non-valvular atrial fibrillation as well as treatment of venous thromboembolism based on the ROCKET AF, EINSTEIN DVT, and EINSTEIN PE studies.2–4 While hemopericardium is not listed as a known side effect of Rivaroxaban, previous cases of hemopericardium secondary to Rivaroxaban have been described in the literature secondary to pre-disposing risk factors including CYP450 drug interactions or cardiac device implantations.5–9
Timeline
10 days prior Patient presents with atypical chest pain. Diagnostic workup including troponins, electrocardiogram, and echocardiogram was unremarkable. Computed tomography (CT) angiogram of chest, abdomen, and pelvis was obtained to assess the aorta, which revealed no acute pathology but did note the presence of retroperitoneal lymphadenopathy. The patient was discharged with outpatient follow-up.
3 days prior Patient holds Rivaroxaban in anticipation of gastrointestinal endoscopy for evaluation of chronic anaemia.
1 day prior Patient undergoes upper and lower gastrointestinal endoscopy which reveals no overt bleeding or evidence of malignancy.
Hour 1 Patient presents with generalized malaise, lightheadedness, and dizziness. Found to be hypotensive with a narrow pulse pressure and blood pressure of 80/60 mmHg and tachycardic with a heart rate over 110 b.p.m. On exam, patient is intermittently somnolent with evidence of jugular venous distension, distant heart sounds, prolonged capillary refill, and cool extremities.
Hour 3 Intravenous crystalloids administered and right internal jugular central venous catheter placed for profound hypotension.
Hour 4 Vasopressors initiated with norepinephrine and vasopressin. Admitted to cardiac critical care unit.
Hour 6 Bedside echocardiogram reveals a large global pericardial effusion with concern for cardiac tamponade physiology.
Hour 9 Urgent prothrombin complex concentrate administered to reverse elevated international normalized ratio.
Hour 10 Urgent pericardial drain placed with 1.5 L of haemorrhagic fluid output.
Day 2 Improvement in tamponade physiology on transthoracic echocardiogram.
Day 3 Vasopressors discontinued and pericardial drain removed.
Day 7 Bone marrow biopsy performed. CT-guided biopsy of retroperitoneal lymph node biopsy not performed as the lymph nodes are too small to be biopsied per interventional radiology.
Day 11 Discharged successfully without further complications.
Month 1 Follow-up with haematology outpatient noted unremarkable malignancy workup including pericardial fluid cytology, bone marrow biopsy, flow cytometry of marrow, and chromosome studies of marrow.
Month 3 Evaluated by haematology at another quaternary centre, further testing and bone marrow biopsy were reviewed with no new conclusions.
Month 4 Follow-up CT with contrast of chest, abdomen and pelvis demonstrated no progression of lymphadenopathy or ascending aorta dilation.
Month 5 Follow-up with haematology outpatient with no new developments. Plan for observation and active surveillance.
Case presentation
An 84-year-old man with a past medical history of paroxysmal atrial fibrillation on Rivaroxaban, chronic pancytopenia, coronary artery disease status post remote percutaneous coronary intervention, asymptomatic dilated ascending aorta (5.0 cm in diameter, followed serially, stable for 8 years), essential hypertension and hypothyroidism was admitted for general malaise, lightheadedness, and dizziness. The last dose of Rivaroxaban was 72 h prior to presentation as the patient underwent upper and lower gastrointestinal endoscopy 24 h prior to presentation, for evaluation of chronic anaemia, which revealed non-obstructive schatzki’s ring, mild diverticulosis, three small polyps in ascending colon which were resected with follow-up pathology showing tubular adenoma, and non-bleeding internal haemorrhoids. The patient was not taking any medications known to interact with Rivaroxaban. Upon presentation to the emergency department, the patient was noted to be hypotensive with a narrow pulse pressure and blood pressure of 80/60 mmHg and tachycardic with a heart rate over 110 b.p.m. On exam, patient was intermittently somnolent with evidence of jugular venous distension, distant heart sounds, prolonged capillary refill, and cool extremities. The platelet count on arrival was 219 × 109/L (150–450 × 109/L). There was no significant troponin elevation. Electrocardiogram revealed atrial fibrillation with a rate of 87 and T-wave inversions in the inferolateral leads without associated electrical alternans (Figure 1). Chest radiograph showed a right pleural effusion with an enlarged cardiac silhouette increased in size from a previous radiograph (Figure 2). Following inadequate response to 2.5 L of isotonic crystalloid, the patient was transferred to the intensive care unit and started on high doses of multiple vasopressors. He was noted to have an elevated lactate of 4.3 mmol/L (0.4–2.0 mmol/L), creatinine of 0.225 mmol/L (0.0530–0.1149 mmol/L), aspartate transaminase (AST) of 1499 U/L (0–41 U/L), alanine transaminase (ALT) of 1813 U/L (0–40 U/L), and international normalized ratio (INR) of 3.7 (0.9–1.2) concerning for renal and hepatic hypoperfusion. Bedside echocardiogram was performed which revealed a large global pericardial effusion with a maximal depth of 30 mm with respiratory collapse of the right ventricle consistent with cardiac tamponade physiology (Video 1). Due to worsening hypoxia and haemodynamic instability, the patient underwent immediate INR reversal with prothrombin complex concentrate and then urgent pericardiocentesis via subxiphoid approach, while on non-invasive positive pressure ventilation, which yielded 1.5 L of grossly bloody fluid (Table 1). A pericardial drain was inserted to prevent further fluid accumulation. Repeat INR was 2.2 (0.9–1.2). Post-procedure echocardiogram revealed resolution of tamponade physiology with newly reduced ejection fraction of 35% and severe mitral regurgitation (Video 2). The patient’s oxygenation and haemodynamic parameters improved following the procedure and he was successfully discharged without further complications. The patient was discharged without anticoagulation due to concern for significant bleeding risk and potential for recurrent haemorrhagic pericardial effusion.
Figure 1 Initial electrocardiogram demonstrating atrial fibrillation and T-wave inversions in inferolateral leads.
Figure 2 Chest X-ray from 8 days prior (A) compared to chest X-ray on admission (B) demonstrating enlarged cardiac silhouette.
Table 1 Biochemical and histological examination of the pericardial fluid
Specimen type Pericardial fluid
Colour Red
Clarity Grossly bloody
Red blood cell count 2 617 534/µL
Nucleated cell count 1553/µL
Neutrophils 92%
Lymphocyte 4%
Macrophages 4%
Amylase 47 U/L
Glucose 10 mg/dL
LDH 779 U/L
Total protein 6 g/dL
Culture No growth after 5 days
Gram stain WBC present on direct smear, no organisms seen
Anaerobic culture No growth after 5 days
Fungal smear No fungal elements seen on concentrated smear
Fungal culture No fungus isolated after 4 weeks
AFB smear No acid fast bacilli (concentrated smear)
AFB culture No acid fast bacilli isolated in 8 weeks
Cytology No malignant cells identified
Notably, 10 days prior, patient had presented to the hospital with atypical chest pain. Diagnostic workup including troponins, electrocardiogram, and echocardiogram was unremarkable. Computed tomography (CT) angiogram of chest, abdomen, and pelvis was obtained to assess the aorta, which revealed no acute pathology but did note the presence of retroperitoneal lymphadenopathy (Figure 3). The patient was discharged as the chest pain was deemed to be pleuritic in nature, of non-cardiac aetiology and resolved spontaneously. Given subsequent presentation for hemopericardium, there was concern for underlying malignant effusion, but cytology of the pericardial fluid revealed no evidence of malignant cells. Bone marrow biopsy revealed no overt dysplasia, only normal cellularity with trilineage haematopoiesis. Flow cytometry and chromosome studies of marrow were also unremarkable. A retroperitoneal lymph node biopsy was not performed as the lymph nodes were not deemed pathological by size criteria and were too small to be biopsied per interventional radiology. Haematology recommended long-term follow-up with repeat imaging. Follow-up CT with contrast of chest, abdomen and pelvis 4 months later demonstrated no progression of lymphadenopathy or ascending aorta dilation. Evaluation by two independent haematologists at major quaternary centres including a repeat reading of the bone marrow biopsy, found no evidence of malignancy, recommending observation and active surveillance.
Figure 3 Retroperitoneal lymphadenopathy demonstrated on computed tomography angiogram abdomen with axial view (A) and coronal view (B).
Discussion
Previous cases of hemopericardium due to Rivaroxaban have been attributed to interactions with CYP3A4 via inhibitors such as saw palmetto or amiodarone leading to increased haemorrhagic risk.7,10 In addition, two reported cases detail patients who underwent elective pacemaker or cardiac device implantation 3–6 months prior.8,9 Typically, grossly haemorrhagic pericardial fluid raises suspicion for underlying malignancy, and given our patient’s history of chronic pancytopenia, a thorough workup was conducted which ruled out this possibility. Another aetiology includes myocardial infarction, but this was less likely based on electrocardiographic and laboratory evidence. While this appears to be a spontaneous event in the setting of Rivaroxaban use, the patient’s underlying pancytopenia may have increased the risk of hemopericardium.
Rivaroxaban is primarily metabolized via hepatic cytochrome P450 enzymes including CYP3A4/5 and CYP2J2 but approximately one-third of the dose is unmetabolized and eliminated via renal excretion via P-glycoprotein transporters.11 The remainder is via breast cancer resistance proteins and oxidative biotransformation and non-CYP mediated hydrolysis of amide bonds.12 Cases of hemopericardium are sporadic overall but given the possibility of severe complications, changes to guidelines and protocols for monitoring levels of these NOACs may be indicated. A higher level of clinical suspicion may be appropriate in patients currently taking NOACs who present with non-specific symptoms similar to our gentleman with anaemia of unknown aetiology. While significant renal dysfunction is a contraindication for the administration of Rivaroxaban, reduced doses can be utilized in patients with up to stage 4 chronic kidney disease. Subsequently, concurrent medications known to interact with cytochrome P450 must be considered and stratified appropriately, particularly in patients with known underlying renal or hepatic dysfunction. The significance of the interaction must also be considered as many medications may not produce a clinically relevant effect while strong inhibitors such as azole antifungals and protease inhibitors lead to significantly elevated serum levels of Rivaroxaban.12
Typically, anti-Factor Xa chromogenic assays are used to measure the drug concentration of Rivaroxaban but these levels reportedly do not have any direct correlation with anticoagulant activity13 further emphasizing the need for careful assessment of concurrent medications and supplements for potential interactions. For our patient, urgent reversal with recombinant factor Xa was considered but due to the urgent nature of the situation and concurrent hepatic dysfunction, prothrombin concentrate was utilized instead. A previous randomized, double-blind study demonstrated efficacy in reversing elongated prothrombin time induced by Rivaroxaban with prothrombin complex concentrate albeit with a limited sample size.14 However, our patient was felt to be outside the window period for recombinant factor Xa administration as he had not taken his dose of Rivaroxaban prior to presentation. Administration of recombinant factor Xa demonstrated significant haemostasis in a majority of patients within 12 h of major bleeding but currently, data for bleeding outside of intracranial and gastrointestinal sources available based on the ANEXXA-4 study is limited.15 Larger scale trials in the future would be helpful to obtain more information regarding pharmacokinetics and potential reversal agents in order to guide proper clinical use.
Lead author biography
Pinang Shastri, D.O. is a resident physician at the University of Toledo College of Medicine and Life Sciences. His research interests include cardiac imaging, novel anticoagulation therapies, and cardiac critical care.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Supplementary Material
ytaa482_Supplementary_Data Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY-NC | 33644649 | 18,987,635 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anticoagulation drug level above therapeutic'. | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33644653 | 19,008,280 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Factor X deficiency'. | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33644653 | 19,008,280 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neurological symptom'. | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33644653 | 19,008,280 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Purpura'. | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | WARFARIN SODIUM | DrugsGivenReaction | CC BY | 33644653 | 19,008,280 | 2021-01 |
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