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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dermatitis bullous'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dysuria'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Erythema multiforme'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin lesion'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Stomatitis'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
What was the outcome of reaction 'Cheilitis'? | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
What was the outcome of reaction 'Dermatitis bullous'? | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
What was the outcome of reaction 'Dysuria'? | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
What was the outcome of reaction 'Erythema multiforme'? | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
What was the outcome of reaction 'Rash'? | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
What was the outcome of reaction 'Skin lesion'? | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
What was the outcome of reaction 'Stomatitis'? | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematotoxicity'. | How Long is It Safe to Wait for Breast Surgery After Completion of Neoadjuvant Chemotherapy?
This study aimed to evaluate the impact of surgical time on postoperative complications and survival outcomes in breast cancer patients after neoadjuvant chemotherapy (NAC).
We retrospectively reviewed breast cancer patients treated at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II-III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom medical records were available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and with distant metastasis or contralateral breast cancer, were excluded. Eligible patients were divided into three groups based on time to surgery (TTS): (A) ≤21 days; (B) between 21 and 28 days; and (C) >28 days. We collected medical records and followed up patients.
Totally 422 patients were enrolled. The median TTS was 26 days. Among these patients, 119 (28.2%) were in Group A, 152 (36.0%) were in Group B, and 151 (35.8%) were in Group C. Eighty-two (19.4%) patients achieved pathologic complete response (pCR). Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. In multivariate analysis, DFS (HR=2.333, P=0.001) and OS (HR=2.783, P=0.030) were significantly worse when TTS >28 days. Postoperative complications occurred in 96 (22.7%) patients. The incidence of total postoperative complications in the three groups was statistically different (P=0.001) and Group A had worse performance. Multivariate analysis showed that age >50 years old (P=0.004) and TTS ≤21 days (P<0.001) were independent parameters for total postoperative complications.
Postoperative complications and survival outcomes in breast cancer patients seemed to be influenced by TTS after the NAC. The benefits were remarkable in patients undergoing surgery between 21 and 28 days.
Introduction
Neoadjuvant chemotherapy (NAC) has been widely used in breast cancer patients due to its advantages such as reducing tumor stage, increasing the operation opportunity of inoperable patients, improving breast-conserving rate, evaluating drug efficacy and guiding adjuvant treatment strategies.1 Nonetheless, the time interval between surgery and the NAC remains to be determined. Using the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Database, two independent population-based studies were conducted by Bleicher et al.2 It was evidenced from the results that the lower disease-specific survival rate and overall survival rate were closely related to the long-term delay from the diagnosis to the surgery. The timeliness of treatment (including surgery and systemic treatment) could affect the prognosis of patients. Therefore, it can be inferred that prolonged surgery delay affect the prognosis of patients treated with NAC, especially those with high-risk factors. In the past studies, the relationship between the time to surgery (TTS) after NAC and the prognosis of breast cancer patients was controversial. Omarini et al thought that survival would be affected when the TTS was >21 days, while Suleman et al believed that TTS might not affect survival.3,4 Moreover, the incidence of postoperative complications can also affect clinicians’ choice of TTS after NAC. Some studies have suggested that NAC was a risk factor for early postoperative complications, but the specific relationship between TTS and complications was still unknown.5
Therefore, the specific relationship between TTS and patients’ survival was intended to be explored by this study, as well as between TTS and postoperative complications, to obtain the optimal TTS after NAC.
Patients and Methods
Study Population
We retrospectively reviewed patients who were diagnosed with breast cancer at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II–III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom information regarding the treatment records was available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and those with distant metastasis or contralateral breast cancer, were excluded.
In our database, there were 8311 breast cancer patients from January 2013 to December 2018, including 473 patients who received NAC. We extracted the patients’ medical history and treatment information from the database. Then, 422 patients satisfied the criteria and were screened out. And these patients were divided into three groups based on TTS: (A) TTS ≤21 days; (B) TTS between 21 and 28 days; and (C) TTS>28 days.
Before NAC, all patients underwent systemic survey to exclude distant metastasis. With the PET-CT being performed on selected patients, the systemic survey included the brain magnetic resonance imaging (MRI) and bone scans, the chest computed tomography (CT) scans, the ultrasound scans of the liver and the neck, and the serum tumor markers for all the patients. Applying the core-needle biopsy method, all patients’ primary breast cancers were histologically identified. The results of immunohistochemistry were obtained in 365 (86.5%) patients before NAC. Human epidermal growth factor receptor 2 (HER2) positivity was defined as either 3+ on IHC staining or 2+ on IHC with a positive fluorescence in situ hybridization or chromogenic in situ hybridization signal. The molecular subtype of each breast cancer was categorized as follows: ER+ or PR+, and HER2− (luminal); ER+/−, PR+/−, and HER2+ (HER2 enriched); or ER−, PR−, and HER2− (triple-negative). The NAC regimens were determined according to the guidelines. Every two cycles, we evaluated the efficacy of chemotherapy by physical examinations and imaging examinations. Pathologic complete response (pCR) was defined as the absence of histological evidence of malignancy or the presence of only cancer in situ in the primary breast lesions, regardless of axillary lymph node metastasis. Patients with absence of invasive disease in the breast but presence of axillary lymph node metastasis were also defined as pCR patients. The incidence of surgery-related complications and treatment measures were recorded through the patients’ medical records and periodic follow-up. All patients were followed up every six months after surgery. After recurrence or metastasis of tumor, patients were reexamined every two months.
Statistical Analysis
From the initial diagnosis of the primary breast cancer to the tumor recurrence or metastasis, the pertinent time interval was referred to as the disease-free survival (DFS). The overall survival (OS) was considered as the interval between the initial diagnosis of the primary breast cancer and the last follow-up or the death due to any cause. Applying the chi-square test, the rank sum test, or the Fisher’s exact test, the differences in the categorical variables were compared. The Kaplan-Meier method and the Log rank test were used to calculate the actuarial survival rates. In the multivariate analysis, the factors with a p-value<0.05 in the univariate analysis were included. The p<0.05 was considered to be statistically significant in the multivariate analysis, which was performed with the Cox proportional hazards model. The SPSS software (version 17.0.1. SPSS Inc., Chicago, IL) was used in all the statistical analyses.
Ethical Statement
Meeting all the guidelines of the governmental agency, the institutional review committee of the Affiliated Hospital of Qingdao University approved the experimental protocols. All patients provided informed consent, and this study was conducted in accordance with the Declaration of Helsinki.
Results
Cohort Survey
In total, 422 patients were enrolled. Among these patients, 119 (28.2%) patients had surgery within 21 days of their last dose of NAC, 152 (36.0%) patients in 21–28 days, and 151 (35.8%) patients after 28 days. The process of screening and grouping is shown in Figure 1. The median age of all the patients was 49 years old (range, 22–73 years), the median duration of follow-up was 42 months (range, 24 to 93 months), while the median TTS was of 26 days (range, 14 to 63 days) for all the 422 patients. They received anthracycline- or taxane-based NAC, and 82 patients achieved pCR (19.4%). Forty-two (10.0%) patients changed the chemotherapy regimen because of insufficient efficacy, and 20 (4.7%) patients interrupted the scheduled regimen because of the side effects of the drugs.Figure 1 The procedure of screening and grouping patients.
Abbreviations: NAC, neoadjuvant chemotherapy; TTS, time to surgery.
The main pathological type of primary breast cancer is non-specific invasive ductal carcinoma (401/422, 95.0%), in addition to some invasive lobular carcinoma, mucinous carcinoma, medullary carcinoma and so on. In terms of the molecular subtype, 41.2% (174/422), 45.7% (193/422) and 13.0% (55/422) of the patients were luminal, HER2-enriched and triple-negative, respectively. The pCR rates of patients with molecular subtype luminal, HER2-enriched and triple-negative were 7.5% (13/174), 28.0% (54/193) and 27.3% (15/55), respectively. Among these 193 HER2-enriched patients, 72.0% (139/193) patients were treated with trastuzumab in neoadjuvant therapy, and 91.2% (176/193) patients were treated with trastuzumab in adjuvant therapy. Of all 422 patients, 147 (33.3%) patients had tumor recurrence or metastasis during follow-up and 52 (12.3%) patients died. The median DFS was 36 months (range, 4 to 93 months), and the 3-year OS rate was 94.1% (397/422). When tumor progression was first detected, 30 patients had local recurrence, 12 patients were observed to have had distant metastasis and local recurrence both, while 79 patients showed distant metastasis. The lung, followed by the bone, was indicated to be the most common metastatic organ.
Survival Analysis of Patients in the Different TTS Groups
Regarding the different TTS, 442 patients were divided into three groups. Table 1 shows the comparison of patients’ characteristics in three groups. There was no significant difference in age, menstrual state, family history relative to breast cancer, tumor T stage before NAC, axillary lymph nodes involvement before NAC, histological grade, HR status, HER2 status, Ki-67 value, molecular subtype, drugs of NAC, clinical response to NAC, breast surgery type, pCR or non-pCR, pN stage after surgery, adjuvant chemotherapy, adjuvant radiotherapy, and targeted therapy.Table 1 The Comparison of Patients’ Characteristics in Three Groups
Characteristics Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Age (years) ≤50 74 (62.2) 89 (58.6) 79 (52.3) 0.248
>50 45 (37.8) 63 (41.4) 72 (47.7)
Menstrual state Premenopausal 73 (61.3) 93 (61.2) 79 (52.3) 0.204
Postmenopausal 46 (38.7) 59 (38.8) 72 (47.7)
Family history No 117 (98.3) 147 (96.7) 145 (96.0) 0.516
Yes 2 (1.7) 5 (3.3) 6 (4.0)
Initial T stage 1 6 (5.0) 17 (11.2) 11 (7.3) 0.196
2 80 (67.2) 83 (54.6) 90 (59.6)
3 33 (27.7) 52 (34.2) 50 (33.1)
Initial axillary LN Uninvolved 17 (14.3) 21 (13.8) 26 (17.2) 0.677
Involved 102 (85.7) 131 (86.2) 125 (82.8)
Histological grade 1–2 76 (63.9) 95 (62.5) 101 (66.9) 0.718
3 43 (36.1) 57 (37.5) 50 (33.1)
HR status Positive 78 (65.5) 101 (66.4) 102 (67.5) 0.941
Negative 41 (34.5) 51 (33.6) 49 (32.5)
HER2 status (FISH or CISH) Positive 49 (41.2) 55 (36.2) 49 (32.5) 0.334
Negative 70 (58.8) 97 (63.8) 102 (67.5)
Ki-67 value ≤20% 35 (29.4) 34 (22.4) 36 (23.8) 0.385
>20% 84 (70.6) 118 (77.6) 115 (76.2)
Molecular subtype Luminal 45 (37.8) 58 (38.2) 71 (47.0) 0.468
HER2-enriched 57 (47.9) 72 (47.4) 64 (42.4)
Triple-negative 17 (14.3) 22 (14.5) 16 (10.6)
NAC drugs Taxane-based 6 (5.0) 6 (3.9) 12 (7.9) 0.236
Anthracycline-based 1 (0.8) 5 (3.3) 6 (4.0)
Taxane- and anthracycline- based 112 (94.1) 141 (92.8) 133 (88.1)
Neoadjuvant targeted therapy Yes 42 (35.3) 52 (34.2) 45 (29.8) 0.582
No 77 (64.7) 100 (65.8) 106 (70.2)
Clinical response CR 6 (5.0) 15 (9.9) 8 (5.3) 0.056
PR 85 (71.4) 110 (72.4) 100 (66.2)
SD 24 (20.2) 23 (15.1) 42 (27.8)
PD 4 (3.4) 4 (2.6) 1 (0.7)
Breast surgery Mastectomy 110 (92.4) 139 (91.4) 140 (92.7) 0.912
BCS 9 (7.6) 13 (8.6) 11 (7.3)
pCR or non-pCR pCR 22 (18.5) 33 (21.7) 27 (17.9) 0.669
Non-pCR 97 (81.5) 119 (78.3) 124 (82.1)
pN stage 0 39 (32.8) 54 (35.5) 53 (35.1) 0.994
1 36 (30.3) 40 (26.3) 44 (29.1)
2 27 (22.7) 36 (23.7) 34 (22.5)
3 17 (14.3) 22 (14.5) 20 (13.2)
Adjuvant chemotherapy Yes 25 (21.0) 23 (15.1) 23 (15.2) 0.355
No 94 (79.0) 129 (84.9) 128 (84.8)
Adjuvant radiotherapy Yes 109 (91.6) 142 (93.4) 130 (86.1) 0.084
No 10 (8.4) 10 (6.6) 21 (13.9)
Adjuvant targeted therapy Yes 52 (43.7) 67 (44.1) 57 (37.7) 0.468
No 67 (56.3) 85 (55.9) 94 (62.3)
Abbreviations: T, tumor; LN, lymph node; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; FISH, fluorescence in situ hybridization; CISH, chromogenic in situ hybridization; NAC, neoadjuvant chemotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; BCS, breast conserving surgery; pCR, pathologic complete response.
The median DFS of the Group A was 43 months (range, 9 to 87 months), the median DFS of the Group B was 35.5 months (range, 4 to 81 months), and the median DFS of the Group C was 33 months (range, 6 to 93 months). In the three groups, the median OS was found to be 46 months (range, 25 to 87 months), 41 months (range, 24 to 81 months) and 39 months (range, 25 to 93 months) respectively. The 3-year OS rate of the three groups was 95.8% (114/119), 96.7% (147/152) and 90.1% (136/151), respectively.
Figure 2 indicates the results of the Kaplan-Meier survival curves using the Log rank test for the DFS and the OS. Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. Between Groups A and B, no significant difference in the DFS (P=0.595) and the OS (P=0.716) was observed. Nonetheless, between Groups A and C, the survival analysis indicated that DFS (P=0.006) and the OS (P=0.014) were found to be significantly different. At the same time, the DFS (P=0.024) and OS (P=0.027) of Group B were significantly different from that of Group C. This indicated that TTS >28 days did affect the survival outcome of these patients.Figure 2 Kaplan–Meier curves for survival according to different time to surgery. (A) Disease-free survival (P=0.012). (B) Overall survival (P=0.015).
Univariate and Multivariate Analyses for DFS and OS
The univariate analysis of DFS showed that pCR, pN stage, adjuvant chemotherapy and TTS were significant factors (P<0.001, P<0.001, P=0.001 and P=0.003, respectively). For OS, the univariate analysis showed that pN stage, adjuvant chemotherapy and TTS were significant factors (P=0.014, P=0.001 and P=0.032, respectively). In the multivariate analyses, DFS and OS were significantly worse when TTS >28 days with a hazard ratio of 2.333 (95% CI, 1.444–3.770, P=0.001) and 2.783 (95% CI, 1.007–7.687, P=0.030) respectively. Patients with pCR, pN2-3 stage and adjuvant chemotherapy were independent parameters for DFS (P=0.042, P<0.001 and P=0.001, respectively), while pN2-3 stage and adjuvant chemotherapy were also independent parameters for OS (P=0.024 and P=0.010, respectively). The relevant statistics are shown in Table 2.Table 2 Univariate and Multivariate Analysis for DFS and OS
Variables DFS OS
3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate) 3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.958 0.488
≤50 71.9 93.4
>50 71.7 95.0
Menstrual state 0.523 0.839
Premenopausal 70.6 93.9
Postmenopausal 73.4 94.4
Initial T stage 0.112 0.713
1 85.3 97.1
2 72.3 94.1
3 67.4 6.7
Initial axillary LN 0.537 0.905
Uninvolved 75.0 93.7
Involved 71.2 94.1
Histological grade 0.769 0.961
1–2 71.3 94.1
3 72.7 94.0
Ki-67 value 0.689 0.125
≤20% 73.3 97.1
>20% 71.3 93.1
Molecular subtype 0.394 0.194
Luminal 75.3 96.6
HER2-enriched 68.9 92.2
Triple-negative 70.9 92.7
Breast surgery 0.599 0.422
Mastectomy 71.5 94.3
BCS 75.8 90.9
pCR or non-pCR <0.001 0.042 0.136
pCR 89.0 1 97.6
Non-pCR 67.6 2.070 (1.026–4.176) 93.2
pN stage <0.001 <0.001 0.014 0.024
0–1 80.8 1 96.2 1
2–3 56.4 2.435 (1.677–3.536) 90.4 2.524 (1.130–5.634)
Adjuvant chemotherapy 0.001 0.001 0.001 0.010
Yes 54.9 2.330 (1.538–3.530) 85.9 3.671 (1.647–8.182)
No 75.2 1 95.7 1
Adjuvant radiotherapy 0.209 0.691
Yes 51.0 94.2
No 37.5 92.7
TTS 0.003 0.001 0.032 0.030
Group A 79.8 1 95.8 1
Group B 75.0 1.469 (0.879–2.453) 0.142 96.7 0.891 (0.257–3.083) 0.855
Group C 62.3 2.333 (1.444–3.770) 0.001 89.0 2.783 (1.007–7.687) 0.048
Abbreviations: DFS, disease-free survival; OS, overall survival; CI, confidence interval; T, tumor; LN, lymph node; HER2, human epidermal growth factor receptor 2; BCS, breast conserving surgery; pCR, pathologic complete response; TTS, time to surgery.
Relationship Between TTS and Postoperative Complications
Postoperative complications occurred in 96 (22.7%) patients, including poor healing of incision, infection, hematoma or hemorrhage, subcutaneous effusion and skin flap necrosis. The incidence of postoperative complications is shown in Table 3 and the classification of severity is shown in Table 4. Most of the patients were treated in the outpatient department; only 4.2% (4/96) of the patients returned to the operating room and received general anesthesia operations. The incidence of total postoperative complications in the three groups was statistically different (P=0.001). Compared with Group B (P=0.003) and Group C (P<0.001), Group A had worse performance in total postoperative complications. The total complication rates of Group B and Group C were similar (P=0.566). This suggested that TTS ≤21 days was significantly associated with a higher incidence of total postoperative complications. And among the five kinds of complications, the incidence of poor incision healing (P=0.024) and infection (P=0.031) was significantly different among the three groups. The univariate analysis indicated that age and TTS were the significant factors for total postoperative complications (P=0.009 and P<0.001, respectively). In the multivariate analysis, age >50 years old and TTS ≤21 days were independent parameters for total postoperative complications (P=0.004 and P<0.001, respectively). The statistical details are shown in Table 5.Table 3 Relationship Between TTS and Postoperative Complications
Postoperative Complications Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Poor incision healing Yes 15 (12.6) 10 (6.6) 6 (4.0) 0.024
No 104 (87.4) 142 (93.4) 145 (96.0)
Infection Yes 12 (10.1) 6 (3.9) 5 (3.3) 0.031
No 107 (89.9) 146 (96.1) 146 (96.7)
Hematoma or hemorrhage Yes 5 (4.2) 5 (3.3) 7 (4.6) 0.832
No 114 (95.8) 147 (96.7) 144 (95.4)
Subcutaneous effusion Yes 9 (7.6) 6 (3.9) 6 (4.0) 0.310
No 110 (92.4) 146 (96.1) 145 (96.0)
Skin flap necrosis Yes 1 (0.8) 2 (1.3) 1 (0.7) 0.833
No 118 (99.2) 150 (98.7) 150 (99.3)
Total Yes 42 (35.3) 29 (19.1) 25 (16.6) 0.001
No 77 (64.7) 123 (80.9) 126 (83.4)
Abbreviation: TTS, time to surgery.
Table 4 Classification of the Severity of Postoperative Complications
Clavien-Dindo Grade Number of Patients Undergone Postoperative Complications (%)
Group A
(n = 42) Group B (n = 29) Group C
(n = 25)
Grade I 13 (31.0) 12 (41.4) 9 (36.0)
Grade II 11 (26.2) 6 (20.7) 5 (20.0)
Grade IIIa 16 (38.1) 10 (34.5) 10 (40.0)
Grade IIIb 2 (4.8) 1 (3.4) 1 (4.0)
Grade IV/V 0 (0) 0 (0) 0 (0)
Table 5 Univariate and Multivariate Analysis for Postoperative Complications
Variables Postoperative Complications
Incidence Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.009 0.004
≤50 18.2 1
>50 28.9 1.996 (1.245–3.201)
BMI 0.984
≤20 23.8
20< BMI≤25 21.9
25< BMI≤30 23.3
>30 23.9
NAC drugs 0.945
Taxane-based 25.0
Anthracycline-based 25.0
Taxane- and anthracycline- based 22.5
Breast surgery 0.826
Mastectomy 22.9
BCS 21.2
TTS <0.001 <0.001
≤21 35.3 2.695 (1.656–4.387)
>21 17.8 1
Abbreviations: CI, confidence interval; BMI, body mass index; NAC, neoadjuvant chemotherapy; BCS, breast conserving surgery; TTS, time to surgery.
Causes of Surgery Delay
The causes of surgery delay in Group C were analyzed. There were six main reasons: neutropenia caused by chemotherapy drugs (47.0%), liver dysfunction caused by chemotherapy drugs (33.1%), heart disease or other comorbidities (14.6%), waiting for breast MRI appointment (9.3%), discussion time of treatment strategy (7.9%) and medical insurance or hospitalization appointment (7.3%). The most common causes were due to the side effects of chemotherapy drugs, such as hematological toxicity and liver toxicity.
Discussion
The effectiveness and safety of NAC in the treatment of breast cancer had been confirmed from the numerous clinical trials.6,7 Besides not presenting any specific interval from the completion of the NAC to the surgery, none of the trials could evaluate the relationship between NAC and postoperative complications. At present, clinicians mainly infer the interval from NAC to surgery based on the interval data of adjuvant chemotherapy, but its applicability to the NAC is unclear.8 Therefore, we conducted this retrospective study to analyze the relationship between TTS and patient survival as well as the relationship between TTS and postoperative complications, trying to find the appropriate TTS interval.
In this study, we retrospectively collected data from 422 patients and analyzed the TTS and survival. Through analysis, it was observed that in the case of the patients with TTS >28 days, the OS and the DFS were evidently different when compared with those from the other two groups. The TTS >28 days also being an independent prognostic factor capable of influencing the survival outcome was simultaneously indicated by the multivariate analysis. This suggested that prolonged TTS did have an adverse effect on the survival of patients, and TTS ≤28 days may be the most favorable surgery time for the prognosis of patients. In addition, we found that pCR, pN2-3 stage and adjuvant chemotherapy were factors affecting DFS; pN2-3 stage and adjuvant chemotherapy were factors affecting OS while pCR did not have an impact on OS. This suggested that pCR after neoadjuvant chemotherapy may not translate into long-term survival benefits. The incidence of tumor recurrence or metastasis in 3 years in patients with adjuvant chemotherapy was significantly higher than that in patients without adjuvant chemotherapy. This may be because most of the patients receiving adjuvant chemotherapy after surgery were patients with worse NAC curative effect, and their tumors may have worse biological characteristics.
The results of Omarini et al indicated that prolonged TTS was not conducive to the survival of patients. They studied 319 patients and found that TTS was an independent prognostic factor for OS (P=0.03) and recurrence-free survival (RFS) (P=0.01), even in the pCR subgroup. And they believed that the best time for surgery was TTS ≤21 days.3 However, some clinicians believed that TTS might have little relationship with the prognosis of patients. Sanford et al followed up 1011 patients and found that although there were differences in 5-year OS among patients with TTS ≤4 weeks, 4–6, and >6 weeks (P=0.03), there was no difference in 5-year RFS (P=0.28) and local recurrence-free survival (LRFS) (P=0.31) among the three groups. In multivariate analysis, OS, LRFS and RFS of patients with TTS ≤4 weeks, 4–6 weeks and >6 weeks were comparable; sensitivity analysis showed that patients who underwent surgery at >8 weeks had worse OS (P=0.02), but there was no significant difference between RFS and LRFS.9 Suleman et al found that TTS had no effect on DFS (P=0.3) and OS (P=0.5), but the pCR rate of ER +/HER2 + patients decreased when TTS ≥8 weeks (12.9% versus 25.3%).4 Although the results of these retrospective studies were suggestive, they were controversial. Large-sample and multi-center clinical cases are needed for further analyses.
By inhibiting the cell division, the protein synthesis, the RNA, or DNA production, most of the antineoplastic drugs were observed to exert their cytotoxic impact in the NAC of breast cancer. Previous animal experimental data showed that wound healing was affected within 28 days after the application of cytotoxic drugs.10 Previous clinical studies have shown that immunosuppression after chemotherapy is a known factor leading to postoperative complications.11,12 The association of TTS in cases of postoperative complications was revealed from this study. In patients with shorter TTS, the incidence of complications such as poor incision healing and infection had an obvious increasing trend. In the multivariate analysis, age <50 years old and TTS ≤21 days were independent parameters for total postoperative complications. The decrease of neutrophils, the increase of vascular fragility and tissue edema may be the reasons for the increased incidence of these complications. However, we also observed that most of the postoperative complications were mild and could be treated in the outpatient department. Similarly, defining the time interval to be 28 days, the higher incidence of postoperative complications was found to have a shorter TTS by a study of Sutton et al.13 It was also observed that with age as the dominant predictor, compared to TTS greater than 28 days (P <0.05), the TTS of 28 days or less was associated with almost 70% increased chances of a wound complication. Considering the influence of chemotherapy and radiotherapy, only a few patients choose immediate reconstruction surgery after NAC, so we failed to evaluate the impact of TTS on postoperative complications of patients with immediate breast reconstruction. In previous studies, in the case of perioperative complications in patients with immediate breast reconstruction, NAC was not observed to be a risk factor.14 As an increase in the number of patients with immediate breast reconstruction in our center recently, we will further do some research in this area.
In clinical practice, the surgery delay after NAC was affected by multiple factors. One of the most common causes of delayed surgery is the time required to recover from the side effects of short-term chemotherapy (mainly hematological toxicity and liver toxicity). Therefore, clinicians should well control the side effects of chemotherapy, such as regular blood examination and timely use of granulocyte colony stimulating factor (G-CSF) preparation, etc.15 It was worth noting that 14 patients delayed the TTS due to the appointment of preoperative breast MRI in Group C. Zhang et al also reported that preoperative breast MRI prolonged the operation waiting time by 11 days.16 This result reminded clinicians to optimize the patient’s examination process and minimize the operation delay due to waiting for examination.
Nonetheless, this study is not free of limitations. First, as is typical of retrospective studies, there could have been potential biases. The TTS of patients were individually selected based upon the condition of the patients, rather than being assigned randomly. The interpretation of the survival analysis was thus limited by the inevitable biases in the selection of the treatment. Second, the follow-up time was short. Especially for the patients who achieved pCR after NAC, we observed fewer death events, so we could not make subgroup analysis on these patients. Third, due to the retrospective study, patients may have memory loss or mistakes in the occurrence of postoperative complications, which affects our analysis. Last but not least, the study represented a single institutional experience and therefore the results may be hard to extrapolate to other institutions or countries with different patient populations and different practice patterns. Nevertheless, this study can provide some ideas and guidance for clinicians’ decisions. At the same time, it also provides the direction for further research.
Conclusion
In conclusion, TTS after NAC seemed to influence survival outcomes and postoperative complications. Breast cancer patients who underwent surgery between 21 and 28 days benefited the most. Clinicians should make a comprehensive evaluation of patients, balance the impact of TTS on short-term complications and long-term survival rate, and select the appropriate operation time.
Disclosure
There are no relevant conflicts of interests to be disclosed by the authors. | TRASTUZUMAB | DrugsGivenReaction | CC BY-NC | 33568945 | 19,625,890 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatic function abnormal'. | How Long is It Safe to Wait for Breast Surgery After Completion of Neoadjuvant Chemotherapy?
This study aimed to evaluate the impact of surgical time on postoperative complications and survival outcomes in breast cancer patients after neoadjuvant chemotherapy (NAC).
We retrospectively reviewed breast cancer patients treated at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II-III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom medical records were available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and with distant metastasis or contralateral breast cancer, were excluded. Eligible patients were divided into three groups based on time to surgery (TTS): (A) ≤21 days; (B) between 21 and 28 days; and (C) >28 days. We collected medical records and followed up patients.
Totally 422 patients were enrolled. The median TTS was 26 days. Among these patients, 119 (28.2%) were in Group A, 152 (36.0%) were in Group B, and 151 (35.8%) were in Group C. Eighty-two (19.4%) patients achieved pathologic complete response (pCR). Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. In multivariate analysis, DFS (HR=2.333, P=0.001) and OS (HR=2.783, P=0.030) were significantly worse when TTS >28 days. Postoperative complications occurred in 96 (22.7%) patients. The incidence of total postoperative complications in the three groups was statistically different (P=0.001) and Group A had worse performance. Multivariate analysis showed that age >50 years old (P=0.004) and TTS ≤21 days (P<0.001) were independent parameters for total postoperative complications.
Postoperative complications and survival outcomes in breast cancer patients seemed to be influenced by TTS after the NAC. The benefits were remarkable in patients undergoing surgery between 21 and 28 days.
Introduction
Neoadjuvant chemotherapy (NAC) has been widely used in breast cancer patients due to its advantages such as reducing tumor stage, increasing the operation opportunity of inoperable patients, improving breast-conserving rate, evaluating drug efficacy and guiding adjuvant treatment strategies.1 Nonetheless, the time interval between surgery and the NAC remains to be determined. Using the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Database, two independent population-based studies were conducted by Bleicher et al.2 It was evidenced from the results that the lower disease-specific survival rate and overall survival rate were closely related to the long-term delay from the diagnosis to the surgery. The timeliness of treatment (including surgery and systemic treatment) could affect the prognosis of patients. Therefore, it can be inferred that prolonged surgery delay affect the prognosis of patients treated with NAC, especially those with high-risk factors. In the past studies, the relationship between the time to surgery (TTS) after NAC and the prognosis of breast cancer patients was controversial. Omarini et al thought that survival would be affected when the TTS was >21 days, while Suleman et al believed that TTS might not affect survival.3,4 Moreover, the incidence of postoperative complications can also affect clinicians’ choice of TTS after NAC. Some studies have suggested that NAC was a risk factor for early postoperative complications, but the specific relationship between TTS and complications was still unknown.5
Therefore, the specific relationship between TTS and patients’ survival was intended to be explored by this study, as well as between TTS and postoperative complications, to obtain the optimal TTS after NAC.
Patients and Methods
Study Population
We retrospectively reviewed patients who were diagnosed with breast cancer at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II–III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom information regarding the treatment records was available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and those with distant metastasis or contralateral breast cancer, were excluded.
In our database, there were 8311 breast cancer patients from January 2013 to December 2018, including 473 patients who received NAC. We extracted the patients’ medical history and treatment information from the database. Then, 422 patients satisfied the criteria and were screened out. And these patients were divided into three groups based on TTS: (A) TTS ≤21 days; (B) TTS between 21 and 28 days; and (C) TTS>28 days.
Before NAC, all patients underwent systemic survey to exclude distant metastasis. With the PET-CT being performed on selected patients, the systemic survey included the brain magnetic resonance imaging (MRI) and bone scans, the chest computed tomography (CT) scans, the ultrasound scans of the liver and the neck, and the serum tumor markers for all the patients. Applying the core-needle biopsy method, all patients’ primary breast cancers were histologically identified. The results of immunohistochemistry were obtained in 365 (86.5%) patients before NAC. Human epidermal growth factor receptor 2 (HER2) positivity was defined as either 3+ on IHC staining or 2+ on IHC with a positive fluorescence in situ hybridization or chromogenic in situ hybridization signal. The molecular subtype of each breast cancer was categorized as follows: ER+ or PR+, and HER2− (luminal); ER+/−, PR+/−, and HER2+ (HER2 enriched); or ER−, PR−, and HER2− (triple-negative). The NAC regimens were determined according to the guidelines. Every two cycles, we evaluated the efficacy of chemotherapy by physical examinations and imaging examinations. Pathologic complete response (pCR) was defined as the absence of histological evidence of malignancy or the presence of only cancer in situ in the primary breast lesions, regardless of axillary lymph node metastasis. Patients with absence of invasive disease in the breast but presence of axillary lymph node metastasis were also defined as pCR patients. The incidence of surgery-related complications and treatment measures were recorded through the patients’ medical records and periodic follow-up. All patients were followed up every six months after surgery. After recurrence or metastasis of tumor, patients were reexamined every two months.
Statistical Analysis
From the initial diagnosis of the primary breast cancer to the tumor recurrence or metastasis, the pertinent time interval was referred to as the disease-free survival (DFS). The overall survival (OS) was considered as the interval between the initial diagnosis of the primary breast cancer and the last follow-up or the death due to any cause. Applying the chi-square test, the rank sum test, or the Fisher’s exact test, the differences in the categorical variables were compared. The Kaplan-Meier method and the Log rank test were used to calculate the actuarial survival rates. In the multivariate analysis, the factors with a p-value<0.05 in the univariate analysis were included. The p<0.05 was considered to be statistically significant in the multivariate analysis, which was performed with the Cox proportional hazards model. The SPSS software (version 17.0.1. SPSS Inc., Chicago, IL) was used in all the statistical analyses.
Ethical Statement
Meeting all the guidelines of the governmental agency, the institutional review committee of the Affiliated Hospital of Qingdao University approved the experimental protocols. All patients provided informed consent, and this study was conducted in accordance with the Declaration of Helsinki.
Results
Cohort Survey
In total, 422 patients were enrolled. Among these patients, 119 (28.2%) patients had surgery within 21 days of their last dose of NAC, 152 (36.0%) patients in 21–28 days, and 151 (35.8%) patients after 28 days. The process of screening and grouping is shown in Figure 1. The median age of all the patients was 49 years old (range, 22–73 years), the median duration of follow-up was 42 months (range, 24 to 93 months), while the median TTS was of 26 days (range, 14 to 63 days) for all the 422 patients. They received anthracycline- or taxane-based NAC, and 82 patients achieved pCR (19.4%). Forty-two (10.0%) patients changed the chemotherapy regimen because of insufficient efficacy, and 20 (4.7%) patients interrupted the scheduled regimen because of the side effects of the drugs.Figure 1 The procedure of screening and grouping patients.
Abbreviations: NAC, neoadjuvant chemotherapy; TTS, time to surgery.
The main pathological type of primary breast cancer is non-specific invasive ductal carcinoma (401/422, 95.0%), in addition to some invasive lobular carcinoma, mucinous carcinoma, medullary carcinoma and so on. In terms of the molecular subtype, 41.2% (174/422), 45.7% (193/422) and 13.0% (55/422) of the patients were luminal, HER2-enriched and triple-negative, respectively. The pCR rates of patients with molecular subtype luminal, HER2-enriched and triple-negative were 7.5% (13/174), 28.0% (54/193) and 27.3% (15/55), respectively. Among these 193 HER2-enriched patients, 72.0% (139/193) patients were treated with trastuzumab in neoadjuvant therapy, and 91.2% (176/193) patients were treated with trastuzumab in adjuvant therapy. Of all 422 patients, 147 (33.3%) patients had tumor recurrence or metastasis during follow-up and 52 (12.3%) patients died. The median DFS was 36 months (range, 4 to 93 months), and the 3-year OS rate was 94.1% (397/422). When tumor progression was first detected, 30 patients had local recurrence, 12 patients were observed to have had distant metastasis and local recurrence both, while 79 patients showed distant metastasis. The lung, followed by the bone, was indicated to be the most common metastatic organ.
Survival Analysis of Patients in the Different TTS Groups
Regarding the different TTS, 442 patients were divided into three groups. Table 1 shows the comparison of patients’ characteristics in three groups. There was no significant difference in age, menstrual state, family history relative to breast cancer, tumor T stage before NAC, axillary lymph nodes involvement before NAC, histological grade, HR status, HER2 status, Ki-67 value, molecular subtype, drugs of NAC, clinical response to NAC, breast surgery type, pCR or non-pCR, pN stage after surgery, adjuvant chemotherapy, adjuvant radiotherapy, and targeted therapy.Table 1 The Comparison of Patients’ Characteristics in Three Groups
Characteristics Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Age (years) ≤50 74 (62.2) 89 (58.6) 79 (52.3) 0.248
>50 45 (37.8) 63 (41.4) 72 (47.7)
Menstrual state Premenopausal 73 (61.3) 93 (61.2) 79 (52.3) 0.204
Postmenopausal 46 (38.7) 59 (38.8) 72 (47.7)
Family history No 117 (98.3) 147 (96.7) 145 (96.0) 0.516
Yes 2 (1.7) 5 (3.3) 6 (4.0)
Initial T stage 1 6 (5.0) 17 (11.2) 11 (7.3) 0.196
2 80 (67.2) 83 (54.6) 90 (59.6)
3 33 (27.7) 52 (34.2) 50 (33.1)
Initial axillary LN Uninvolved 17 (14.3) 21 (13.8) 26 (17.2) 0.677
Involved 102 (85.7) 131 (86.2) 125 (82.8)
Histological grade 1–2 76 (63.9) 95 (62.5) 101 (66.9) 0.718
3 43 (36.1) 57 (37.5) 50 (33.1)
HR status Positive 78 (65.5) 101 (66.4) 102 (67.5) 0.941
Negative 41 (34.5) 51 (33.6) 49 (32.5)
HER2 status (FISH or CISH) Positive 49 (41.2) 55 (36.2) 49 (32.5) 0.334
Negative 70 (58.8) 97 (63.8) 102 (67.5)
Ki-67 value ≤20% 35 (29.4) 34 (22.4) 36 (23.8) 0.385
>20% 84 (70.6) 118 (77.6) 115 (76.2)
Molecular subtype Luminal 45 (37.8) 58 (38.2) 71 (47.0) 0.468
HER2-enriched 57 (47.9) 72 (47.4) 64 (42.4)
Triple-negative 17 (14.3) 22 (14.5) 16 (10.6)
NAC drugs Taxane-based 6 (5.0) 6 (3.9) 12 (7.9) 0.236
Anthracycline-based 1 (0.8) 5 (3.3) 6 (4.0)
Taxane- and anthracycline- based 112 (94.1) 141 (92.8) 133 (88.1)
Neoadjuvant targeted therapy Yes 42 (35.3) 52 (34.2) 45 (29.8) 0.582
No 77 (64.7) 100 (65.8) 106 (70.2)
Clinical response CR 6 (5.0) 15 (9.9) 8 (5.3) 0.056
PR 85 (71.4) 110 (72.4) 100 (66.2)
SD 24 (20.2) 23 (15.1) 42 (27.8)
PD 4 (3.4) 4 (2.6) 1 (0.7)
Breast surgery Mastectomy 110 (92.4) 139 (91.4) 140 (92.7) 0.912
BCS 9 (7.6) 13 (8.6) 11 (7.3)
pCR or non-pCR pCR 22 (18.5) 33 (21.7) 27 (17.9) 0.669
Non-pCR 97 (81.5) 119 (78.3) 124 (82.1)
pN stage 0 39 (32.8) 54 (35.5) 53 (35.1) 0.994
1 36 (30.3) 40 (26.3) 44 (29.1)
2 27 (22.7) 36 (23.7) 34 (22.5)
3 17 (14.3) 22 (14.5) 20 (13.2)
Adjuvant chemotherapy Yes 25 (21.0) 23 (15.1) 23 (15.2) 0.355
No 94 (79.0) 129 (84.9) 128 (84.8)
Adjuvant radiotherapy Yes 109 (91.6) 142 (93.4) 130 (86.1) 0.084
No 10 (8.4) 10 (6.6) 21 (13.9)
Adjuvant targeted therapy Yes 52 (43.7) 67 (44.1) 57 (37.7) 0.468
No 67 (56.3) 85 (55.9) 94 (62.3)
Abbreviations: T, tumor; LN, lymph node; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; FISH, fluorescence in situ hybridization; CISH, chromogenic in situ hybridization; NAC, neoadjuvant chemotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; BCS, breast conserving surgery; pCR, pathologic complete response.
The median DFS of the Group A was 43 months (range, 9 to 87 months), the median DFS of the Group B was 35.5 months (range, 4 to 81 months), and the median DFS of the Group C was 33 months (range, 6 to 93 months). In the three groups, the median OS was found to be 46 months (range, 25 to 87 months), 41 months (range, 24 to 81 months) and 39 months (range, 25 to 93 months) respectively. The 3-year OS rate of the three groups was 95.8% (114/119), 96.7% (147/152) and 90.1% (136/151), respectively.
Figure 2 indicates the results of the Kaplan-Meier survival curves using the Log rank test for the DFS and the OS. Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. Between Groups A and B, no significant difference in the DFS (P=0.595) and the OS (P=0.716) was observed. Nonetheless, between Groups A and C, the survival analysis indicated that DFS (P=0.006) and the OS (P=0.014) were found to be significantly different. At the same time, the DFS (P=0.024) and OS (P=0.027) of Group B were significantly different from that of Group C. This indicated that TTS >28 days did affect the survival outcome of these patients.Figure 2 Kaplan–Meier curves for survival according to different time to surgery. (A) Disease-free survival (P=0.012). (B) Overall survival (P=0.015).
Univariate and Multivariate Analyses for DFS and OS
The univariate analysis of DFS showed that pCR, pN stage, adjuvant chemotherapy and TTS were significant factors (P<0.001, P<0.001, P=0.001 and P=0.003, respectively). For OS, the univariate analysis showed that pN stage, adjuvant chemotherapy and TTS were significant factors (P=0.014, P=0.001 and P=0.032, respectively). In the multivariate analyses, DFS and OS were significantly worse when TTS >28 days with a hazard ratio of 2.333 (95% CI, 1.444–3.770, P=0.001) and 2.783 (95% CI, 1.007–7.687, P=0.030) respectively. Patients with pCR, pN2-3 stage and adjuvant chemotherapy were independent parameters for DFS (P=0.042, P<0.001 and P=0.001, respectively), while pN2-3 stage and adjuvant chemotherapy were also independent parameters for OS (P=0.024 and P=0.010, respectively). The relevant statistics are shown in Table 2.Table 2 Univariate and Multivariate Analysis for DFS and OS
Variables DFS OS
3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate) 3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.958 0.488
≤50 71.9 93.4
>50 71.7 95.0
Menstrual state 0.523 0.839
Premenopausal 70.6 93.9
Postmenopausal 73.4 94.4
Initial T stage 0.112 0.713
1 85.3 97.1
2 72.3 94.1
3 67.4 6.7
Initial axillary LN 0.537 0.905
Uninvolved 75.0 93.7
Involved 71.2 94.1
Histological grade 0.769 0.961
1–2 71.3 94.1
3 72.7 94.0
Ki-67 value 0.689 0.125
≤20% 73.3 97.1
>20% 71.3 93.1
Molecular subtype 0.394 0.194
Luminal 75.3 96.6
HER2-enriched 68.9 92.2
Triple-negative 70.9 92.7
Breast surgery 0.599 0.422
Mastectomy 71.5 94.3
BCS 75.8 90.9
pCR or non-pCR <0.001 0.042 0.136
pCR 89.0 1 97.6
Non-pCR 67.6 2.070 (1.026–4.176) 93.2
pN stage <0.001 <0.001 0.014 0.024
0–1 80.8 1 96.2 1
2–3 56.4 2.435 (1.677–3.536) 90.4 2.524 (1.130–5.634)
Adjuvant chemotherapy 0.001 0.001 0.001 0.010
Yes 54.9 2.330 (1.538–3.530) 85.9 3.671 (1.647–8.182)
No 75.2 1 95.7 1
Adjuvant radiotherapy 0.209 0.691
Yes 51.0 94.2
No 37.5 92.7
TTS 0.003 0.001 0.032 0.030
Group A 79.8 1 95.8 1
Group B 75.0 1.469 (0.879–2.453) 0.142 96.7 0.891 (0.257–3.083) 0.855
Group C 62.3 2.333 (1.444–3.770) 0.001 89.0 2.783 (1.007–7.687) 0.048
Abbreviations: DFS, disease-free survival; OS, overall survival; CI, confidence interval; T, tumor; LN, lymph node; HER2, human epidermal growth factor receptor 2; BCS, breast conserving surgery; pCR, pathologic complete response; TTS, time to surgery.
Relationship Between TTS and Postoperative Complications
Postoperative complications occurred in 96 (22.7%) patients, including poor healing of incision, infection, hematoma or hemorrhage, subcutaneous effusion and skin flap necrosis. The incidence of postoperative complications is shown in Table 3 and the classification of severity is shown in Table 4. Most of the patients were treated in the outpatient department; only 4.2% (4/96) of the patients returned to the operating room and received general anesthesia operations. The incidence of total postoperative complications in the three groups was statistically different (P=0.001). Compared with Group B (P=0.003) and Group C (P<0.001), Group A had worse performance in total postoperative complications. The total complication rates of Group B and Group C were similar (P=0.566). This suggested that TTS ≤21 days was significantly associated with a higher incidence of total postoperative complications. And among the five kinds of complications, the incidence of poor incision healing (P=0.024) and infection (P=0.031) was significantly different among the three groups. The univariate analysis indicated that age and TTS were the significant factors for total postoperative complications (P=0.009 and P<0.001, respectively). In the multivariate analysis, age >50 years old and TTS ≤21 days were independent parameters for total postoperative complications (P=0.004 and P<0.001, respectively). The statistical details are shown in Table 5.Table 3 Relationship Between TTS and Postoperative Complications
Postoperative Complications Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Poor incision healing Yes 15 (12.6) 10 (6.6) 6 (4.0) 0.024
No 104 (87.4) 142 (93.4) 145 (96.0)
Infection Yes 12 (10.1) 6 (3.9) 5 (3.3) 0.031
No 107 (89.9) 146 (96.1) 146 (96.7)
Hematoma or hemorrhage Yes 5 (4.2) 5 (3.3) 7 (4.6) 0.832
No 114 (95.8) 147 (96.7) 144 (95.4)
Subcutaneous effusion Yes 9 (7.6) 6 (3.9) 6 (4.0) 0.310
No 110 (92.4) 146 (96.1) 145 (96.0)
Skin flap necrosis Yes 1 (0.8) 2 (1.3) 1 (0.7) 0.833
No 118 (99.2) 150 (98.7) 150 (99.3)
Total Yes 42 (35.3) 29 (19.1) 25 (16.6) 0.001
No 77 (64.7) 123 (80.9) 126 (83.4)
Abbreviation: TTS, time to surgery.
Table 4 Classification of the Severity of Postoperative Complications
Clavien-Dindo Grade Number of Patients Undergone Postoperative Complications (%)
Group A
(n = 42) Group B (n = 29) Group C
(n = 25)
Grade I 13 (31.0) 12 (41.4) 9 (36.0)
Grade II 11 (26.2) 6 (20.7) 5 (20.0)
Grade IIIa 16 (38.1) 10 (34.5) 10 (40.0)
Grade IIIb 2 (4.8) 1 (3.4) 1 (4.0)
Grade IV/V 0 (0) 0 (0) 0 (0)
Table 5 Univariate and Multivariate Analysis for Postoperative Complications
Variables Postoperative Complications
Incidence Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.009 0.004
≤50 18.2 1
>50 28.9 1.996 (1.245–3.201)
BMI 0.984
≤20 23.8
20< BMI≤25 21.9
25< BMI≤30 23.3
>30 23.9
NAC drugs 0.945
Taxane-based 25.0
Anthracycline-based 25.0
Taxane- and anthracycline- based 22.5
Breast surgery 0.826
Mastectomy 22.9
BCS 21.2
TTS <0.001 <0.001
≤21 35.3 2.695 (1.656–4.387)
>21 17.8 1
Abbreviations: CI, confidence interval; BMI, body mass index; NAC, neoadjuvant chemotherapy; BCS, breast conserving surgery; TTS, time to surgery.
Causes of Surgery Delay
The causes of surgery delay in Group C were analyzed. There were six main reasons: neutropenia caused by chemotherapy drugs (47.0%), liver dysfunction caused by chemotherapy drugs (33.1%), heart disease or other comorbidities (14.6%), waiting for breast MRI appointment (9.3%), discussion time of treatment strategy (7.9%) and medical insurance or hospitalization appointment (7.3%). The most common causes were due to the side effects of chemotherapy drugs, such as hematological toxicity and liver toxicity.
Discussion
The effectiveness and safety of NAC in the treatment of breast cancer had been confirmed from the numerous clinical trials.6,7 Besides not presenting any specific interval from the completion of the NAC to the surgery, none of the trials could evaluate the relationship between NAC and postoperative complications. At present, clinicians mainly infer the interval from NAC to surgery based on the interval data of adjuvant chemotherapy, but its applicability to the NAC is unclear.8 Therefore, we conducted this retrospective study to analyze the relationship between TTS and patient survival as well as the relationship between TTS and postoperative complications, trying to find the appropriate TTS interval.
In this study, we retrospectively collected data from 422 patients and analyzed the TTS and survival. Through analysis, it was observed that in the case of the patients with TTS >28 days, the OS and the DFS were evidently different when compared with those from the other two groups. The TTS >28 days also being an independent prognostic factor capable of influencing the survival outcome was simultaneously indicated by the multivariate analysis. This suggested that prolonged TTS did have an adverse effect on the survival of patients, and TTS ≤28 days may be the most favorable surgery time for the prognosis of patients. In addition, we found that pCR, pN2-3 stage and adjuvant chemotherapy were factors affecting DFS; pN2-3 stage and adjuvant chemotherapy were factors affecting OS while pCR did not have an impact on OS. This suggested that pCR after neoadjuvant chemotherapy may not translate into long-term survival benefits. The incidence of tumor recurrence or metastasis in 3 years in patients with adjuvant chemotherapy was significantly higher than that in patients without adjuvant chemotherapy. This may be because most of the patients receiving adjuvant chemotherapy after surgery were patients with worse NAC curative effect, and their tumors may have worse biological characteristics.
The results of Omarini et al indicated that prolonged TTS was not conducive to the survival of patients. They studied 319 patients and found that TTS was an independent prognostic factor for OS (P=0.03) and recurrence-free survival (RFS) (P=0.01), even in the pCR subgroup. And they believed that the best time for surgery was TTS ≤21 days.3 However, some clinicians believed that TTS might have little relationship with the prognosis of patients. Sanford et al followed up 1011 patients and found that although there were differences in 5-year OS among patients with TTS ≤4 weeks, 4–6, and >6 weeks (P=0.03), there was no difference in 5-year RFS (P=0.28) and local recurrence-free survival (LRFS) (P=0.31) among the three groups. In multivariate analysis, OS, LRFS and RFS of patients with TTS ≤4 weeks, 4–6 weeks and >6 weeks were comparable; sensitivity analysis showed that patients who underwent surgery at >8 weeks had worse OS (P=0.02), but there was no significant difference between RFS and LRFS.9 Suleman et al found that TTS had no effect on DFS (P=0.3) and OS (P=0.5), but the pCR rate of ER +/HER2 + patients decreased when TTS ≥8 weeks (12.9% versus 25.3%).4 Although the results of these retrospective studies were suggestive, they were controversial. Large-sample and multi-center clinical cases are needed for further analyses.
By inhibiting the cell division, the protein synthesis, the RNA, or DNA production, most of the antineoplastic drugs were observed to exert their cytotoxic impact in the NAC of breast cancer. Previous animal experimental data showed that wound healing was affected within 28 days after the application of cytotoxic drugs.10 Previous clinical studies have shown that immunosuppression after chemotherapy is a known factor leading to postoperative complications.11,12 The association of TTS in cases of postoperative complications was revealed from this study. In patients with shorter TTS, the incidence of complications such as poor incision healing and infection had an obvious increasing trend. In the multivariate analysis, age <50 years old and TTS ≤21 days were independent parameters for total postoperative complications. The decrease of neutrophils, the increase of vascular fragility and tissue edema may be the reasons for the increased incidence of these complications. However, we also observed that most of the postoperative complications were mild and could be treated in the outpatient department. Similarly, defining the time interval to be 28 days, the higher incidence of postoperative complications was found to have a shorter TTS by a study of Sutton et al.13 It was also observed that with age as the dominant predictor, compared to TTS greater than 28 days (P <0.05), the TTS of 28 days or less was associated with almost 70% increased chances of a wound complication. Considering the influence of chemotherapy and radiotherapy, only a few patients choose immediate reconstruction surgery after NAC, so we failed to evaluate the impact of TTS on postoperative complications of patients with immediate breast reconstruction. In previous studies, in the case of perioperative complications in patients with immediate breast reconstruction, NAC was not observed to be a risk factor.14 As an increase in the number of patients with immediate breast reconstruction in our center recently, we will further do some research in this area.
In clinical practice, the surgery delay after NAC was affected by multiple factors. One of the most common causes of delayed surgery is the time required to recover from the side effects of short-term chemotherapy (mainly hematological toxicity and liver toxicity). Therefore, clinicians should well control the side effects of chemotherapy, such as regular blood examination and timely use of granulocyte colony stimulating factor (G-CSF) preparation, etc.15 It was worth noting that 14 patients delayed the TTS due to the appointment of preoperative breast MRI in Group C. Zhang et al also reported that preoperative breast MRI prolonged the operation waiting time by 11 days.16 This result reminded clinicians to optimize the patient’s examination process and minimize the operation delay due to waiting for examination.
Nonetheless, this study is not free of limitations. First, as is typical of retrospective studies, there could have been potential biases. The TTS of patients were individually selected based upon the condition of the patients, rather than being assigned randomly. The interpretation of the survival analysis was thus limited by the inevitable biases in the selection of the treatment. Second, the follow-up time was short. Especially for the patients who achieved pCR after NAC, we observed fewer death events, so we could not make subgroup analysis on these patients. Third, due to the retrospective study, patients may have memory loss or mistakes in the occurrence of postoperative complications, which affects our analysis. Last but not least, the study represented a single institutional experience and therefore the results may be hard to extrapolate to other institutions or countries with different patient populations and different practice patterns. Nevertheless, this study can provide some ideas and guidance for clinicians’ decisions. At the same time, it also provides the direction for further research.
Conclusion
In conclusion, TTS after NAC seemed to influence survival outcomes and postoperative complications. Breast cancer patients who underwent surgery between 21 and 28 days benefited the most. Clinicians should make a comprehensive evaluation of patients, balance the impact of TTS on short-term complications and long-term survival rate, and select the appropriate operation time.
Disclosure
There are no relevant conflicts of interests to be disclosed by the authors. | TRASTUZUMAB | DrugsGivenReaction | CC BY-NC | 33568945 | 19,625,890 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatotoxicity'. | How Long is It Safe to Wait for Breast Surgery After Completion of Neoadjuvant Chemotherapy?
This study aimed to evaluate the impact of surgical time on postoperative complications and survival outcomes in breast cancer patients after neoadjuvant chemotherapy (NAC).
We retrospectively reviewed breast cancer patients treated at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II-III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom medical records were available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and with distant metastasis or contralateral breast cancer, were excluded. Eligible patients were divided into three groups based on time to surgery (TTS): (A) ≤21 days; (B) between 21 and 28 days; and (C) >28 days. We collected medical records and followed up patients.
Totally 422 patients were enrolled. The median TTS was 26 days. Among these patients, 119 (28.2%) were in Group A, 152 (36.0%) were in Group B, and 151 (35.8%) were in Group C. Eighty-two (19.4%) patients achieved pathologic complete response (pCR). Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. In multivariate analysis, DFS (HR=2.333, P=0.001) and OS (HR=2.783, P=0.030) were significantly worse when TTS >28 days. Postoperative complications occurred in 96 (22.7%) patients. The incidence of total postoperative complications in the three groups was statistically different (P=0.001) and Group A had worse performance. Multivariate analysis showed that age >50 years old (P=0.004) and TTS ≤21 days (P<0.001) were independent parameters for total postoperative complications.
Postoperative complications and survival outcomes in breast cancer patients seemed to be influenced by TTS after the NAC. The benefits were remarkable in patients undergoing surgery between 21 and 28 days.
Introduction
Neoadjuvant chemotherapy (NAC) has been widely used in breast cancer patients due to its advantages such as reducing tumor stage, increasing the operation opportunity of inoperable patients, improving breast-conserving rate, evaluating drug efficacy and guiding adjuvant treatment strategies.1 Nonetheless, the time interval between surgery and the NAC remains to be determined. Using the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Database, two independent population-based studies were conducted by Bleicher et al.2 It was evidenced from the results that the lower disease-specific survival rate and overall survival rate were closely related to the long-term delay from the diagnosis to the surgery. The timeliness of treatment (including surgery and systemic treatment) could affect the prognosis of patients. Therefore, it can be inferred that prolonged surgery delay affect the prognosis of patients treated with NAC, especially those with high-risk factors. In the past studies, the relationship between the time to surgery (TTS) after NAC and the prognosis of breast cancer patients was controversial. Omarini et al thought that survival would be affected when the TTS was >21 days, while Suleman et al believed that TTS might not affect survival.3,4 Moreover, the incidence of postoperative complications can also affect clinicians’ choice of TTS after NAC. Some studies have suggested that NAC was a risk factor for early postoperative complications, but the specific relationship between TTS and complications was still unknown.5
Therefore, the specific relationship between TTS and patients’ survival was intended to be explored by this study, as well as between TTS and postoperative complications, to obtain the optimal TTS after NAC.
Patients and Methods
Study Population
We retrospectively reviewed patients who were diagnosed with breast cancer at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II–III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom information regarding the treatment records was available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and those with distant metastasis or contralateral breast cancer, were excluded.
In our database, there were 8311 breast cancer patients from January 2013 to December 2018, including 473 patients who received NAC. We extracted the patients’ medical history and treatment information from the database. Then, 422 patients satisfied the criteria and were screened out. And these patients were divided into three groups based on TTS: (A) TTS ≤21 days; (B) TTS between 21 and 28 days; and (C) TTS>28 days.
Before NAC, all patients underwent systemic survey to exclude distant metastasis. With the PET-CT being performed on selected patients, the systemic survey included the brain magnetic resonance imaging (MRI) and bone scans, the chest computed tomography (CT) scans, the ultrasound scans of the liver and the neck, and the serum tumor markers for all the patients. Applying the core-needle biopsy method, all patients’ primary breast cancers were histologically identified. The results of immunohistochemistry were obtained in 365 (86.5%) patients before NAC. Human epidermal growth factor receptor 2 (HER2) positivity was defined as either 3+ on IHC staining or 2+ on IHC with a positive fluorescence in situ hybridization or chromogenic in situ hybridization signal. The molecular subtype of each breast cancer was categorized as follows: ER+ or PR+, and HER2− (luminal); ER+/−, PR+/−, and HER2+ (HER2 enriched); or ER−, PR−, and HER2− (triple-negative). The NAC regimens were determined according to the guidelines. Every two cycles, we evaluated the efficacy of chemotherapy by physical examinations and imaging examinations. Pathologic complete response (pCR) was defined as the absence of histological evidence of malignancy or the presence of only cancer in situ in the primary breast lesions, regardless of axillary lymph node metastasis. Patients with absence of invasive disease in the breast but presence of axillary lymph node metastasis were also defined as pCR patients. The incidence of surgery-related complications and treatment measures were recorded through the patients’ medical records and periodic follow-up. All patients were followed up every six months after surgery. After recurrence or metastasis of tumor, patients were reexamined every two months.
Statistical Analysis
From the initial diagnosis of the primary breast cancer to the tumor recurrence or metastasis, the pertinent time interval was referred to as the disease-free survival (DFS). The overall survival (OS) was considered as the interval between the initial diagnosis of the primary breast cancer and the last follow-up or the death due to any cause. Applying the chi-square test, the rank sum test, or the Fisher’s exact test, the differences in the categorical variables were compared. The Kaplan-Meier method and the Log rank test were used to calculate the actuarial survival rates. In the multivariate analysis, the factors with a p-value<0.05 in the univariate analysis were included. The p<0.05 was considered to be statistically significant in the multivariate analysis, which was performed with the Cox proportional hazards model. The SPSS software (version 17.0.1. SPSS Inc., Chicago, IL) was used in all the statistical analyses.
Ethical Statement
Meeting all the guidelines of the governmental agency, the institutional review committee of the Affiliated Hospital of Qingdao University approved the experimental protocols. All patients provided informed consent, and this study was conducted in accordance with the Declaration of Helsinki.
Results
Cohort Survey
In total, 422 patients were enrolled. Among these patients, 119 (28.2%) patients had surgery within 21 days of their last dose of NAC, 152 (36.0%) patients in 21–28 days, and 151 (35.8%) patients after 28 days. The process of screening and grouping is shown in Figure 1. The median age of all the patients was 49 years old (range, 22–73 years), the median duration of follow-up was 42 months (range, 24 to 93 months), while the median TTS was of 26 days (range, 14 to 63 days) for all the 422 patients. They received anthracycline- or taxane-based NAC, and 82 patients achieved pCR (19.4%). Forty-two (10.0%) patients changed the chemotherapy regimen because of insufficient efficacy, and 20 (4.7%) patients interrupted the scheduled regimen because of the side effects of the drugs.Figure 1 The procedure of screening and grouping patients.
Abbreviations: NAC, neoadjuvant chemotherapy; TTS, time to surgery.
The main pathological type of primary breast cancer is non-specific invasive ductal carcinoma (401/422, 95.0%), in addition to some invasive lobular carcinoma, mucinous carcinoma, medullary carcinoma and so on. In terms of the molecular subtype, 41.2% (174/422), 45.7% (193/422) and 13.0% (55/422) of the patients were luminal, HER2-enriched and triple-negative, respectively. The pCR rates of patients with molecular subtype luminal, HER2-enriched and triple-negative were 7.5% (13/174), 28.0% (54/193) and 27.3% (15/55), respectively. Among these 193 HER2-enriched patients, 72.0% (139/193) patients were treated with trastuzumab in neoadjuvant therapy, and 91.2% (176/193) patients were treated with trastuzumab in adjuvant therapy. Of all 422 patients, 147 (33.3%) patients had tumor recurrence or metastasis during follow-up and 52 (12.3%) patients died. The median DFS was 36 months (range, 4 to 93 months), and the 3-year OS rate was 94.1% (397/422). When tumor progression was first detected, 30 patients had local recurrence, 12 patients were observed to have had distant metastasis and local recurrence both, while 79 patients showed distant metastasis. The lung, followed by the bone, was indicated to be the most common metastatic organ.
Survival Analysis of Patients in the Different TTS Groups
Regarding the different TTS, 442 patients were divided into three groups. Table 1 shows the comparison of patients’ characteristics in three groups. There was no significant difference in age, menstrual state, family history relative to breast cancer, tumor T stage before NAC, axillary lymph nodes involvement before NAC, histological grade, HR status, HER2 status, Ki-67 value, molecular subtype, drugs of NAC, clinical response to NAC, breast surgery type, pCR or non-pCR, pN stage after surgery, adjuvant chemotherapy, adjuvant radiotherapy, and targeted therapy.Table 1 The Comparison of Patients’ Characteristics in Three Groups
Characteristics Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Age (years) ≤50 74 (62.2) 89 (58.6) 79 (52.3) 0.248
>50 45 (37.8) 63 (41.4) 72 (47.7)
Menstrual state Premenopausal 73 (61.3) 93 (61.2) 79 (52.3) 0.204
Postmenopausal 46 (38.7) 59 (38.8) 72 (47.7)
Family history No 117 (98.3) 147 (96.7) 145 (96.0) 0.516
Yes 2 (1.7) 5 (3.3) 6 (4.0)
Initial T stage 1 6 (5.0) 17 (11.2) 11 (7.3) 0.196
2 80 (67.2) 83 (54.6) 90 (59.6)
3 33 (27.7) 52 (34.2) 50 (33.1)
Initial axillary LN Uninvolved 17 (14.3) 21 (13.8) 26 (17.2) 0.677
Involved 102 (85.7) 131 (86.2) 125 (82.8)
Histological grade 1–2 76 (63.9) 95 (62.5) 101 (66.9) 0.718
3 43 (36.1) 57 (37.5) 50 (33.1)
HR status Positive 78 (65.5) 101 (66.4) 102 (67.5) 0.941
Negative 41 (34.5) 51 (33.6) 49 (32.5)
HER2 status (FISH or CISH) Positive 49 (41.2) 55 (36.2) 49 (32.5) 0.334
Negative 70 (58.8) 97 (63.8) 102 (67.5)
Ki-67 value ≤20% 35 (29.4) 34 (22.4) 36 (23.8) 0.385
>20% 84 (70.6) 118 (77.6) 115 (76.2)
Molecular subtype Luminal 45 (37.8) 58 (38.2) 71 (47.0) 0.468
HER2-enriched 57 (47.9) 72 (47.4) 64 (42.4)
Triple-negative 17 (14.3) 22 (14.5) 16 (10.6)
NAC drugs Taxane-based 6 (5.0) 6 (3.9) 12 (7.9) 0.236
Anthracycline-based 1 (0.8) 5 (3.3) 6 (4.0)
Taxane- and anthracycline- based 112 (94.1) 141 (92.8) 133 (88.1)
Neoadjuvant targeted therapy Yes 42 (35.3) 52 (34.2) 45 (29.8) 0.582
No 77 (64.7) 100 (65.8) 106 (70.2)
Clinical response CR 6 (5.0) 15 (9.9) 8 (5.3) 0.056
PR 85 (71.4) 110 (72.4) 100 (66.2)
SD 24 (20.2) 23 (15.1) 42 (27.8)
PD 4 (3.4) 4 (2.6) 1 (0.7)
Breast surgery Mastectomy 110 (92.4) 139 (91.4) 140 (92.7) 0.912
BCS 9 (7.6) 13 (8.6) 11 (7.3)
pCR or non-pCR pCR 22 (18.5) 33 (21.7) 27 (17.9) 0.669
Non-pCR 97 (81.5) 119 (78.3) 124 (82.1)
pN stage 0 39 (32.8) 54 (35.5) 53 (35.1) 0.994
1 36 (30.3) 40 (26.3) 44 (29.1)
2 27 (22.7) 36 (23.7) 34 (22.5)
3 17 (14.3) 22 (14.5) 20 (13.2)
Adjuvant chemotherapy Yes 25 (21.0) 23 (15.1) 23 (15.2) 0.355
No 94 (79.0) 129 (84.9) 128 (84.8)
Adjuvant radiotherapy Yes 109 (91.6) 142 (93.4) 130 (86.1) 0.084
No 10 (8.4) 10 (6.6) 21 (13.9)
Adjuvant targeted therapy Yes 52 (43.7) 67 (44.1) 57 (37.7) 0.468
No 67 (56.3) 85 (55.9) 94 (62.3)
Abbreviations: T, tumor; LN, lymph node; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; FISH, fluorescence in situ hybridization; CISH, chromogenic in situ hybridization; NAC, neoadjuvant chemotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; BCS, breast conserving surgery; pCR, pathologic complete response.
The median DFS of the Group A was 43 months (range, 9 to 87 months), the median DFS of the Group B was 35.5 months (range, 4 to 81 months), and the median DFS of the Group C was 33 months (range, 6 to 93 months). In the three groups, the median OS was found to be 46 months (range, 25 to 87 months), 41 months (range, 24 to 81 months) and 39 months (range, 25 to 93 months) respectively. The 3-year OS rate of the three groups was 95.8% (114/119), 96.7% (147/152) and 90.1% (136/151), respectively.
Figure 2 indicates the results of the Kaplan-Meier survival curves using the Log rank test for the DFS and the OS. Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. Between Groups A and B, no significant difference in the DFS (P=0.595) and the OS (P=0.716) was observed. Nonetheless, between Groups A and C, the survival analysis indicated that DFS (P=0.006) and the OS (P=0.014) were found to be significantly different. At the same time, the DFS (P=0.024) and OS (P=0.027) of Group B were significantly different from that of Group C. This indicated that TTS >28 days did affect the survival outcome of these patients.Figure 2 Kaplan–Meier curves for survival according to different time to surgery. (A) Disease-free survival (P=0.012). (B) Overall survival (P=0.015).
Univariate and Multivariate Analyses for DFS and OS
The univariate analysis of DFS showed that pCR, pN stage, adjuvant chemotherapy and TTS were significant factors (P<0.001, P<0.001, P=0.001 and P=0.003, respectively). For OS, the univariate analysis showed that pN stage, adjuvant chemotherapy and TTS were significant factors (P=0.014, P=0.001 and P=0.032, respectively). In the multivariate analyses, DFS and OS were significantly worse when TTS >28 days with a hazard ratio of 2.333 (95% CI, 1.444–3.770, P=0.001) and 2.783 (95% CI, 1.007–7.687, P=0.030) respectively. Patients with pCR, pN2-3 stage and adjuvant chemotherapy were independent parameters for DFS (P=0.042, P<0.001 and P=0.001, respectively), while pN2-3 stage and adjuvant chemotherapy were also independent parameters for OS (P=0.024 and P=0.010, respectively). The relevant statistics are shown in Table 2.Table 2 Univariate and Multivariate Analysis for DFS and OS
Variables DFS OS
3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate) 3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.958 0.488
≤50 71.9 93.4
>50 71.7 95.0
Menstrual state 0.523 0.839
Premenopausal 70.6 93.9
Postmenopausal 73.4 94.4
Initial T stage 0.112 0.713
1 85.3 97.1
2 72.3 94.1
3 67.4 6.7
Initial axillary LN 0.537 0.905
Uninvolved 75.0 93.7
Involved 71.2 94.1
Histological grade 0.769 0.961
1–2 71.3 94.1
3 72.7 94.0
Ki-67 value 0.689 0.125
≤20% 73.3 97.1
>20% 71.3 93.1
Molecular subtype 0.394 0.194
Luminal 75.3 96.6
HER2-enriched 68.9 92.2
Triple-negative 70.9 92.7
Breast surgery 0.599 0.422
Mastectomy 71.5 94.3
BCS 75.8 90.9
pCR or non-pCR <0.001 0.042 0.136
pCR 89.0 1 97.6
Non-pCR 67.6 2.070 (1.026–4.176) 93.2
pN stage <0.001 <0.001 0.014 0.024
0–1 80.8 1 96.2 1
2–3 56.4 2.435 (1.677–3.536) 90.4 2.524 (1.130–5.634)
Adjuvant chemotherapy 0.001 0.001 0.001 0.010
Yes 54.9 2.330 (1.538–3.530) 85.9 3.671 (1.647–8.182)
No 75.2 1 95.7 1
Adjuvant radiotherapy 0.209 0.691
Yes 51.0 94.2
No 37.5 92.7
TTS 0.003 0.001 0.032 0.030
Group A 79.8 1 95.8 1
Group B 75.0 1.469 (0.879–2.453) 0.142 96.7 0.891 (0.257–3.083) 0.855
Group C 62.3 2.333 (1.444–3.770) 0.001 89.0 2.783 (1.007–7.687) 0.048
Abbreviations: DFS, disease-free survival; OS, overall survival; CI, confidence interval; T, tumor; LN, lymph node; HER2, human epidermal growth factor receptor 2; BCS, breast conserving surgery; pCR, pathologic complete response; TTS, time to surgery.
Relationship Between TTS and Postoperative Complications
Postoperative complications occurred in 96 (22.7%) patients, including poor healing of incision, infection, hematoma or hemorrhage, subcutaneous effusion and skin flap necrosis. The incidence of postoperative complications is shown in Table 3 and the classification of severity is shown in Table 4. Most of the patients were treated in the outpatient department; only 4.2% (4/96) of the patients returned to the operating room and received general anesthesia operations. The incidence of total postoperative complications in the three groups was statistically different (P=0.001). Compared with Group B (P=0.003) and Group C (P<0.001), Group A had worse performance in total postoperative complications. The total complication rates of Group B and Group C were similar (P=0.566). This suggested that TTS ≤21 days was significantly associated with a higher incidence of total postoperative complications. And among the five kinds of complications, the incidence of poor incision healing (P=0.024) and infection (P=0.031) was significantly different among the three groups. The univariate analysis indicated that age and TTS were the significant factors for total postoperative complications (P=0.009 and P<0.001, respectively). In the multivariate analysis, age >50 years old and TTS ≤21 days were independent parameters for total postoperative complications (P=0.004 and P<0.001, respectively). The statistical details are shown in Table 5.Table 3 Relationship Between TTS and Postoperative Complications
Postoperative Complications Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Poor incision healing Yes 15 (12.6) 10 (6.6) 6 (4.0) 0.024
No 104 (87.4) 142 (93.4) 145 (96.0)
Infection Yes 12 (10.1) 6 (3.9) 5 (3.3) 0.031
No 107 (89.9) 146 (96.1) 146 (96.7)
Hematoma or hemorrhage Yes 5 (4.2) 5 (3.3) 7 (4.6) 0.832
No 114 (95.8) 147 (96.7) 144 (95.4)
Subcutaneous effusion Yes 9 (7.6) 6 (3.9) 6 (4.0) 0.310
No 110 (92.4) 146 (96.1) 145 (96.0)
Skin flap necrosis Yes 1 (0.8) 2 (1.3) 1 (0.7) 0.833
No 118 (99.2) 150 (98.7) 150 (99.3)
Total Yes 42 (35.3) 29 (19.1) 25 (16.6) 0.001
No 77 (64.7) 123 (80.9) 126 (83.4)
Abbreviation: TTS, time to surgery.
Table 4 Classification of the Severity of Postoperative Complications
Clavien-Dindo Grade Number of Patients Undergone Postoperative Complications (%)
Group A
(n = 42) Group B (n = 29) Group C
(n = 25)
Grade I 13 (31.0) 12 (41.4) 9 (36.0)
Grade II 11 (26.2) 6 (20.7) 5 (20.0)
Grade IIIa 16 (38.1) 10 (34.5) 10 (40.0)
Grade IIIb 2 (4.8) 1 (3.4) 1 (4.0)
Grade IV/V 0 (0) 0 (0) 0 (0)
Table 5 Univariate and Multivariate Analysis for Postoperative Complications
Variables Postoperative Complications
Incidence Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.009 0.004
≤50 18.2 1
>50 28.9 1.996 (1.245–3.201)
BMI 0.984
≤20 23.8
20< BMI≤25 21.9
25< BMI≤30 23.3
>30 23.9
NAC drugs 0.945
Taxane-based 25.0
Anthracycline-based 25.0
Taxane- and anthracycline- based 22.5
Breast surgery 0.826
Mastectomy 22.9
BCS 21.2
TTS <0.001 <0.001
≤21 35.3 2.695 (1.656–4.387)
>21 17.8 1
Abbreviations: CI, confidence interval; BMI, body mass index; NAC, neoadjuvant chemotherapy; BCS, breast conserving surgery; TTS, time to surgery.
Causes of Surgery Delay
The causes of surgery delay in Group C were analyzed. There were six main reasons: neutropenia caused by chemotherapy drugs (47.0%), liver dysfunction caused by chemotherapy drugs (33.1%), heart disease or other comorbidities (14.6%), waiting for breast MRI appointment (9.3%), discussion time of treatment strategy (7.9%) and medical insurance or hospitalization appointment (7.3%). The most common causes were due to the side effects of chemotherapy drugs, such as hematological toxicity and liver toxicity.
Discussion
The effectiveness and safety of NAC in the treatment of breast cancer had been confirmed from the numerous clinical trials.6,7 Besides not presenting any specific interval from the completion of the NAC to the surgery, none of the trials could evaluate the relationship between NAC and postoperative complications. At present, clinicians mainly infer the interval from NAC to surgery based on the interval data of adjuvant chemotherapy, but its applicability to the NAC is unclear.8 Therefore, we conducted this retrospective study to analyze the relationship between TTS and patient survival as well as the relationship between TTS and postoperative complications, trying to find the appropriate TTS interval.
In this study, we retrospectively collected data from 422 patients and analyzed the TTS and survival. Through analysis, it was observed that in the case of the patients with TTS >28 days, the OS and the DFS were evidently different when compared with those from the other two groups. The TTS >28 days also being an independent prognostic factor capable of influencing the survival outcome was simultaneously indicated by the multivariate analysis. This suggested that prolonged TTS did have an adverse effect on the survival of patients, and TTS ≤28 days may be the most favorable surgery time for the prognosis of patients. In addition, we found that pCR, pN2-3 stage and adjuvant chemotherapy were factors affecting DFS; pN2-3 stage and adjuvant chemotherapy were factors affecting OS while pCR did not have an impact on OS. This suggested that pCR after neoadjuvant chemotherapy may not translate into long-term survival benefits. The incidence of tumor recurrence or metastasis in 3 years in patients with adjuvant chemotherapy was significantly higher than that in patients without adjuvant chemotherapy. This may be because most of the patients receiving adjuvant chemotherapy after surgery were patients with worse NAC curative effect, and their tumors may have worse biological characteristics.
The results of Omarini et al indicated that prolonged TTS was not conducive to the survival of patients. They studied 319 patients and found that TTS was an independent prognostic factor for OS (P=0.03) and recurrence-free survival (RFS) (P=0.01), even in the pCR subgroup. And they believed that the best time for surgery was TTS ≤21 days.3 However, some clinicians believed that TTS might have little relationship with the prognosis of patients. Sanford et al followed up 1011 patients and found that although there were differences in 5-year OS among patients with TTS ≤4 weeks, 4–6, and >6 weeks (P=0.03), there was no difference in 5-year RFS (P=0.28) and local recurrence-free survival (LRFS) (P=0.31) among the three groups. In multivariate analysis, OS, LRFS and RFS of patients with TTS ≤4 weeks, 4–6 weeks and >6 weeks were comparable; sensitivity analysis showed that patients who underwent surgery at >8 weeks had worse OS (P=0.02), but there was no significant difference between RFS and LRFS.9 Suleman et al found that TTS had no effect on DFS (P=0.3) and OS (P=0.5), but the pCR rate of ER +/HER2 + patients decreased when TTS ≥8 weeks (12.9% versus 25.3%).4 Although the results of these retrospective studies were suggestive, they were controversial. Large-sample and multi-center clinical cases are needed for further analyses.
By inhibiting the cell division, the protein synthesis, the RNA, or DNA production, most of the antineoplastic drugs were observed to exert their cytotoxic impact in the NAC of breast cancer. Previous animal experimental data showed that wound healing was affected within 28 days after the application of cytotoxic drugs.10 Previous clinical studies have shown that immunosuppression after chemotherapy is a known factor leading to postoperative complications.11,12 The association of TTS in cases of postoperative complications was revealed from this study. In patients with shorter TTS, the incidence of complications such as poor incision healing and infection had an obvious increasing trend. In the multivariate analysis, age <50 years old and TTS ≤21 days were independent parameters for total postoperative complications. The decrease of neutrophils, the increase of vascular fragility and tissue edema may be the reasons for the increased incidence of these complications. However, we also observed that most of the postoperative complications were mild and could be treated in the outpatient department. Similarly, defining the time interval to be 28 days, the higher incidence of postoperative complications was found to have a shorter TTS by a study of Sutton et al.13 It was also observed that with age as the dominant predictor, compared to TTS greater than 28 days (P <0.05), the TTS of 28 days or less was associated with almost 70% increased chances of a wound complication. Considering the influence of chemotherapy and radiotherapy, only a few patients choose immediate reconstruction surgery after NAC, so we failed to evaluate the impact of TTS on postoperative complications of patients with immediate breast reconstruction. In previous studies, in the case of perioperative complications in patients with immediate breast reconstruction, NAC was not observed to be a risk factor.14 As an increase in the number of patients with immediate breast reconstruction in our center recently, we will further do some research in this area.
In clinical practice, the surgery delay after NAC was affected by multiple factors. One of the most common causes of delayed surgery is the time required to recover from the side effects of short-term chemotherapy (mainly hematological toxicity and liver toxicity). Therefore, clinicians should well control the side effects of chemotherapy, such as regular blood examination and timely use of granulocyte colony stimulating factor (G-CSF) preparation, etc.15 It was worth noting that 14 patients delayed the TTS due to the appointment of preoperative breast MRI in Group C. Zhang et al also reported that preoperative breast MRI prolonged the operation waiting time by 11 days.16 This result reminded clinicians to optimize the patient’s examination process and minimize the operation delay due to waiting for examination.
Nonetheless, this study is not free of limitations. First, as is typical of retrospective studies, there could have been potential biases. The TTS of patients were individually selected based upon the condition of the patients, rather than being assigned randomly. The interpretation of the survival analysis was thus limited by the inevitable biases in the selection of the treatment. Second, the follow-up time was short. Especially for the patients who achieved pCR after NAC, we observed fewer death events, so we could not make subgroup analysis on these patients. Third, due to the retrospective study, patients may have memory loss or mistakes in the occurrence of postoperative complications, which affects our analysis. Last but not least, the study represented a single institutional experience and therefore the results may be hard to extrapolate to other institutions or countries with different patient populations and different practice patterns. Nevertheless, this study can provide some ideas and guidance for clinicians’ decisions. At the same time, it also provides the direction for further research.
Conclusion
In conclusion, TTS after NAC seemed to influence survival outcomes and postoperative complications. Breast cancer patients who underwent surgery between 21 and 28 days benefited the most. Clinicians should make a comprehensive evaluation of patients, balance the impact of TTS on short-term complications and long-term survival rate, and select the appropriate operation time.
Disclosure
There are no relevant conflicts of interests to be disclosed by the authors. | TRASTUZUMAB | DrugsGivenReaction | CC BY-NC | 33568945 | 19,625,890 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | How Long is It Safe to Wait for Breast Surgery After Completion of Neoadjuvant Chemotherapy?
This study aimed to evaluate the impact of surgical time on postoperative complications and survival outcomes in breast cancer patients after neoadjuvant chemotherapy (NAC).
We retrospectively reviewed breast cancer patients treated at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II-III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom medical records were available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and with distant metastasis or contralateral breast cancer, were excluded. Eligible patients were divided into three groups based on time to surgery (TTS): (A) ≤21 days; (B) between 21 and 28 days; and (C) >28 days. We collected medical records and followed up patients.
Totally 422 patients were enrolled. The median TTS was 26 days. Among these patients, 119 (28.2%) were in Group A, 152 (36.0%) were in Group B, and 151 (35.8%) were in Group C. Eighty-two (19.4%) patients achieved pathologic complete response (pCR). Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. In multivariate analysis, DFS (HR=2.333, P=0.001) and OS (HR=2.783, P=0.030) were significantly worse when TTS >28 days. Postoperative complications occurred in 96 (22.7%) patients. The incidence of total postoperative complications in the three groups was statistically different (P=0.001) and Group A had worse performance. Multivariate analysis showed that age >50 years old (P=0.004) and TTS ≤21 days (P<0.001) were independent parameters for total postoperative complications.
Postoperative complications and survival outcomes in breast cancer patients seemed to be influenced by TTS after the NAC. The benefits were remarkable in patients undergoing surgery between 21 and 28 days.
Introduction
Neoadjuvant chemotherapy (NAC) has been widely used in breast cancer patients due to its advantages such as reducing tumor stage, increasing the operation opportunity of inoperable patients, improving breast-conserving rate, evaluating drug efficacy and guiding adjuvant treatment strategies.1 Nonetheless, the time interval between surgery and the NAC remains to be determined. Using the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Database, two independent population-based studies were conducted by Bleicher et al.2 It was evidenced from the results that the lower disease-specific survival rate and overall survival rate were closely related to the long-term delay from the diagnosis to the surgery. The timeliness of treatment (including surgery and systemic treatment) could affect the prognosis of patients. Therefore, it can be inferred that prolonged surgery delay affect the prognosis of patients treated with NAC, especially those with high-risk factors. In the past studies, the relationship between the time to surgery (TTS) after NAC and the prognosis of breast cancer patients was controversial. Omarini et al thought that survival would be affected when the TTS was >21 days, while Suleman et al believed that TTS might not affect survival.3,4 Moreover, the incidence of postoperative complications can also affect clinicians’ choice of TTS after NAC. Some studies have suggested that NAC was a risk factor for early postoperative complications, but the specific relationship between TTS and complications was still unknown.5
Therefore, the specific relationship between TTS and patients’ survival was intended to be explored by this study, as well as between TTS and postoperative complications, to obtain the optimal TTS after NAC.
Patients and Methods
Study Population
We retrospectively reviewed patients who were diagnosed with breast cancer at Breast Disease Center of the Affiliated Hospital of Qingdao University, from January 2013 to December 2018. The eligibility criteria were female patients with histologically confirmed primary stage II–III breast cancer and initially treated with NAC, who were <75 years old, and patients for whom information regarding the treatment records was available. The patients with severe comorbidities of other organs, with previous histories of other malignancies or breast cancer, and those with distant metastasis or contralateral breast cancer, were excluded.
In our database, there were 8311 breast cancer patients from January 2013 to December 2018, including 473 patients who received NAC. We extracted the patients’ medical history and treatment information from the database. Then, 422 patients satisfied the criteria and were screened out. And these patients were divided into three groups based on TTS: (A) TTS ≤21 days; (B) TTS between 21 and 28 days; and (C) TTS>28 days.
Before NAC, all patients underwent systemic survey to exclude distant metastasis. With the PET-CT being performed on selected patients, the systemic survey included the brain magnetic resonance imaging (MRI) and bone scans, the chest computed tomography (CT) scans, the ultrasound scans of the liver and the neck, and the serum tumor markers for all the patients. Applying the core-needle biopsy method, all patients’ primary breast cancers were histologically identified. The results of immunohistochemistry were obtained in 365 (86.5%) patients before NAC. Human epidermal growth factor receptor 2 (HER2) positivity was defined as either 3+ on IHC staining or 2+ on IHC with a positive fluorescence in situ hybridization or chromogenic in situ hybridization signal. The molecular subtype of each breast cancer was categorized as follows: ER+ or PR+, and HER2− (luminal); ER+/−, PR+/−, and HER2+ (HER2 enriched); or ER−, PR−, and HER2− (triple-negative). The NAC regimens were determined according to the guidelines. Every two cycles, we evaluated the efficacy of chemotherapy by physical examinations and imaging examinations. Pathologic complete response (pCR) was defined as the absence of histological evidence of malignancy or the presence of only cancer in situ in the primary breast lesions, regardless of axillary lymph node metastasis. Patients with absence of invasive disease in the breast but presence of axillary lymph node metastasis were also defined as pCR patients. The incidence of surgery-related complications and treatment measures were recorded through the patients’ medical records and periodic follow-up. All patients were followed up every six months after surgery. After recurrence or metastasis of tumor, patients were reexamined every two months.
Statistical Analysis
From the initial diagnosis of the primary breast cancer to the tumor recurrence or metastasis, the pertinent time interval was referred to as the disease-free survival (DFS). The overall survival (OS) was considered as the interval between the initial diagnosis of the primary breast cancer and the last follow-up or the death due to any cause. Applying the chi-square test, the rank sum test, or the Fisher’s exact test, the differences in the categorical variables were compared. The Kaplan-Meier method and the Log rank test were used to calculate the actuarial survival rates. In the multivariate analysis, the factors with a p-value<0.05 in the univariate analysis were included. The p<0.05 was considered to be statistically significant in the multivariate analysis, which was performed with the Cox proportional hazards model. The SPSS software (version 17.0.1. SPSS Inc., Chicago, IL) was used in all the statistical analyses.
Ethical Statement
Meeting all the guidelines of the governmental agency, the institutional review committee of the Affiliated Hospital of Qingdao University approved the experimental protocols. All patients provided informed consent, and this study was conducted in accordance with the Declaration of Helsinki.
Results
Cohort Survey
In total, 422 patients were enrolled. Among these patients, 119 (28.2%) patients had surgery within 21 days of their last dose of NAC, 152 (36.0%) patients in 21–28 days, and 151 (35.8%) patients after 28 days. The process of screening and grouping is shown in Figure 1. The median age of all the patients was 49 years old (range, 22–73 years), the median duration of follow-up was 42 months (range, 24 to 93 months), while the median TTS was of 26 days (range, 14 to 63 days) for all the 422 patients. They received anthracycline- or taxane-based NAC, and 82 patients achieved pCR (19.4%). Forty-two (10.0%) patients changed the chemotherapy regimen because of insufficient efficacy, and 20 (4.7%) patients interrupted the scheduled regimen because of the side effects of the drugs.Figure 1 The procedure of screening and grouping patients.
Abbreviations: NAC, neoadjuvant chemotherapy; TTS, time to surgery.
The main pathological type of primary breast cancer is non-specific invasive ductal carcinoma (401/422, 95.0%), in addition to some invasive lobular carcinoma, mucinous carcinoma, medullary carcinoma and so on. In terms of the molecular subtype, 41.2% (174/422), 45.7% (193/422) and 13.0% (55/422) of the patients were luminal, HER2-enriched and triple-negative, respectively. The pCR rates of patients with molecular subtype luminal, HER2-enriched and triple-negative were 7.5% (13/174), 28.0% (54/193) and 27.3% (15/55), respectively. Among these 193 HER2-enriched patients, 72.0% (139/193) patients were treated with trastuzumab in neoadjuvant therapy, and 91.2% (176/193) patients were treated with trastuzumab in adjuvant therapy. Of all 422 patients, 147 (33.3%) patients had tumor recurrence or metastasis during follow-up and 52 (12.3%) patients died. The median DFS was 36 months (range, 4 to 93 months), and the 3-year OS rate was 94.1% (397/422). When tumor progression was first detected, 30 patients had local recurrence, 12 patients were observed to have had distant metastasis and local recurrence both, while 79 patients showed distant metastasis. The lung, followed by the bone, was indicated to be the most common metastatic organ.
Survival Analysis of Patients in the Different TTS Groups
Regarding the different TTS, 442 patients were divided into three groups. Table 1 shows the comparison of patients’ characteristics in three groups. There was no significant difference in age, menstrual state, family history relative to breast cancer, tumor T stage before NAC, axillary lymph nodes involvement before NAC, histological grade, HR status, HER2 status, Ki-67 value, molecular subtype, drugs of NAC, clinical response to NAC, breast surgery type, pCR or non-pCR, pN stage after surgery, adjuvant chemotherapy, adjuvant radiotherapy, and targeted therapy.Table 1 The Comparison of Patients’ Characteristics in Three Groups
Characteristics Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Age (years) ≤50 74 (62.2) 89 (58.6) 79 (52.3) 0.248
>50 45 (37.8) 63 (41.4) 72 (47.7)
Menstrual state Premenopausal 73 (61.3) 93 (61.2) 79 (52.3) 0.204
Postmenopausal 46 (38.7) 59 (38.8) 72 (47.7)
Family history No 117 (98.3) 147 (96.7) 145 (96.0) 0.516
Yes 2 (1.7) 5 (3.3) 6 (4.0)
Initial T stage 1 6 (5.0) 17 (11.2) 11 (7.3) 0.196
2 80 (67.2) 83 (54.6) 90 (59.6)
3 33 (27.7) 52 (34.2) 50 (33.1)
Initial axillary LN Uninvolved 17 (14.3) 21 (13.8) 26 (17.2) 0.677
Involved 102 (85.7) 131 (86.2) 125 (82.8)
Histological grade 1–2 76 (63.9) 95 (62.5) 101 (66.9) 0.718
3 43 (36.1) 57 (37.5) 50 (33.1)
HR status Positive 78 (65.5) 101 (66.4) 102 (67.5) 0.941
Negative 41 (34.5) 51 (33.6) 49 (32.5)
HER2 status (FISH or CISH) Positive 49 (41.2) 55 (36.2) 49 (32.5) 0.334
Negative 70 (58.8) 97 (63.8) 102 (67.5)
Ki-67 value ≤20% 35 (29.4) 34 (22.4) 36 (23.8) 0.385
>20% 84 (70.6) 118 (77.6) 115 (76.2)
Molecular subtype Luminal 45 (37.8) 58 (38.2) 71 (47.0) 0.468
HER2-enriched 57 (47.9) 72 (47.4) 64 (42.4)
Triple-negative 17 (14.3) 22 (14.5) 16 (10.6)
NAC drugs Taxane-based 6 (5.0) 6 (3.9) 12 (7.9) 0.236
Anthracycline-based 1 (0.8) 5 (3.3) 6 (4.0)
Taxane- and anthracycline- based 112 (94.1) 141 (92.8) 133 (88.1)
Neoadjuvant targeted therapy Yes 42 (35.3) 52 (34.2) 45 (29.8) 0.582
No 77 (64.7) 100 (65.8) 106 (70.2)
Clinical response CR 6 (5.0) 15 (9.9) 8 (5.3) 0.056
PR 85 (71.4) 110 (72.4) 100 (66.2)
SD 24 (20.2) 23 (15.1) 42 (27.8)
PD 4 (3.4) 4 (2.6) 1 (0.7)
Breast surgery Mastectomy 110 (92.4) 139 (91.4) 140 (92.7) 0.912
BCS 9 (7.6) 13 (8.6) 11 (7.3)
pCR or non-pCR pCR 22 (18.5) 33 (21.7) 27 (17.9) 0.669
Non-pCR 97 (81.5) 119 (78.3) 124 (82.1)
pN stage 0 39 (32.8) 54 (35.5) 53 (35.1) 0.994
1 36 (30.3) 40 (26.3) 44 (29.1)
2 27 (22.7) 36 (23.7) 34 (22.5)
3 17 (14.3) 22 (14.5) 20 (13.2)
Adjuvant chemotherapy Yes 25 (21.0) 23 (15.1) 23 (15.2) 0.355
No 94 (79.0) 129 (84.9) 128 (84.8)
Adjuvant radiotherapy Yes 109 (91.6) 142 (93.4) 130 (86.1) 0.084
No 10 (8.4) 10 (6.6) 21 (13.9)
Adjuvant targeted therapy Yes 52 (43.7) 67 (44.1) 57 (37.7) 0.468
No 67 (56.3) 85 (55.9) 94 (62.3)
Abbreviations: T, tumor; LN, lymph node; HR, hormone receptor; HER2, human epidermal growth factor receptor 2; FISH, fluorescence in situ hybridization; CISH, chromogenic in situ hybridization; NAC, neoadjuvant chemotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; BCS, breast conserving surgery; pCR, pathologic complete response.
The median DFS of the Group A was 43 months (range, 9 to 87 months), the median DFS of the Group B was 35.5 months (range, 4 to 81 months), and the median DFS of the Group C was 33 months (range, 6 to 93 months). In the three groups, the median OS was found to be 46 months (range, 25 to 87 months), 41 months (range, 24 to 81 months) and 39 months (range, 25 to 93 months) respectively. The 3-year OS rate of the three groups was 95.8% (114/119), 96.7% (147/152) and 90.1% (136/151), respectively.
Figure 2 indicates the results of the Kaplan-Meier survival curves using the Log rank test for the DFS and the OS. Survival analysis showed that DFS (P=0.012) and OS (P=0.015) were significantly different among three groups. Between Groups A and B, no significant difference in the DFS (P=0.595) and the OS (P=0.716) was observed. Nonetheless, between Groups A and C, the survival analysis indicated that DFS (P=0.006) and the OS (P=0.014) were found to be significantly different. At the same time, the DFS (P=0.024) and OS (P=0.027) of Group B were significantly different from that of Group C. This indicated that TTS >28 days did affect the survival outcome of these patients.Figure 2 Kaplan–Meier curves for survival according to different time to surgery. (A) Disease-free survival (P=0.012). (B) Overall survival (P=0.015).
Univariate and Multivariate Analyses for DFS and OS
The univariate analysis of DFS showed that pCR, pN stage, adjuvant chemotherapy and TTS were significant factors (P<0.001, P<0.001, P=0.001 and P=0.003, respectively). For OS, the univariate analysis showed that pN stage, adjuvant chemotherapy and TTS were significant factors (P=0.014, P=0.001 and P=0.032, respectively). In the multivariate analyses, DFS and OS were significantly worse when TTS >28 days with a hazard ratio of 2.333 (95% CI, 1.444–3.770, P=0.001) and 2.783 (95% CI, 1.007–7.687, P=0.030) respectively. Patients with pCR, pN2-3 stage and adjuvant chemotherapy were independent parameters for DFS (P=0.042, P<0.001 and P=0.001, respectively), while pN2-3 stage and adjuvant chemotherapy were also independent parameters for OS (P=0.024 and P=0.010, respectively). The relevant statistics are shown in Table 2.Table 2 Univariate and Multivariate Analysis for DFS and OS
Variables DFS OS
3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate) 3-Year Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.958 0.488
≤50 71.9 93.4
>50 71.7 95.0
Menstrual state 0.523 0.839
Premenopausal 70.6 93.9
Postmenopausal 73.4 94.4
Initial T stage 0.112 0.713
1 85.3 97.1
2 72.3 94.1
3 67.4 6.7
Initial axillary LN 0.537 0.905
Uninvolved 75.0 93.7
Involved 71.2 94.1
Histological grade 0.769 0.961
1–2 71.3 94.1
3 72.7 94.0
Ki-67 value 0.689 0.125
≤20% 73.3 97.1
>20% 71.3 93.1
Molecular subtype 0.394 0.194
Luminal 75.3 96.6
HER2-enriched 68.9 92.2
Triple-negative 70.9 92.7
Breast surgery 0.599 0.422
Mastectomy 71.5 94.3
BCS 75.8 90.9
pCR or non-pCR <0.001 0.042 0.136
pCR 89.0 1 97.6
Non-pCR 67.6 2.070 (1.026–4.176) 93.2
pN stage <0.001 <0.001 0.014 0.024
0–1 80.8 1 96.2 1
2–3 56.4 2.435 (1.677–3.536) 90.4 2.524 (1.130–5.634)
Adjuvant chemotherapy 0.001 0.001 0.001 0.010
Yes 54.9 2.330 (1.538–3.530) 85.9 3.671 (1.647–8.182)
No 75.2 1 95.7 1
Adjuvant radiotherapy 0.209 0.691
Yes 51.0 94.2
No 37.5 92.7
TTS 0.003 0.001 0.032 0.030
Group A 79.8 1 95.8 1
Group B 75.0 1.469 (0.879–2.453) 0.142 96.7 0.891 (0.257–3.083) 0.855
Group C 62.3 2.333 (1.444–3.770) 0.001 89.0 2.783 (1.007–7.687) 0.048
Abbreviations: DFS, disease-free survival; OS, overall survival; CI, confidence interval; T, tumor; LN, lymph node; HER2, human epidermal growth factor receptor 2; BCS, breast conserving surgery; pCR, pathologic complete response; TTS, time to surgery.
Relationship Between TTS and Postoperative Complications
Postoperative complications occurred in 96 (22.7%) patients, including poor healing of incision, infection, hematoma or hemorrhage, subcutaneous effusion and skin flap necrosis. The incidence of postoperative complications is shown in Table 3 and the classification of severity is shown in Table 4. Most of the patients were treated in the outpatient department; only 4.2% (4/96) of the patients returned to the operating room and received general anesthesia operations. The incidence of total postoperative complications in the three groups was statistically different (P=0.001). Compared with Group B (P=0.003) and Group C (P<0.001), Group A had worse performance in total postoperative complications. The total complication rates of Group B and Group C were similar (P=0.566). This suggested that TTS ≤21 days was significantly associated with a higher incidence of total postoperative complications. And among the five kinds of complications, the incidence of poor incision healing (P=0.024) and infection (P=0.031) was significantly different among the three groups. The univariate analysis indicated that age and TTS were the significant factors for total postoperative complications (P=0.009 and P<0.001, respectively). In the multivariate analysis, age >50 years old and TTS ≤21 days were independent parameters for total postoperative complications (P=0.004 and P<0.001, respectively). The statistical details are shown in Table 5.Table 3 Relationship Between TTS and Postoperative Complications
Postoperative Complications Number of Patients (%) p value
Group A (n = 119) Group B (n = 152) Group C (n = 151)
Poor incision healing Yes 15 (12.6) 10 (6.6) 6 (4.0) 0.024
No 104 (87.4) 142 (93.4) 145 (96.0)
Infection Yes 12 (10.1) 6 (3.9) 5 (3.3) 0.031
No 107 (89.9) 146 (96.1) 146 (96.7)
Hematoma or hemorrhage Yes 5 (4.2) 5 (3.3) 7 (4.6) 0.832
No 114 (95.8) 147 (96.7) 144 (95.4)
Subcutaneous effusion Yes 9 (7.6) 6 (3.9) 6 (4.0) 0.310
No 110 (92.4) 146 (96.1) 145 (96.0)
Skin flap necrosis Yes 1 (0.8) 2 (1.3) 1 (0.7) 0.833
No 118 (99.2) 150 (98.7) 150 (99.3)
Total Yes 42 (35.3) 29 (19.1) 25 (16.6) 0.001
No 77 (64.7) 123 (80.9) 126 (83.4)
Abbreviation: TTS, time to surgery.
Table 4 Classification of the Severity of Postoperative Complications
Clavien-Dindo Grade Number of Patients Undergone Postoperative Complications (%)
Group A
(n = 42) Group B (n = 29) Group C
(n = 25)
Grade I 13 (31.0) 12 (41.4) 9 (36.0)
Grade II 11 (26.2) 6 (20.7) 5 (20.0)
Grade IIIa 16 (38.1) 10 (34.5) 10 (40.0)
Grade IIIb 2 (4.8) 1 (3.4) 1 (4.0)
Grade IV/V 0 (0) 0 (0) 0 (0)
Table 5 Univariate and Multivariate Analysis for Postoperative Complications
Variables Postoperative Complications
Incidence Rate, % p value (Univariate) Hazard Ratio (95% CI) p value (Multivariate)
Age (years) 0.009 0.004
≤50 18.2 1
>50 28.9 1.996 (1.245–3.201)
BMI 0.984
≤20 23.8
20< BMI≤25 21.9
25< BMI≤30 23.3
>30 23.9
NAC drugs 0.945
Taxane-based 25.0
Anthracycline-based 25.0
Taxane- and anthracycline- based 22.5
Breast surgery 0.826
Mastectomy 22.9
BCS 21.2
TTS <0.001 <0.001
≤21 35.3 2.695 (1.656–4.387)
>21 17.8 1
Abbreviations: CI, confidence interval; BMI, body mass index; NAC, neoadjuvant chemotherapy; BCS, breast conserving surgery; TTS, time to surgery.
Causes of Surgery Delay
The causes of surgery delay in Group C were analyzed. There were six main reasons: neutropenia caused by chemotherapy drugs (47.0%), liver dysfunction caused by chemotherapy drugs (33.1%), heart disease or other comorbidities (14.6%), waiting for breast MRI appointment (9.3%), discussion time of treatment strategy (7.9%) and medical insurance or hospitalization appointment (7.3%). The most common causes were due to the side effects of chemotherapy drugs, such as hematological toxicity and liver toxicity.
Discussion
The effectiveness and safety of NAC in the treatment of breast cancer had been confirmed from the numerous clinical trials.6,7 Besides not presenting any specific interval from the completion of the NAC to the surgery, none of the trials could evaluate the relationship between NAC and postoperative complications. At present, clinicians mainly infer the interval from NAC to surgery based on the interval data of adjuvant chemotherapy, but its applicability to the NAC is unclear.8 Therefore, we conducted this retrospective study to analyze the relationship between TTS and patient survival as well as the relationship between TTS and postoperative complications, trying to find the appropriate TTS interval.
In this study, we retrospectively collected data from 422 patients and analyzed the TTS and survival. Through analysis, it was observed that in the case of the patients with TTS >28 days, the OS and the DFS were evidently different when compared with those from the other two groups. The TTS >28 days also being an independent prognostic factor capable of influencing the survival outcome was simultaneously indicated by the multivariate analysis. This suggested that prolonged TTS did have an adverse effect on the survival of patients, and TTS ≤28 days may be the most favorable surgery time for the prognosis of patients. In addition, we found that pCR, pN2-3 stage and adjuvant chemotherapy were factors affecting DFS; pN2-3 stage and adjuvant chemotherapy were factors affecting OS while pCR did not have an impact on OS. This suggested that pCR after neoadjuvant chemotherapy may not translate into long-term survival benefits. The incidence of tumor recurrence or metastasis in 3 years in patients with adjuvant chemotherapy was significantly higher than that in patients without adjuvant chemotherapy. This may be because most of the patients receiving adjuvant chemotherapy after surgery were patients with worse NAC curative effect, and their tumors may have worse biological characteristics.
The results of Omarini et al indicated that prolonged TTS was not conducive to the survival of patients. They studied 319 patients and found that TTS was an independent prognostic factor for OS (P=0.03) and recurrence-free survival (RFS) (P=0.01), even in the pCR subgroup. And they believed that the best time for surgery was TTS ≤21 days.3 However, some clinicians believed that TTS might have little relationship with the prognosis of patients. Sanford et al followed up 1011 patients and found that although there were differences in 5-year OS among patients with TTS ≤4 weeks, 4–6, and >6 weeks (P=0.03), there was no difference in 5-year RFS (P=0.28) and local recurrence-free survival (LRFS) (P=0.31) among the three groups. In multivariate analysis, OS, LRFS and RFS of patients with TTS ≤4 weeks, 4–6 weeks and >6 weeks were comparable; sensitivity analysis showed that patients who underwent surgery at >8 weeks had worse OS (P=0.02), but there was no significant difference between RFS and LRFS.9 Suleman et al found that TTS had no effect on DFS (P=0.3) and OS (P=0.5), but the pCR rate of ER +/HER2 + patients decreased when TTS ≥8 weeks (12.9% versus 25.3%).4 Although the results of these retrospective studies were suggestive, they were controversial. Large-sample and multi-center clinical cases are needed for further analyses.
By inhibiting the cell division, the protein synthesis, the RNA, or DNA production, most of the antineoplastic drugs were observed to exert their cytotoxic impact in the NAC of breast cancer. Previous animal experimental data showed that wound healing was affected within 28 days after the application of cytotoxic drugs.10 Previous clinical studies have shown that immunosuppression after chemotherapy is a known factor leading to postoperative complications.11,12 The association of TTS in cases of postoperative complications was revealed from this study. In patients with shorter TTS, the incidence of complications such as poor incision healing and infection had an obvious increasing trend. In the multivariate analysis, age <50 years old and TTS ≤21 days were independent parameters for total postoperative complications. The decrease of neutrophils, the increase of vascular fragility and tissue edema may be the reasons for the increased incidence of these complications. However, we also observed that most of the postoperative complications were mild and could be treated in the outpatient department. Similarly, defining the time interval to be 28 days, the higher incidence of postoperative complications was found to have a shorter TTS by a study of Sutton et al.13 It was also observed that with age as the dominant predictor, compared to TTS greater than 28 days (P <0.05), the TTS of 28 days or less was associated with almost 70% increased chances of a wound complication. Considering the influence of chemotherapy and radiotherapy, only a few patients choose immediate reconstruction surgery after NAC, so we failed to evaluate the impact of TTS on postoperative complications of patients with immediate breast reconstruction. In previous studies, in the case of perioperative complications in patients with immediate breast reconstruction, NAC was not observed to be a risk factor.14 As an increase in the number of patients with immediate breast reconstruction in our center recently, we will further do some research in this area.
In clinical practice, the surgery delay after NAC was affected by multiple factors. One of the most common causes of delayed surgery is the time required to recover from the side effects of short-term chemotherapy (mainly hematological toxicity and liver toxicity). Therefore, clinicians should well control the side effects of chemotherapy, such as regular blood examination and timely use of granulocyte colony stimulating factor (G-CSF) preparation, etc.15 It was worth noting that 14 patients delayed the TTS due to the appointment of preoperative breast MRI in Group C. Zhang et al also reported that preoperative breast MRI prolonged the operation waiting time by 11 days.16 This result reminded clinicians to optimize the patient’s examination process and minimize the operation delay due to waiting for examination.
Nonetheless, this study is not free of limitations. First, as is typical of retrospective studies, there could have been potential biases. The TTS of patients were individually selected based upon the condition of the patients, rather than being assigned randomly. The interpretation of the survival analysis was thus limited by the inevitable biases in the selection of the treatment. Second, the follow-up time was short. Especially for the patients who achieved pCR after NAC, we observed fewer death events, so we could not make subgroup analysis on these patients. Third, due to the retrospective study, patients may have memory loss or mistakes in the occurrence of postoperative complications, which affects our analysis. Last but not least, the study represented a single institutional experience and therefore the results may be hard to extrapolate to other institutions or countries with different patient populations and different practice patterns. Nevertheless, this study can provide some ideas and guidance for clinicians’ decisions. At the same time, it also provides the direction for further research.
Conclusion
In conclusion, TTS after NAC seemed to influence survival outcomes and postoperative complications. Breast cancer patients who underwent surgery between 21 and 28 days benefited the most. Clinicians should make a comprehensive evaluation of patients, balance the impact of TTS on short-term complications and long-term survival rate, and select the appropriate operation time.
Disclosure
There are no relevant conflicts of interests to be disclosed by the authors. | TRASTUZUMAB | DrugsGivenReaction | CC BY-NC | 33568945 | 19,625,890 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | CAPECITABINE, DOCETAXEL, GEMCITABINE, PACLITAXEL, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukopenia'. | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | CAPECITABINE, DOCETAXEL, GEMCITABINE, PACLITAXEL, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver disorder'. | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | CAPECITABINE, DOCETAXEL, GEMCITABINE, PACLITAXEL, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | CAPECITABINE, DOCETAXEL, GEMCITABINE, PACLITAXEL, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palmar-plantar erythrodysaesthesia syndrome'. | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | CAPECITABINE, DOCETAXEL, GEMCITABINE, PACLITAXEL, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | CAPECITABINE, DOCETAXEL, GEMCITABINE, PACLITAXEL, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
What was the administration route of drug 'CAPECITABINE'? | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
What was the dosage of drug 'CAPECITABINE'? | Comparison of capecitabine-based regimens with platinum-based regimens in Chinese triple-negative breast cancer patients with liver metastasis.
Capecitabine-based chemotherapy (CBC) presents potential value in patients with liver metastasis; platinum-based chemotherapy (PBC) has shown promising benefit in patients with triple-negative breast cancer (TNBC). For TNBC patients with liver metastasis, which treatment strategy is better remains to be further studied. The aim of this study was to report the first real-world data evaluating the efficacy and safety of PBC versus CBC in the first-line treatment in Chinese TNBC patients with liver metastasis.
TNBC patients with liver metastasis pretreated with anthracyclines/taxanes in 4 institutions of China between January 2010 and December 2019 were included. Objective response rate (ORR), overall survival, treatment pattern, and toxicity profile were assessed between PBC and CBC groups.
A total of 59 TNBC patients with liver metastasis were identified. Among these, 33 were treated with PBC and 26 were treated with CBC. The ORR was higher in the CBC group than in the PBC group (57.7% versus 30.3%, P=0.035). Median overall survival was also greatly improved (19.2 versus 14.4 months, P=0.041). Docetaxel/cisplatin was more likely to be used for PBC, and paclitaxel/capecitabine was the main regimen for CBC. Multivariable Cox regression analysis indicated that CBC was an independent predictor for overall survival after adjustment for baseline factors including age, tumor size, nodal status, prior anthracyclines/taxanes use, and tumor grade (odds ratio =0.51; 95% confidence interval, 0.27-0.98; P=0.042). Adverse events were not different except gastrointestinal tract toxicities, hand-foot syndrome and hematologic toxicity.
For TNBC patients with liver metastasis, capecitabin-based chemotherapy might be more suitable than the platinum-based regimen in the first-line treatment, as measured by objective response rate and overall survival. Further large-scale studies are warranted.
pmcIntroduction
Triple-negative breast cancer (TNBC) refers to the absence of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER-2). It is a specific subtype of breast cancer accounting for 15–20% of all breast cancers (1). TNBC presents a trend of early visceral metastasis, and has poorer prognosis (2). Among patients with metastatic breast cancer (MBC), approximately half will develop liver metastases (LM), and 12% of patients develop metastasis of primary liver cancer (3), leading to liver dysfunction and poor survival (4).
Instead of available target agents, chemotherapy represents the mainstay systemic treatment for metastasis TNBC (mTNBC) (5). Anthracyclines and taxanes are fundamental regimens with proven efficacy in every stage of breast cancer (6). However, for patients with anthracycline/taxanes-pretreated breast cancers, there are no standard regimens currently (7).
For patients with mTNBC, platinum-based chemotherapy (PBC) has shown promising results in increasing preclinical and clinical trials. Platinum can lead to DNA damage, and TNBC is more sensitive to these agents compared to other subtypes of breast cancers. The benefit of platinum regimens was confirmed by several II or III clinical trials (8-10).
For patients with LM, capecitabine-based chemotherapy (CBC) seems to show potential value. Capecitabine is among the drugs of first choice for breast cancer patients resistant to anthracycline or taxane (11). It is activated in the liver and further forms 5-FU in the tumor tissue (12-14), suggesting higher concentration in the liver and the potential benefit for patients with liver metastases (LM).
However, for mTNBC patients with LM, which agents are more suitable is uncertain. In this study, we present the result of the comparison of the PBC and CBC in patients with mTNBC-LM.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-4590).
Methods
Patients and data collection
In this study, we retrospectively compared the efficacy and toxicity of CBC and PBC in mTNBC patients with LM. We reviewed the electronic medical records of patients with mTNBC who received systematical chemotherapy at four cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital) between January 2010 and December 2019.
Inclusion criteria were as follows for eligible patients: (I) immunohistochemical (IHC) staining method was applied to determine the ER/PgR/HER-2status. Triple negativity breast cancer was defined as the deficiency of expression of ER, PgR, and HER-2. “ER/PgR negative” were defined when less than 1% positive tumor cells were detected with nuclear staining by IHC according to the guidelines of new College of American Pathologists. HER-2 status was evaluated by IHC and fluorescence in situ hybridization (FISH). “HER-2 negative” was defined as IHC scoring 0 or 1+ or FISH nonamplied according to the American Society of Clinical Oncology (ASCO) guidelines. (II) Breast cancers patients had initial isolated liver metastasis. (III) Patients received PBC or CBC as the first-line treatment. (IV) Patients had completed treatment records and follow-up information. Finally, 59 eligible TNBC patients with LM were included in this study (Figure 1). Initial LM was defined as LM that occurred as the first evidence of metastasis, and isolated LM was characterized by the absence of extrahepatic metastasis.
Figure 1 Flow diagram of patient selection.
Patients were further allocated into two groups by their regimens in their salvage chemotherapies: the PBC group and CBC group. PBC referred to chemotherapy that included cisplatin or carboplatin alone or in combination with another regimen. CBC was defined as chemotherapy that included capecitabine alone or in combination with other regimens. Clinical data were collected and analyzed, including demographic characteristics, disease stage at diagnosis, treatment regimens, response to treatment, adverse events, and overall survival.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). It was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Response assessment and follow-up
Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) 1.1 guideline, which was classified into four categories: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Tumor response to treatment was assessed every 2 cycles during chemotherapy and then every 3 months after chemotherapy. The efficacy of chemotherapy was evaluated in terms of objective response rate (ORR) and overall survival (OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) 4.03.
Statistical analysis
OS was defined as the interval from the time of diagnosis of the liver metastasis to the time of death or until the date of the last follow-up visit. OS was computed according to the Kaplan-Meier method, and compared by the log-rank test. Multivariate survival analysis was performed according to the Cox proportional hazards model. Statistical analysis was performed via SPSS software version 22.0. A P value less than 0.05 was considered to be statistically significant.
Results
Characteristics of patients
We identified 12,568 patients with breast cancer who had available treatment data from 2003 to 2019. Of these patients, 5,785 received palliative chemotherapy for the treatment of metastatic or recurrent breast cancer at four major cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Beijing Chaoyang Hospital, Beijing Sanhuan Cancer Hospital). Of the 5,785 patients, 961 patients with MBC were excluded due to their unknown ER/PgR/HER2 status. Among the remaining patients, 4,329 patients who were not TNBCs or had incomplete chemotherapy records were excluded from this study. Eighty-two patients were diagnosed with initial LM on the basis of abdominal computed tomographic scans or magnetic resonance imaging scans. LM was confirmed pathologically if necessary. Among these, patients who were not isolated LM and did not receive PBC or CBC as the first-line treatment were excluded. Finally, 59 patients were confirmed eligible and included for the final analysis (Figure 1).
Patient demographics at baseline are presented in Table 1. In total, 59 eligible patients were included in this study between January 2003 and December 2019. Of these patients, 33 patients were treated with PBC, and 26 were treated with CBC. The median age at diagnosis of the two cohorts was 48 [32–73] years and 52 [28–73] years, respectively. Premenopausal patients were dominant in the two groups. All patients had failed treatment with anthracyclines and taxanes. The majority of patients (66.7% for PBC; 53.8% for CBC) presented with pathological T2 tumors, and more than half (54.6% for PBC; 61.6% for docetaxel) had N0/1 axillary nodes. The median Ki67 expression was 40% in PBC and 50% in CBC. Disease-free interval (DFI) was 21.7 months in patients with PBC, similar with that in CBC (P=0.56). Overall, the two groups were well balanced in baseline characteristics.
Table 1 Baseline characteristics of patient with metastatic triple-negative breast cancer
Demographic PBC (n=33) CBC (n=26) P
Median age (range), yr 48 [32–73] 52 [28–73] 0.84
Menopausal status, n (%) 0.64
Premenopausal 21 (63.6) 15 (57.7)
Postmenopausal 12 (36.4) 11 (42.3)
Prior anthracyclines, n (%) 0.61
Neoadjuvant 7 (21.2) 7 (26.9)
Adjuvant 26 (78.8) 19 (73.1)
Prior taxanes, n (%) 0.4
Neoadjuvant 7 (21.2) 8 (30.8)
Adjuvant 26 (78.8) 18 (69.2)
TNM staging
Tumor classification, n (%) 0.49
T1 7 (21.2) 6 (23.1)
T2 22 (66.7) 14 (53.8)
T3-4 4 (12.1) 6 (23.1)
Lymph node classification, n (%) 0.47
N0 9 (27.3) 10 (38.5)
N1 9 (27.3) 6 (23.1)
N2 10 (30.3) 4 (15.4)
N3 5 (15.2) 6 (23.1)
Histological grade, n (%) 0.85
II 26 (78.8) 21 (80.8)
III 7 (21.2) 5 (19.2)
DFI (months, range) 21.7 (2.4–121.2) 18.4 (1.2–90.0) 0.56
Number of metastatic organ, n (%) 0.49
Single 13 (39.4) 8 (30.8)
Multiple 20 (60.6) 18 (69.2)
Ki67 (median)a 40 [10–90] 50 [25–90] 0.53
a, some of Ki67 index from local hospital were missing. CBC, carboplatin-based chemotherapy; DFI, disease-free interval defined as the time from operation to first relapse; PBC, platinum-based chemotherapy.
Chemotherapy regimens
In the PBC group, 19 (57.6%) patients received platinum agents (carboplatin or cisplatin) combined with taxanes (TP), 9 (27.2%) patients were treated with gemcitabine+platinum (GP), and 5 (15.1%) were treated with vinorelbine+platinum (NP). The main strategies of CBC were taxane-containing regimens (TX, n=18, 65.3%), followed by vinorelbine/capecitabine combinations (NX, n=6, 23.1%), and capecitabine monotherapy (X, n=1, 3.8%). Carboplatin was administered at the area under the curve equal to 5 (AUC =5) on the first day every 3 weeks. Cisplatin was given at a dose of 25 mg/m2/day on the first 3 days every 3 weeks. Capecitabine was delivered at a dose of 1,250 mg/m2 for the first 2 weeks every 21 days. The treatment strategies in the two cohorts are listed in Table 2.
Table 2 Chemotherapy regimens
PBC (n=33) Dose and schedules n (%) CBC (n=26) Dose and schedules n (%)
Gemcitabine/Cisplatin DDP 75 mg/m2 d1, Gem 1.0 g/m2 d1, 8, Q21d 8 (24.2) Vinorelbine/Capecitabine Cap 1,000 mg/m2 d1–14, NVB 25 mg/m2 d1, 8, Q21d 6 (23.1)
Vinorelbine/Cisplatin DDP 75 mg/m2 d1, NVB 25 mg/m2 d1, 8, Q21d 4 (12.1) Gemcitabine/Capecitabine Cap 1,000 mg/m2 d1–14, Gem 1.0 g/m2 d1, Q21d 1 (3.8)
Gemcitabine/Carboplatin CBP AUC 5 d1, Gem 1.0 g/m2 d1, 8, Q21d 1 (3.0) Docetaxel/Capecitabine Cap 1,000 mg/m2 d1–14, TXT 75 mg/m2 d1, Q21d 8 (30.8)
Vinorelbine/Carboplatin CBP AUC 5 d1, NVB 25 mg/m2 d1, 8, Q21d 1 (3.0) Paclitaxel/Capecitabine Cap 1,000 mg/m2 d1–14, PTX 175 mg/m2 d1, Q21d 10 (34.5)
Docetaxel/Cisplatin DDP 75 mg/m2 d1, TXT 75 mg/m2 d1, Q21d 11 (33.3) Capecitabine Cap 1,250 mg/m2 d1–14, Q21d 1 (3.8)
Paclitaxel/Cisplatin DDP 75 mg/m2 d1, PTX 175 mg/m2 d1, Q21d 2 (6.1)
Docetaxel/Carboplatin CBP AUC 5 d1, TXT 75 mg/m2 d1, Q21d 3 (9.1)
Paclitaxel/Carboplatin CBP AUC 5 d1, PTX 175 mg/m2 d1, Q21d 3 (9.1)
AUC, area under the curve; Cap, capecitabine; CBC, capecitabine-based chemotherapy; CBP, carboplatin; DDP, cisplatin; Gem, gemcitabine; NVB, vinorelbine; PTX, paclitaxel; PBC, platinum-based chemotherapy; TXT, docetaxel.
Response and survival
The overall response rate (ORR) was 30.3% (10/33) in the PBC group, including 1 complete response (CR, 3.1%) and 9 partial response (PR, 27.3%); 15(45.5%) patients had stable disease (SD) and 8 (24.2%) experienced progressive disease (PD) during the systematic treatment. In the CBC cohort, ORR was 57.7% (15/26), consisting of 1 (3.8%) CR, 14 (53.8%) PR, 8 (30.8%) SD, and 3 (11.5%) PD. There was a significantly higher response rate in patients who received CBC (57.7%) than that in patients who received PBC (30.3%, P=0.035, Table 3).
Table 3 Best tumor response to chemotherapy
Tumor response PBC (n=33, %) CBC (n=26, %)
CR 1 (3.1) 1 (3.8)
PR 9 (27.3) 14 (53.8)
SD 15 (45.5) 8 (30.8)
PD 8 (24.2) 3 (11.5)
CBC, capecitabine-based chemotherapy; CR, complete response; PBC, platinum-based chemotherapy; PD, progression disease; PR, partial response; SD, stable disease.
During the follow-up, 42 patients died and 17 patients remained alive. Median OS in the PBC group was 14.4 months (95% CI, 9.9–18.9 months), which was statistically longer than that in the CBC group (19.2 months, 95% CI, 10.7–27.7 months, P=0.041), as illustrated in Figure 2. Multivariate Cox proportional hazards analysis was performed to eliminate confounding variables and to clarify whether CBC alone conferred a survival benefit. Univariate analysis was performed to explore potential prognostic factors; all of the variables with P<0.1 were included in the Cox multivariate analysis (Table 4). The results indicated that CBC remained an independent predictor for OS after adjustment for baseline factors including age, tumor size, nodal status, prior anthracycline/taxane use, and tumor grade (OR 0.51; 95% CI, 0.27–0.98; P=0.042, Table 4).
Figure 2 Kaplan-Meier curves of overall survival for patients treated with capecitabine-based chemotherapy (N=26) and platinum-based chemotherapy (N=33).
Table 4 Univariate and multivariate Cox regression analyses
Variables Univariate analysis Multivariate analysis
P HR P HR
Age at recurrence, y (≤50 vs. >50) 0.4 1.238
Tumor size, cm (1,2 vs. 3,4) 0.42 0.732
Number of LNM (0,1 vs. 2,3) 0.5 0.657
First-line chemotherapy (CBC vs. PBC) 0.05 0.536 0.042* 0.514
Tumor grade (II vs. III) 0.38 0.756
Prior anthracyclines (yes vs. no) 0.46 0.733
Prior taxanes (yes vs. no) 0.21 0.593
Number of metastatic organs (single vs. multiple) 0.065 0.537 0.056
*, P values <0.05. CBC, capecitabine-based chemotherapy; LNM, lymph node metastases; HR, hazard ratio; PBC, platinum-based chemotherapy.
Toxicity
Major treatment-related adverse effects (TRAEs) are shown in Table 5, mainly including vomiting, neutropenia, leucopenia, hand-foot syndrome, hepatic abnormalities, and fatigue. During the treatment, 93.9% of patients treated with PBC had at least one TRAEs compared with 96.2% of those treated with CBC. Gastrointestinal tract adverse events occurred more frequently and were more severe with PBC than CBC at grade 1/2 (P=0.015) and at grade 3/4 (P=0.045). Hand-foot syndrome was more common in the CBP group especially at grade 3/4 (37.2% vs. 18.0%, P=0.037). Neutropenia (75.8% vs. 38.5%, P=0.004) and leucopenia (78.8% vs. 46.2%, P=0.009) at grade 1/2 also occurred more frequently in the PBC group than in the CBC groups. Incidences of diarrhea, fatigue, and hepatic abnormalities were comparable between the two groups. There were no treatment-related deaths in either group. Generally, both treatment strategies were tolerated and quite manageable.
Table 5 Percent frequency of selected treatment-related adverse events
Toxicity PBC (n=33), No. (%) CBC (n=26), No. (%) P (grade 1–2) P (grade 3–4)
Grade 1–2 Grade 3–4 Grade 1–2 Grade 3–4
Vomiting 18 (54.5) 10 (30.3) 6 (23.1) 2 (7.7) 0.015* 0.045*
Neutropenia 25 (75.8) 7 (21.2) 10 (38.5) 4 (15.4) 0.004* 0.57
Hand–foot syndrome 0 0 15 (57.7) 2 (7.7) <0.001* <0.001*
Leucopenia 26 (78.8) 6 (18.2) 12 (46.2) 2 (7.7) 0.009* 0.43
Fatigue 11 (33.3) 0 9 (34.6) 0 0.92 NA
Hepatic abnormalities 5 (16.0) 2 (8.0) 5 (20.1) 1 (4.7) 0.68 0.7
*, indicates statistically significant. CBC, capecitabine-based chemotherapy; PBC, platinum-based chemotherapy; NA, not applicable.
Discussion
Studies focused on mTNBC indicated that capecitabine-based regimens could prolong the survival time (15-17). Most recent studies showed that PBC in TNBC patients has promising results in increasing preclinical and clinical trials. The platinum-based regimen has higher ORR and better survival than the platinum-free regimen (8-10). However, study focused on TNBC patients with LM is scarce.
With regard to the present study, we compared the efficacy and safety profile of capecitabine-based regimens with platinum-based regimens in TNBC patients with LM. The result demonstrated that the CBC group achieved higher ORR and longer OS than that in the PBC group, with tolerable adverse events except incidence of hand-foot syndrome. To the best of our knowledge, this is the first investigation to compare the role of PBC with CBC in TNBC patients with LM.
Our data showed that the ORR (57.7% vs. 30.3%, P=0.035) was higher in the CBC group, and the median OS (19.2 vs. 14.4 months, P=0.041) was greatly improved compared with the PBC group. These findings are also consist with most other studies supporting a statistically significant benefit on response rates and median OS from capecitabine in anthracycline- and taxane-pretreated MBC (15-17). Results from several meta-analysis showed that capecitabine could significantly improve the survival both in patients with early and advanced breast cancer (18,19). Capecitabine might prolong OS in patients with ER-negative or HER2-negative breast cancer in the first-line treatment. Moreover, adjuvant capecitabine therapy showed effectiveness in triple-negative subgroup (19).
In our study, we found that capecitabine showed an active efficacy in a liver metastatic setting. This observation was in line with the previous studies (20-27). Findings from the study of colorectal cancer patients with LM indicated that the concentration of 5-FU (precursor of capecitabine) in liver metastasis tissue was higher than normal colorectal tissue and reached about 70% of the number in colorectal tumor tissue (20). Possible explanations might be the higher concentration of 5-Fu in the liver (21,22). The chemotherapy response may be influenced by the distribution of drugs and its concentration in tumor tissues. Capecitabine is an oral chemotherapy drug and is enzymatically converted into 5-FU in the liver and tumor tissues (23,24). The activity of thymidine phosphorylase (TP) is much higher in normal liver tissues than that in other tissues (25). The benefit of capecitabine-based therapy (CBT) is significantly affected by the activity of TP (26). Another possible explanation might be the maintenance chemotherapy of capecitabine (27). Maintenance chemotherapy refers to the continuous treatment of part of the primary agents in patients after the initial standard treatment, which can significantly prolong the survival time. Capecitabine-based regimens usually ends with the maintenance of capecitabine monotherapy (28,29).
Generally, both strategies were well tolerated and manageable. In the CBC group, the most frequent adverse effects were neutropenia, leucopenia and hand–foot syndrome. In the PBC group, the incidence of gastrointestinal, leukopenia, and neutropenia adverse events was more common than that of CBC. These results are in line with the previous studies (30-33).
Although the treatment option for breast cancer LM is palliative, different local treatment modalities, such as surgery and stereotactic body radiotherapy (SBRT), have been applied together with systemic chemotherapeutic agents in order to improve outcomes (34,35).
For breast cancer patients with LM receiving metastasectomy, the median 3-, and 5-year survival rates range between 49–94% and 5–78%, respectively (36-39). Findings from a case-matched analysis showed that liver resection combined with systemic treatment resulted in improved OS compared to systemic treatment alone. Median OS of the resection group was 82 months with a 3- and 5-year OS of 81% and 69%, respectively, compared with a median OS of 31 months in the systemic group with a 3- and 5-year OS of 32% and 24%, respectively (40). A systematic review (41) analyzed 956 patients receiving resection of breast cancer LM. The median 3-, and 5-year survival were 52.9% and 33% respectively. Despite some promising reports, surgical resection of BCLM is still controversial because of its invasiveness. In addition, many patients develop unpredictable recurrent disease (42).
SBRT offers an alternative, non-invasive approach for LM, with highly conformal doses delivered to tumor sites and a steep dose gradient, which allows normal liver tissues to be spared. Retrospective and prospective studies have demonstrated the feasibility of SBRT for LM with local control rates ranging from 60–90% at 2 years after treatment (43,44). Findings from a recent study revealed that SBRT might be an effective and safe treatment option in selected breast cancer patients with LM (45). Another study reported that the median OS after SBRT of breast patients with LM was 21 months (46). The patient selection criteria, and optimal dose and fractionation for liver SBRT are still under investigation. Several clinical trials evaluating SBRT on patients with limited MBC are on-going. An on-going randomized phase II/III trial (NCT02364557) studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to the standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Another phase II/III multi-center randomized randomised controlled trial (The CORE study, NCT02759783) in patients with breast, prostate or non-small cell lung cancer (NSCLC) primary cancer is comparing standard of care with or without SBRT for extra-cranial metastases, and will help to clarify whether SBRT is a viable therapeutic approach for breast cancer metastases.
Our study should be considered in the context of its limitations. First, this was a retrospective study and the sample size was relatively small. Second, TNBC is a heterogeneous disease and treatment response to chemotherapy might vary between basal and non-basal breast cancer. In spite of its limitations, this study provided clinical reference that capecitabine is considerably effective in TNBC with LM, and capecitabine, rather than platinum, might be a better choice in first-line chemotherapy for TNBC patients with LM, if not contraindicated.
In conclusion, our study indicates that CBC, with its acceptable toxicity profile, might be used as an effective alternative treatment in patients with TNBC LM. In the future, studies involving larger number of patients are needed, and more clinical trials could perhaps be carried out.
Supplementary
The article’s supplementary files as
10.21037/atm-20-4590 10.21037/atm-20-4590 10.21037/atm-20-4590
Acknowledgments
We thank our colleagues at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Chao-Yang Hospital, Chinese PLA General Hospital, and Beijing Sanhuan Cancer Hospital for their support and assistance. In addition, we would like to thank patients and their family members for supporting our study.
Funding: None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (No.: 15-115/1042). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-4590
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-20-4590
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-4590). The authors have no conflicts of interest to declare. | FIRST 2 WEEKS EVERY 21 DAYS | DrugDosageText | CC BY-NC-ND | 33569411 | 18,944,069 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haematuria'. | Direct oral anticoagulant therapy in patients with morbid obesity after intermediate- or high-risk pulmonary emboli.
There is little reported on the efficacy and safety of direct oral anticoagulants (DOACs) in morbid obesity after venous thromboembolism (VTE). In this observational study, patients were followed up after intermediate- or high-risk pulmonary embolism (PE) at the University of Rochester Pulmonary Hypertension Clinic 2-4 months after the initial event. All patients had echocardiography and V/Q imaging regardless of symptoms. Outcomes of interest were the rates of recurrent VTE, thrombus resolution and development of chronic thromboembolic pulmonary hypertension (CTEPH) in patients with morbid obesity treated with a DOAC compared to treatment with vitamin K antagonists and to non-morbidly obese patients after PE. Using the electronic medical record, recurrent events were assessed up to 12 months after the event. 107 patients (body mass index (BMI)>40 kg·m-2, n=32; BMI 30-39.9 kg·m-2, n=39; BMI<30 kg·m-2, n=36) attended follow-up appointments after treatment for PE. A DOAC was used in 70 patients (BMI>40 kg·m-2, n=19; BMI 30-39.9 kg·m-2, n=27; BMI<30 kg·m-2, n=24). There were no recurrent events within the first 12 months of initial diagnosis based on symptoms and imaging in any patient. There was no difference in rate of residual unmatched perfusion defect with DOACs or conventional anticoagulation (49% versus 49%). This finding remained in the subset of morbidly obese patients (47% versus 50%). For the overall cohort, there was no difference in the rate of CTEPH development based on anticoagulation with a DOAC (5% versus 8% with warfarin). There were no major bleeding complications with a DOAC. DOAC therapy appears to be effective and safe in morbid obesity even after intermediate- or high-risk PE. .
Introduction
Direct oral anticoagulants (DOACs) used for the treatment of venous thromboembolism (VTE) have been available for almost a decade and are recommended over vitamin K antagonist therapy in the treatment of VTE [1, 2]. There are two classes of DOACs currently approved for treatment of VTE: direct thrombin inhibitors (dabigatran [3]) and direct Xa inhibitors (rivaroxaban [4], apixaban [5] and edoxapan [6]). However, despite the clear advantages, DOACs are not often used in morbidly obese patients. The International Society of Thrombosis and Haemostasis (ISTH) recommends against DOAC use in patients with a body mass index (BMI)≥40 kg·m−2 or weight>120 kg because of the lack of available safety and efficacy data. Further, if they are used, the ISTH recommends checking anti-Xa levels [7], even though therapeutic ranges have not been established for any DOAC. Interestingly, BMI and weight were not exclusionary criteria in any of the DOAC trials, and there is no evidence that DOAC therapy is ineffective in morbidly obese patients. Unfortunately, this ISTH consensus has led many providers to avoid DOAC therapy in morbid obesity, and these patients are frequently treated with warfarin despite the significant challenges in achieving therapeutic levels [8].
With the growing obesity epidemic, almost 40% of US adults are considered obese [9] and ∼7% are considered morbidly obese with a BMI≥40 kg·m−2 [10]. Obesity is not only an independent risk factor for VTE [11–13] but is also associated with an increased risk for recurrent VTE [14]. Morbid obesity is even more prevalent among hospitalised patients (one estimate of 16% [15]), many of whom are likely to require some anticoagulation therapy during hospitalisation. Therefore, an effective and easy to manage anticoagulation strategy in this population is critical to decrease their risk for long-term complications, including recurrent VTE. Our institutional approach to intermediate- and high-risk pulmonary embolism (PE) [16] includes programmatic follow-up for the majority of patients, many of whom are morbidly obese. We thus had an opportunity to address disease recurrence among people treated with DOACS and we performed a single-centre study observing the efficacy and safety of DOAC and warfarin therapy. In particular, we explicitly compared morbidly obese with obese and non-obese patients.
Methods
This was an initially retrospective and subsequently prospective observational cohort study evaluating imaging and clinical outcomes after inpatient management for an intermediate- or high-risk PE at the University of Rochester Medical Center, NY, USA, between November 2016 and June 2019. The study protocol (00003058) was approved by the University of Rochester Medical Center Institutional Review Board. Beginning in August 2017, at the time of hospital discharge for an acute intermediate- or high-risk PE [16], all patients with estimated survival >1 year (based on the assessment of the discharging physician) were offered follow-up at our Pulmonary Hypertension Association-accredited Comprehensive Care Center. We scheduled a V/Q scan, echocardiogram and office visit to assess for PE resolution or recurrent thrombosis. PE on initial computed tomography angiography was classified as saddle, main, lobar or segmental depending on the location of the most proximal clot. Ventilation perfusion scans were performed using 30 mCi of aerosolised technetium (Tc)-99m-diethylene-triamine-pentaacetate followed by intravenous administration of 2–4 mCi Tc-99m-macroaggregated albumin. Six standard projections were obtained for both sets of images using a large field of view dual-head γ-camera fitted with general purpose parallel hole collimators, for a minimum of 100 000 counts per ventilation image and 500 000 counts per perfusion image. Residual unmatched perfusion defects at follow-up were defined as mismatched or partly mismatched segmental ventilation–perfusion defects. Board-certified cardiologists using standardised criteria [17] interpreted the echocardiograms. The pulmonary hypertension physicians (D.J.L. and R.J.W.) made clinical and functional assessments. Once patients were optimised in regards to apparent volume status, those in whom pre-capillary pulmonary hypertension (PH) could be expected were referred for right heart catheterisation (RHC) with angiography to assess for chronic thromboembolic pulmonary hypertension (CTEPH) after ≥3 months of appropriate anticoagulation. Patients were classified as having confirmed CTEPH based on the haemodynamic definition in the 5th World Symposium on Pulmonary Hypertension [18] in the presence of perfusion defects with angiography. Patients were classified as having “suspected CTEPH” if the clinical assessment strongly suggested CTEPH but patients declined catheterisation for sensible reasons like advanced neurological disease (dementia).
Statistical analysis
Variables are expressed as mean±sd or median (interquartile range). Non-parametric testing was performed with Mann–Whitney and Kruskal–Wallis testing using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Statistical significance was defined as p<0.05.
Results
Of 122 patients, 107 attended follow-up appointments at our PH clinic 2–4 months after management of acute intermediate- or high-risk PE. Patient demographics and presentation are shown in tables 1 and 2. Of the 15 that were not followed up, two died before their scheduled appointment because of complications related to malignancy (not VTE or bleeding mediated), eight were never scheduled and five did not keep their appointments. For the 13 patients not seen in the clinic, electronic medical record evidence showed them to be alive and without evidence of recurrent pulmonary emboli or major bleeding. The majority of patients who were followed up were obese with an average BMI of 35.7 kg·m−2 (table 1); 32 patients had a BMI≥40 kg·m−2 (morbid obesity) and 39 patients had a BMI of 30–39 kg·m−2 (obese) (table 1). The most common treatment during hospitalisation was anticoagulation with heparin (either unfractionated or low-molecular weight), while 28% received advanced therapies (e.g. thrombolytics, table 2). At discharge, 67% of patients were prescribed a DOAC and 26% were prescribed warfarin (table 2).
TABLE 1 Baseline demographics
BMI<30 kg·m−2 BMI 30–39 kg·m−2 BMI≥40 kg·m−2
Subjects n 36 39 32
Age years 69 (28–93) 62 (29–85) 50 (25–75)
Male 23 (64) 21 (54) 14 (44)
Caucasian 28 (78) 32 (82) 25 (78)
BMI kg·m−2 27 (23–29) 34 (30–39) 46 (40–68)
Active smoking 3 (8) 5 (13) 4 (13)
HFpEF 9 (25) 15 (38) 28 (88)
CAD 4 (11) 2 (5) 4 (13)
CKD>II 1 (3) 2 (5) 2 (6)
Atrial fibrillation 3 (8) 4 (10) 3 (9)
Diabetes 6 (17) 10 (26) 9 (28)
Hypertension 14 (39) 25 (64) 23 (72)
Splenectomy 2 (6) 2 (5) 2 (6)
Hypothyroidism 5 (14) 8 (21) 32 (6)
OSA# 7 (19) 11 (28) 20 (63)
Provoked 14 (39) 11 (28) 9 (28)
Post-operative 6 (17) 9 (23) 6 (28)
Active malignancy 6 (17) 1 (3) 0
Prior VTE 10 (28) 7 (18) 5 (16)
Prior gastric bypass surgery (Rou-En-Y) 1 (3) 2 (5) 2 (6)
Data presented as mean (interquartile range) or n (%), unless otherwise indicated. BMI: body mass index; HFpEF: heart failure preserved ejection fraction; CAD: coronary artery disease; CKD: chronic kidney disease; OSA: obstructive sleep apnoea; VTE: venous thromboembolism. #: diagnosis made prior to presentation or after.
TABLE 2 Clinical information at presentation and during hospitalisation
BMI<30 kg·m−2 BMI 30–39 kg·m−2 BMI≥40 kg·m−2
Subjects n 36 39 32
Pulmonary embolus
High risk 4 (11) 7 (18) 1 (3)
Intermediate risk 32 (89) 32 (82) 31 (97)
Duration of symptoms days 3 (1–15) 1 (1–4) 3 (1–7)
Signs/symptoms at presentation
Cardiac arrest 1 (3) 2 (5) 0
Chest pain 13 (36) 19 (49) 12 (38)
Syncope 9 (25) 7 (18) 5 (16)
Pre-syncope 6 (17) 14 (36) 9 (28)
Dyspnoea 29 (81) 36 (92) 29 (91)
Hypoxia 20 (56) 29 (74) 18 (56)
Admission NT-proBNP pg·mL−1 1698 (485–4497) 908 (473–2540) 1161 (224–3564)
CT imaging
Saddle 12 (33) 20 (51) 6 (28)
Main 10 (28) 9 (23) 12 (38)
Lobar 11 (31) 7 (18) 11 (31)
Right heart enlargement 30 (83) 31 (79) 23 (72)
Echocardiogram
Moderate/severe RV enlargement 23 (63) 24 (62) 22 (69)
Moderate/severe RV dysfunction 20 (56) 25 (64) 20 (63)
Confirmed DVT on ultrasound 20 (56) 22 (56) 19 (59)
treatment
Anticoagulation only 26 (72) 23 (59) 28 (88)
Advanced therapies# 10 (28) 16 (41) 4 (12)
Hospital stay days 5 (2–8) 5 (3–11) 4 (3–7)
Anticoagulation on discharge
DOAC 24 (67) 27 (69) 19 (59)
Apixaban 14 (39) 15 (38) 8 (25)
Rivaroxaban 10 (28) 12 (31) 11 (34)
Vitamin K antagonist 8 (22) 10 (26) 10 (31)
Data presented as mean (interquartile range) or n (%), unless otherwise indicated. BMI: body mass index; NT-proBNP: N-terminal pro-brain natriuretic peptide; CT: computed tomography; RV: right ventricle; DVT: deep vein thrombosis; DOAC: direct oral anticoagulants. #: systemic thrombolysis, catheter-directed lysis, surgical embolectomy.
Recurrent events and residual perfusion defect
Between hospital discharge and 6 months after the index event, no patients had diagnostic evidence for recurrent PE or deep vein thrombosis. At follow-up, 68 patients who were taking DOACs and 35 taking warfarin or low-molecular weight heparin had V/Q testing regardless of symptoms (four patients were evaluated without V/Q imaging). 50 patients (49%) had residual unmatched perfusion defects. There was no difference between patients treated with a DOAC or with conventional anticoagulation (33 out of 68 (49%) versus 17 out of 35 (49%), p=0.99). Similarly, there was no difference in the rate of residual unmatched perfusion defects in the subset of morbidly obese patients treated with a DOAC or conventional anticoagulation (9 (47%) versus 6 (50%), p=0.99, table 3).
TABLE 3 Clinical assessment 2–4 months after pulmonary embolus
BMI<30 kg·m−2 BMI 30–39 kg·m−2 BMI≥40 kg·m−2
Subjects n 36 39 32
Self-limiting activity 15 (42) 22 (56) 22 (69)
NYHA functional class 34 35 29
I 16 (47) 18 (51) 5 (17)
II 16 (47) 15 (43) 19 (66)
III 2 (6) 2 (6) 5 (17)
6MWT m 395 (308–496) 408 (351–482) 338 (219–407)
Decompensated heart failure# 6 (17) 13 (33) 22 (69)
Iron deficiency¶ 7 (19) 10 (26) 14 (44)
New OSA diagnosis at follow-up 3 (8) 12 (31) 6 (19)
Sleep study recommended but not completed 8 (22) 9 (23) 7 (22)
Echocardiogram 35 39 32
RV size
Normal 23 (66) 29 (74) 14 (44)
Mild enlargement 8 (23) 7 (18) 16 (50)
RV dysfunction
None 24 (69) 26 (67) 23 (72)
Mild 10 (29) 13 (33) 6 (19)
Residual unmatched perfusion defects+ 18 (50) 17 (44) 15 (47)
Recurrent VTE§ 1 (3) 0 0
Confirmed CTEPH 5 (14) 2 (5) 2 (6)
Suspected CTEPH 2 (5) 4 (10) 5 (16)
Total CTEPH 7 (19) 6 (15) 7 (22)
Data presented as mean (interquartile range) or n (%), unless otherwise indicated. BMI: body mass index; NYHA: New York Heart Association; 6MWT: 6-min walk test; OSA: obstructive sleep apnoea; RV: right ventricle; VTE: venous thromboembolism; CTEPH: chronic thromboembolic pulmonary hypertension. #: clinical diagnosis; ¶: criteria from Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial; +: 100 patients underwent V/Q testing (three patients in the heparin group and one embolectomy patient did not have testing); §: recurrent VTE occurred >1 year after the index event.
CTEPH
At follow-up, 59 patients (55%) reported self-limited activity because of breathlessness. Based on symptoms and imaging concerning for CTEPH, CTEPH was diagnosed in eight out of 11 patients who underwent RHC after the requisite 3 months of anticoagulation. One patient was directly referred for CTEPH surgery after index hospitalisation without being seen in clinic, giving a total of nine patients diagnosed with CTEPH (table 3). RHC and angiography were recommended in 11 patients who declined testing because of preference or severe cognitive impairment. Including these patients who declined testing resulted in an estimated prevalence of confirmed or suspected CTEPH after intermediate- or high-risk PE of >15% (15–20 patients) (table 3).
There was no difference in the rate of confirmed CTEPH whether patients were treated with DOACs or conventional anticoagulation (4 (6%) versus 4 (11%), p=0.45). There was no difference in the rate of confirmed CTEPH in morbid obesity when comparing DOACs with conventional anticoagulation (1 (5%) versus 1 (8%), p=0.99, table 3). Even assuming that all patients who were recommended for further testing had CTEPH, patients with morbid obesity treated with a DOAC did not have a higher rate of CTEPH than those treated with conventional anticoagulation therapy (2 (11%) versus 5 (41%), p=0.06). There was no difference in the rate of CTEPH in the obese and non-obese patients based on type of anticoagulation.
Right ventricular recovery
At the time of acute presentation, the majority of patients (63%) had moderate or severe right ventricle enlargement without differences between obese and non-obese patients (table 2). At follow-up, 106 patients had an echocardiogram: 69 treated with a DOAC (19 morbidly obese) and 37 treated with conventional warfarin or enoxaparin anticoagulation (13 morbidly obese) (table 3). In total, 97 patients had a normal or mildly enlarged right ventricle, and nine had a moderately enlarged right ventricle (table 3). 102 patients had normal or mildly reduced right ventricular function, and four had moderately reduced function (table 3).
There was no difference in the rate of having a normal or mildly enlarged right ventricle at follow-up when comparing DOACs to conventional therapy (63 (92%) versus 34 (92%), table 3). 18 (95%) morbidly obese patients treated with a DOAC had a normal or mildly enlarged right ventricle at follow-up compared to 12 (92%) morbidly obese patients treated with warfarin or enoxaparin (table 3). Similarly, there were no differences between the obese and non-obese groups.
There was no difference in the rate of recovery in right ventricular function (normal or mildly reduced at follow-up) comparing DOACs to conventional anticoagulation (68 (99%) versus 34 (92%)). 18 of 19 (95%) morbidly obese patients treated with DOACs had normal or mildly impaired right ventricular function while 11 of 13 (84%) treated with conventional anticoagulation had a normal or mildly impaired right ventricle (p=0.55).
N-terminal pro-brain natriuretic peptide and 6-min walk assessment
At follow-up, 55 patients had their levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) assessed because of breathlessness or signs of heart failure: 22 morbidly obese (13 on DOAC therapy and nine on conventional therapy), 18 obese (10 on DOAC therapy and eight on conventional therapy) and 15 non-obese (10 on DOAC therapy and five on conventional therapy). Owing to staffing limitations, only 58 patients completed a 6-min walk test (6MWT) regardless of symptoms, 16 of whom were morbidly obese (nine on DOAC therapy and seven on conventional therapy).
There was no difference in NT-proBNP when comparing patients treated with DOAC therapy and patients treated with conventional therapy (97 pg·mL−1
versus 167 pg·mL−1, p=0.13), for the entire cohort. There was no difference in NT-proBNP based on DOAC versus conventional therapy in morbid obesity (97 pg·mL−1
versus 183 pg·mL−1, p=0.19). There was no difference in 6MWT distance based on DOAC versus conventional therapy (399 m versus 338 m, p=0.09), for the entire cohort or for the three subgroups based on BMI.
Bleeding
There were two patients on non-DOAC therapy with bleeding complications that required intervention. One morbidly obese patient treated with warfarin developed haematuria in the setting of an elevated international normalised ratio and required hospitalisation. Another morbidly obese patient developed a spontaneous retroperitoneal bleed on low-molecular weight heparin that required hospitalisation. No patients on DOAC therapy were hospitalised owing to bleeding complications. One morbidly obese patient required a dose reduction from 20 mg to 10 mg of rivaroxaban because of gingival bleeding in the setting of poor dentition. The bleeding stopped and there were no further complications at this dose.
Discussion
In an observational cohort of higher-risk PE patients, DOAC therapy in morbidly obese patients was not associated with an increased risk of recurrent VTE compared to warfarin anticoagulation therapy within 6 months of management of acute PE, and these higher-risk patients had similar recovery of right ventricle function on DOAC therapy as those treated with warfarin (even among morbidly obese patients). This work is strengthened by the rigorous follow-up and imaging acquisition in almost all patients regardless of symptoms.
Fixed-dose DOAC therapies have greatly simplified management of acute PE by preventing recurrent VTE without the need for laboratory monitoring and the associated effort to make warfarin dose adjustments. For patients, the “real-world” rates of bleeding are low [19], and there is relatively little concern for drug–diet or drug–drug interactions [20]. The initial concern about using fixed-dose DOAC therapy in morbid obesity was understandable. Both unfractionated and low-molecular weight heparin are weight-based drugs, and vitamin K antagonist doses are typically higher in morbid obesity [8]. Theoretically, it would make sense that morbidly obese patients would require higher doses of DOAC therapy based on a fixed dose diluted in a larger volume of distribution, but limited pharmacokinetic and pharmacodynamic studies evaluating DOAC in morbid obesity suggest weight does not influence dosing [21–25]. Furthermore, there is no clear relationship between drug levels and clinical outcomes like VTE recurrence or bleeding [3–6]. No therapeutic range of Xa inhibition is established for DOAC. Given the difficulty in achieving therapeutic levels with warfarin [8], having a simplified option could decrease recurrent events.
The current consensus guidelines from ISTH [7] and the European Society of Cardiology [26] both caution against using DOAC therapy for patients with a BMI>40 kg·m−2; if DOACs are used, these documents recommend measuring anti-Xa activity despite the fact that no therapeutic range has been established. The American Society of Hematology does not address morbid obesity in their 2018 VTE guidelines [27]. Papers being published today still caution against DOAC use in morbidly obese patients owing to the lack of clinical data, with calls for prospective trials to be completed before DOAC use can be recommended in this population [28–30]. However, at least one meta-analysis found no reduction in efficacy in the registration trials when looking at obese versus non-obese patients [31]. To the best of our knowledge, there are no active clinical trials evaluating DOAC therapy for VTE in morbid obesity (clinicaltrials.gov, October 2020).
The majority of patients included in the original DOAC clinical trials were low-risk VTE and not obese. However, it is important to note that neither BMI nor weight was an exclusionary criterion in the registration trials. A meta-analysis determined that 20% of participants in the registration trials were “high body weight” at randomisation (either >100 kg or >90 kg) [31]. None of the registration trials reported event rates specifically in morbid obesity, but they did report no differences in recurrent events in the high body weight groups treated with DOAC versus conventional therapy [3–6].
Recurrent VTE events often occur within 3–6 months at a rate of 4%–8% [32, 33] and typically present in a similar manner as the index event [34, 35]. With obesity being a risk factor for initial [11–13] and recurrent [14] VTE, if effective anticoagulation was not provided, the observed VTE recurrence rate would likely be much higher than the reported baseline of ∼4%–8%. We did not observe an elevated recurrence rate in our cohort. There is evolving retrospective data on the efficacy of DOAC therapy in morbid obesity. Kushnir
et al. [36] used single-centre chart review and determined a 2% risk for recurrent VTE in 366 morbidly obese (BMI>40 kg·m−2) patients with any DOAC-treated VTE event. Using two US claims databases, Spyropoulos
et al. [37] found a similar rate of risk of recurrent thrombotic events in morbid obesity. Although both studies relied on coding, their findings are real-world evidence that DOACs are effective in morbid obesity. We do not know if some of their recurrent VTE could have been unrecognised CTEPH or chronic clot.
We complement these larger studies with rigorous clinical follow-up and detailed chart review including echocardiogram, V/Q scan and RHC. We did not observe any recurrent PE within the first year in any patient, regardless of weight group or type of anticoagulation. We were able to differentiate CTEPH from recurrent PE. Furthermore, we did not observe any difference in the resolution of thrombotic disease on perfusion lung scanning, and DOAC-treated patients were just as likely to achieve right ventricle recovery (an indirect measure that the pulmonary circulation is no longer obstructed) after higher-risk PE. Our numbers are small, but DOACs did not appear to leave patients at higher risk for CTEPH. None of the registration clinical trials reported rates of CTEPH development, and given the large numbers of patients involved, CTEPH would be expected in some patients. Our data strengthen a growing body of literature supporting the clinical efficacy of DOAC therapy in morbid obesity because none of the previously reported studies detailed follow-up data on imaging and physiological recovery.
There are limitations to our study. We have data on a small number of morbidly obese patients on DOAC therapy that took 2 years to collect. However, given that this is a high-risk group, DOAC failure with recurrent events should have been observed. Our data are observational and anticoagulation was chosen based on the preference of the discharging attending physician and patient. Peak and trough drug concentrations were not measured, and we have no measurements of anti-Xa levels. We only included patients who had an intermediate- or high-risk PE. We did not include atrial fibrillation in our analysis and therefore our results may not be applicable to patients with BMI>40 kg·m−2 and atrial fibrillation.
In conclusion, we found that DOAC therapy does not put patients with morbid obesity at higher risk for recurrent VTE after intermediate- or high-risk PE compared to warfarin anticoagulation; we observed similar outcomes in obese and non-obese patients. Perfusion lung scanning did not suggest a difference in the rate of thrombus resolution, and echocardiography suggested similar rates of right ventricular recovery regardless of anticoagulation choice. In patients with PE, we believe that the available evidence makes DOAC therapy a reasonable option even in morbid obesity; we propose prospective clinical trials to address this directly.
Author contributions: D.J. Lachant, C. Bach, A. Fe, R.J. White and N.A. Lachant all contributed to the study design, analysis of the results and writing the manuscript, and approved the manuscript.
Conflict of interest: D.J. Lachant has nothing to disclose.
Conflict of interest: C. Bach has nothing to disclose.
Conflict of interest: A. Fe has nothing to disclose.
Conflict of interest: R.J. White has nothing to disclose.
Conflict of interest: N.A. Lachant has nothing to disclose. | WARFARIN SODIUM | DrugsGivenReaction | CC BY-NC | 33569503 | 19,037,050 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'International normalised ratio increased'. | Direct oral anticoagulant therapy in patients with morbid obesity after intermediate- or high-risk pulmonary emboli.
There is little reported on the efficacy and safety of direct oral anticoagulants (DOACs) in morbid obesity after venous thromboembolism (VTE). In this observational study, patients were followed up after intermediate- or high-risk pulmonary embolism (PE) at the University of Rochester Pulmonary Hypertension Clinic 2-4 months after the initial event. All patients had echocardiography and V/Q imaging regardless of symptoms. Outcomes of interest were the rates of recurrent VTE, thrombus resolution and development of chronic thromboembolic pulmonary hypertension (CTEPH) in patients with morbid obesity treated with a DOAC compared to treatment with vitamin K antagonists and to non-morbidly obese patients after PE. Using the electronic medical record, recurrent events were assessed up to 12 months after the event. 107 patients (body mass index (BMI)>40 kg·m-2, n=32; BMI 30-39.9 kg·m-2, n=39; BMI<30 kg·m-2, n=36) attended follow-up appointments after treatment for PE. A DOAC was used in 70 patients (BMI>40 kg·m-2, n=19; BMI 30-39.9 kg·m-2, n=27; BMI<30 kg·m-2, n=24). There were no recurrent events within the first 12 months of initial diagnosis based on symptoms and imaging in any patient. There was no difference in rate of residual unmatched perfusion defect with DOACs or conventional anticoagulation (49% versus 49%). This finding remained in the subset of morbidly obese patients (47% versus 50%). For the overall cohort, there was no difference in the rate of CTEPH development based on anticoagulation with a DOAC (5% versus 8% with warfarin). There were no major bleeding complications with a DOAC. DOAC therapy appears to be effective and safe in morbid obesity even after intermediate- or high-risk PE. .
Introduction
Direct oral anticoagulants (DOACs) used for the treatment of venous thromboembolism (VTE) have been available for almost a decade and are recommended over vitamin K antagonist therapy in the treatment of VTE [1, 2]. There are two classes of DOACs currently approved for treatment of VTE: direct thrombin inhibitors (dabigatran [3]) and direct Xa inhibitors (rivaroxaban [4], apixaban [5] and edoxapan [6]). However, despite the clear advantages, DOACs are not often used in morbidly obese patients. The International Society of Thrombosis and Haemostasis (ISTH) recommends against DOAC use in patients with a body mass index (BMI)≥40 kg·m−2 or weight>120 kg because of the lack of available safety and efficacy data. Further, if they are used, the ISTH recommends checking anti-Xa levels [7], even though therapeutic ranges have not been established for any DOAC. Interestingly, BMI and weight were not exclusionary criteria in any of the DOAC trials, and there is no evidence that DOAC therapy is ineffective in morbidly obese patients. Unfortunately, this ISTH consensus has led many providers to avoid DOAC therapy in morbid obesity, and these patients are frequently treated with warfarin despite the significant challenges in achieving therapeutic levels [8].
With the growing obesity epidemic, almost 40% of US adults are considered obese [9] and ∼7% are considered morbidly obese with a BMI≥40 kg·m−2 [10]. Obesity is not only an independent risk factor for VTE [11–13] but is also associated with an increased risk for recurrent VTE [14]. Morbid obesity is even more prevalent among hospitalised patients (one estimate of 16% [15]), many of whom are likely to require some anticoagulation therapy during hospitalisation. Therefore, an effective and easy to manage anticoagulation strategy in this population is critical to decrease their risk for long-term complications, including recurrent VTE. Our institutional approach to intermediate- and high-risk pulmonary embolism (PE) [16] includes programmatic follow-up for the majority of patients, many of whom are morbidly obese. We thus had an opportunity to address disease recurrence among people treated with DOACS and we performed a single-centre study observing the efficacy and safety of DOAC and warfarin therapy. In particular, we explicitly compared morbidly obese with obese and non-obese patients.
Methods
This was an initially retrospective and subsequently prospective observational cohort study evaluating imaging and clinical outcomes after inpatient management for an intermediate- or high-risk PE at the University of Rochester Medical Center, NY, USA, between November 2016 and June 2019. The study protocol (00003058) was approved by the University of Rochester Medical Center Institutional Review Board. Beginning in August 2017, at the time of hospital discharge for an acute intermediate- or high-risk PE [16], all patients with estimated survival >1 year (based on the assessment of the discharging physician) were offered follow-up at our Pulmonary Hypertension Association-accredited Comprehensive Care Center. We scheduled a V/Q scan, echocardiogram and office visit to assess for PE resolution or recurrent thrombosis. PE on initial computed tomography angiography was classified as saddle, main, lobar or segmental depending on the location of the most proximal clot. Ventilation perfusion scans were performed using 30 mCi of aerosolised technetium (Tc)-99m-diethylene-triamine-pentaacetate followed by intravenous administration of 2–4 mCi Tc-99m-macroaggregated albumin. Six standard projections were obtained for both sets of images using a large field of view dual-head γ-camera fitted with general purpose parallel hole collimators, for a minimum of 100 000 counts per ventilation image and 500 000 counts per perfusion image. Residual unmatched perfusion defects at follow-up were defined as mismatched or partly mismatched segmental ventilation–perfusion defects. Board-certified cardiologists using standardised criteria [17] interpreted the echocardiograms. The pulmonary hypertension physicians (D.J.L. and R.J.W.) made clinical and functional assessments. Once patients were optimised in regards to apparent volume status, those in whom pre-capillary pulmonary hypertension (PH) could be expected were referred for right heart catheterisation (RHC) with angiography to assess for chronic thromboembolic pulmonary hypertension (CTEPH) after ≥3 months of appropriate anticoagulation. Patients were classified as having confirmed CTEPH based on the haemodynamic definition in the 5th World Symposium on Pulmonary Hypertension [18] in the presence of perfusion defects with angiography. Patients were classified as having “suspected CTEPH” if the clinical assessment strongly suggested CTEPH but patients declined catheterisation for sensible reasons like advanced neurological disease (dementia).
Statistical analysis
Variables are expressed as mean±sd or median (interquartile range). Non-parametric testing was performed with Mann–Whitney and Kruskal–Wallis testing using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Statistical significance was defined as p<0.05.
Results
Of 122 patients, 107 attended follow-up appointments at our PH clinic 2–4 months after management of acute intermediate- or high-risk PE. Patient demographics and presentation are shown in tables 1 and 2. Of the 15 that were not followed up, two died before their scheduled appointment because of complications related to malignancy (not VTE or bleeding mediated), eight were never scheduled and five did not keep their appointments. For the 13 patients not seen in the clinic, electronic medical record evidence showed them to be alive and without evidence of recurrent pulmonary emboli or major bleeding. The majority of patients who were followed up were obese with an average BMI of 35.7 kg·m−2 (table 1); 32 patients had a BMI≥40 kg·m−2 (morbid obesity) and 39 patients had a BMI of 30–39 kg·m−2 (obese) (table 1). The most common treatment during hospitalisation was anticoagulation with heparin (either unfractionated or low-molecular weight), while 28% received advanced therapies (e.g. thrombolytics, table 2). At discharge, 67% of patients were prescribed a DOAC and 26% were prescribed warfarin (table 2).
TABLE 1 Baseline demographics
BMI<30 kg·m−2 BMI 30–39 kg·m−2 BMI≥40 kg·m−2
Subjects n 36 39 32
Age years 69 (28–93) 62 (29–85) 50 (25–75)
Male 23 (64) 21 (54) 14 (44)
Caucasian 28 (78) 32 (82) 25 (78)
BMI kg·m−2 27 (23–29) 34 (30–39) 46 (40–68)
Active smoking 3 (8) 5 (13) 4 (13)
HFpEF 9 (25) 15 (38) 28 (88)
CAD 4 (11) 2 (5) 4 (13)
CKD>II 1 (3) 2 (5) 2 (6)
Atrial fibrillation 3 (8) 4 (10) 3 (9)
Diabetes 6 (17) 10 (26) 9 (28)
Hypertension 14 (39) 25 (64) 23 (72)
Splenectomy 2 (6) 2 (5) 2 (6)
Hypothyroidism 5 (14) 8 (21) 32 (6)
OSA# 7 (19) 11 (28) 20 (63)
Provoked 14 (39) 11 (28) 9 (28)
Post-operative 6 (17) 9 (23) 6 (28)
Active malignancy 6 (17) 1 (3) 0
Prior VTE 10 (28) 7 (18) 5 (16)
Prior gastric bypass surgery (Rou-En-Y) 1 (3) 2 (5) 2 (6)
Data presented as mean (interquartile range) or n (%), unless otherwise indicated. BMI: body mass index; HFpEF: heart failure preserved ejection fraction; CAD: coronary artery disease; CKD: chronic kidney disease; OSA: obstructive sleep apnoea; VTE: venous thromboembolism. #: diagnosis made prior to presentation or after.
TABLE 2 Clinical information at presentation and during hospitalisation
BMI<30 kg·m−2 BMI 30–39 kg·m−2 BMI≥40 kg·m−2
Subjects n 36 39 32
Pulmonary embolus
High risk 4 (11) 7 (18) 1 (3)
Intermediate risk 32 (89) 32 (82) 31 (97)
Duration of symptoms days 3 (1–15) 1 (1–4) 3 (1–7)
Signs/symptoms at presentation
Cardiac arrest 1 (3) 2 (5) 0
Chest pain 13 (36) 19 (49) 12 (38)
Syncope 9 (25) 7 (18) 5 (16)
Pre-syncope 6 (17) 14 (36) 9 (28)
Dyspnoea 29 (81) 36 (92) 29 (91)
Hypoxia 20 (56) 29 (74) 18 (56)
Admission NT-proBNP pg·mL−1 1698 (485–4497) 908 (473–2540) 1161 (224–3564)
CT imaging
Saddle 12 (33) 20 (51) 6 (28)
Main 10 (28) 9 (23) 12 (38)
Lobar 11 (31) 7 (18) 11 (31)
Right heart enlargement 30 (83) 31 (79) 23 (72)
Echocardiogram
Moderate/severe RV enlargement 23 (63) 24 (62) 22 (69)
Moderate/severe RV dysfunction 20 (56) 25 (64) 20 (63)
Confirmed DVT on ultrasound 20 (56) 22 (56) 19 (59)
treatment
Anticoagulation only 26 (72) 23 (59) 28 (88)
Advanced therapies# 10 (28) 16 (41) 4 (12)
Hospital stay days 5 (2–8) 5 (3–11) 4 (3–7)
Anticoagulation on discharge
DOAC 24 (67) 27 (69) 19 (59)
Apixaban 14 (39) 15 (38) 8 (25)
Rivaroxaban 10 (28) 12 (31) 11 (34)
Vitamin K antagonist 8 (22) 10 (26) 10 (31)
Data presented as mean (interquartile range) or n (%), unless otherwise indicated. BMI: body mass index; NT-proBNP: N-terminal pro-brain natriuretic peptide; CT: computed tomography; RV: right ventricle; DVT: deep vein thrombosis; DOAC: direct oral anticoagulants. #: systemic thrombolysis, catheter-directed lysis, surgical embolectomy.
Recurrent events and residual perfusion defect
Between hospital discharge and 6 months after the index event, no patients had diagnostic evidence for recurrent PE or deep vein thrombosis. At follow-up, 68 patients who were taking DOACs and 35 taking warfarin or low-molecular weight heparin had V/Q testing regardless of symptoms (four patients were evaluated without V/Q imaging). 50 patients (49%) had residual unmatched perfusion defects. There was no difference between patients treated with a DOAC or with conventional anticoagulation (33 out of 68 (49%) versus 17 out of 35 (49%), p=0.99). Similarly, there was no difference in the rate of residual unmatched perfusion defects in the subset of morbidly obese patients treated with a DOAC or conventional anticoagulation (9 (47%) versus 6 (50%), p=0.99, table 3).
TABLE 3 Clinical assessment 2–4 months after pulmonary embolus
BMI<30 kg·m−2 BMI 30–39 kg·m−2 BMI≥40 kg·m−2
Subjects n 36 39 32
Self-limiting activity 15 (42) 22 (56) 22 (69)
NYHA functional class 34 35 29
I 16 (47) 18 (51) 5 (17)
II 16 (47) 15 (43) 19 (66)
III 2 (6) 2 (6) 5 (17)
6MWT m 395 (308–496) 408 (351–482) 338 (219–407)
Decompensated heart failure# 6 (17) 13 (33) 22 (69)
Iron deficiency¶ 7 (19) 10 (26) 14 (44)
New OSA diagnosis at follow-up 3 (8) 12 (31) 6 (19)
Sleep study recommended but not completed 8 (22) 9 (23) 7 (22)
Echocardiogram 35 39 32
RV size
Normal 23 (66) 29 (74) 14 (44)
Mild enlargement 8 (23) 7 (18) 16 (50)
RV dysfunction
None 24 (69) 26 (67) 23 (72)
Mild 10 (29) 13 (33) 6 (19)
Residual unmatched perfusion defects+ 18 (50) 17 (44) 15 (47)
Recurrent VTE§ 1 (3) 0 0
Confirmed CTEPH 5 (14) 2 (5) 2 (6)
Suspected CTEPH 2 (5) 4 (10) 5 (16)
Total CTEPH 7 (19) 6 (15) 7 (22)
Data presented as mean (interquartile range) or n (%), unless otherwise indicated. BMI: body mass index; NYHA: New York Heart Association; 6MWT: 6-min walk test; OSA: obstructive sleep apnoea; RV: right ventricle; VTE: venous thromboembolism; CTEPH: chronic thromboembolic pulmonary hypertension. #: clinical diagnosis; ¶: criteria from Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial; +: 100 patients underwent V/Q testing (three patients in the heparin group and one embolectomy patient did not have testing); §: recurrent VTE occurred >1 year after the index event.
CTEPH
At follow-up, 59 patients (55%) reported self-limited activity because of breathlessness. Based on symptoms and imaging concerning for CTEPH, CTEPH was diagnosed in eight out of 11 patients who underwent RHC after the requisite 3 months of anticoagulation. One patient was directly referred for CTEPH surgery after index hospitalisation without being seen in clinic, giving a total of nine patients diagnosed with CTEPH (table 3). RHC and angiography were recommended in 11 patients who declined testing because of preference or severe cognitive impairment. Including these patients who declined testing resulted in an estimated prevalence of confirmed or suspected CTEPH after intermediate- or high-risk PE of >15% (15–20 patients) (table 3).
There was no difference in the rate of confirmed CTEPH whether patients were treated with DOACs or conventional anticoagulation (4 (6%) versus 4 (11%), p=0.45). There was no difference in the rate of confirmed CTEPH in morbid obesity when comparing DOACs with conventional anticoagulation (1 (5%) versus 1 (8%), p=0.99, table 3). Even assuming that all patients who were recommended for further testing had CTEPH, patients with morbid obesity treated with a DOAC did not have a higher rate of CTEPH than those treated with conventional anticoagulation therapy (2 (11%) versus 5 (41%), p=0.06). There was no difference in the rate of CTEPH in the obese and non-obese patients based on type of anticoagulation.
Right ventricular recovery
At the time of acute presentation, the majority of patients (63%) had moderate or severe right ventricle enlargement without differences between obese and non-obese patients (table 2). At follow-up, 106 patients had an echocardiogram: 69 treated with a DOAC (19 morbidly obese) and 37 treated with conventional warfarin or enoxaparin anticoagulation (13 morbidly obese) (table 3). In total, 97 patients had a normal or mildly enlarged right ventricle, and nine had a moderately enlarged right ventricle (table 3). 102 patients had normal or mildly reduced right ventricular function, and four had moderately reduced function (table 3).
There was no difference in the rate of having a normal or mildly enlarged right ventricle at follow-up when comparing DOACs to conventional therapy (63 (92%) versus 34 (92%), table 3). 18 (95%) morbidly obese patients treated with a DOAC had a normal or mildly enlarged right ventricle at follow-up compared to 12 (92%) morbidly obese patients treated with warfarin or enoxaparin (table 3). Similarly, there were no differences between the obese and non-obese groups.
There was no difference in the rate of recovery in right ventricular function (normal or mildly reduced at follow-up) comparing DOACs to conventional anticoagulation (68 (99%) versus 34 (92%)). 18 of 19 (95%) morbidly obese patients treated with DOACs had normal or mildly impaired right ventricular function while 11 of 13 (84%) treated with conventional anticoagulation had a normal or mildly impaired right ventricle (p=0.55).
N-terminal pro-brain natriuretic peptide and 6-min walk assessment
At follow-up, 55 patients had their levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) assessed because of breathlessness or signs of heart failure: 22 morbidly obese (13 on DOAC therapy and nine on conventional therapy), 18 obese (10 on DOAC therapy and eight on conventional therapy) and 15 non-obese (10 on DOAC therapy and five on conventional therapy). Owing to staffing limitations, only 58 patients completed a 6-min walk test (6MWT) regardless of symptoms, 16 of whom were morbidly obese (nine on DOAC therapy and seven on conventional therapy).
There was no difference in NT-proBNP when comparing patients treated with DOAC therapy and patients treated with conventional therapy (97 pg·mL−1
versus 167 pg·mL−1, p=0.13), for the entire cohort. There was no difference in NT-proBNP based on DOAC versus conventional therapy in morbid obesity (97 pg·mL−1
versus 183 pg·mL−1, p=0.19). There was no difference in 6MWT distance based on DOAC versus conventional therapy (399 m versus 338 m, p=0.09), for the entire cohort or for the three subgroups based on BMI.
Bleeding
There were two patients on non-DOAC therapy with bleeding complications that required intervention. One morbidly obese patient treated with warfarin developed haematuria in the setting of an elevated international normalised ratio and required hospitalisation. Another morbidly obese patient developed a spontaneous retroperitoneal bleed on low-molecular weight heparin that required hospitalisation. No patients on DOAC therapy were hospitalised owing to bleeding complications. One morbidly obese patient required a dose reduction from 20 mg to 10 mg of rivaroxaban because of gingival bleeding in the setting of poor dentition. The bleeding stopped and there were no further complications at this dose.
Discussion
In an observational cohort of higher-risk PE patients, DOAC therapy in morbidly obese patients was not associated with an increased risk of recurrent VTE compared to warfarin anticoagulation therapy within 6 months of management of acute PE, and these higher-risk patients had similar recovery of right ventricle function on DOAC therapy as those treated with warfarin (even among morbidly obese patients). This work is strengthened by the rigorous follow-up and imaging acquisition in almost all patients regardless of symptoms.
Fixed-dose DOAC therapies have greatly simplified management of acute PE by preventing recurrent VTE without the need for laboratory monitoring and the associated effort to make warfarin dose adjustments. For patients, the “real-world” rates of bleeding are low [19], and there is relatively little concern for drug–diet or drug–drug interactions [20]. The initial concern about using fixed-dose DOAC therapy in morbid obesity was understandable. Both unfractionated and low-molecular weight heparin are weight-based drugs, and vitamin K antagonist doses are typically higher in morbid obesity [8]. Theoretically, it would make sense that morbidly obese patients would require higher doses of DOAC therapy based on a fixed dose diluted in a larger volume of distribution, but limited pharmacokinetic and pharmacodynamic studies evaluating DOAC in morbid obesity suggest weight does not influence dosing [21–25]. Furthermore, there is no clear relationship between drug levels and clinical outcomes like VTE recurrence or bleeding [3–6]. No therapeutic range of Xa inhibition is established for DOAC. Given the difficulty in achieving therapeutic levels with warfarin [8], having a simplified option could decrease recurrent events.
The current consensus guidelines from ISTH [7] and the European Society of Cardiology [26] both caution against using DOAC therapy for patients with a BMI>40 kg·m−2; if DOACs are used, these documents recommend measuring anti-Xa activity despite the fact that no therapeutic range has been established. The American Society of Hematology does not address morbid obesity in their 2018 VTE guidelines [27]. Papers being published today still caution against DOAC use in morbidly obese patients owing to the lack of clinical data, with calls for prospective trials to be completed before DOAC use can be recommended in this population [28–30]. However, at least one meta-analysis found no reduction in efficacy in the registration trials when looking at obese versus non-obese patients [31]. To the best of our knowledge, there are no active clinical trials evaluating DOAC therapy for VTE in morbid obesity (clinicaltrials.gov, October 2020).
The majority of patients included in the original DOAC clinical trials were low-risk VTE and not obese. However, it is important to note that neither BMI nor weight was an exclusionary criterion in the registration trials. A meta-analysis determined that 20% of participants in the registration trials were “high body weight” at randomisation (either >100 kg or >90 kg) [31]. None of the registration trials reported event rates specifically in morbid obesity, but they did report no differences in recurrent events in the high body weight groups treated with DOAC versus conventional therapy [3–6].
Recurrent VTE events often occur within 3–6 months at a rate of 4%–8% [32, 33] and typically present in a similar manner as the index event [34, 35]. With obesity being a risk factor for initial [11–13] and recurrent [14] VTE, if effective anticoagulation was not provided, the observed VTE recurrence rate would likely be much higher than the reported baseline of ∼4%–8%. We did not observe an elevated recurrence rate in our cohort. There is evolving retrospective data on the efficacy of DOAC therapy in morbid obesity. Kushnir
et al. [36] used single-centre chart review and determined a 2% risk for recurrent VTE in 366 morbidly obese (BMI>40 kg·m−2) patients with any DOAC-treated VTE event. Using two US claims databases, Spyropoulos
et al. [37] found a similar rate of risk of recurrent thrombotic events in morbid obesity. Although both studies relied on coding, their findings are real-world evidence that DOACs are effective in morbid obesity. We do not know if some of their recurrent VTE could have been unrecognised CTEPH or chronic clot.
We complement these larger studies with rigorous clinical follow-up and detailed chart review including echocardiogram, V/Q scan and RHC. We did not observe any recurrent PE within the first year in any patient, regardless of weight group or type of anticoagulation. We were able to differentiate CTEPH from recurrent PE. Furthermore, we did not observe any difference in the resolution of thrombotic disease on perfusion lung scanning, and DOAC-treated patients were just as likely to achieve right ventricle recovery (an indirect measure that the pulmonary circulation is no longer obstructed) after higher-risk PE. Our numbers are small, but DOACs did not appear to leave patients at higher risk for CTEPH. None of the registration clinical trials reported rates of CTEPH development, and given the large numbers of patients involved, CTEPH would be expected in some patients. Our data strengthen a growing body of literature supporting the clinical efficacy of DOAC therapy in morbid obesity because none of the previously reported studies detailed follow-up data on imaging and physiological recovery.
There are limitations to our study. We have data on a small number of morbidly obese patients on DOAC therapy that took 2 years to collect. However, given that this is a high-risk group, DOAC failure with recurrent events should have been observed. Our data are observational and anticoagulation was chosen based on the preference of the discharging attending physician and patient. Peak and trough drug concentrations were not measured, and we have no measurements of anti-Xa levels. We only included patients who had an intermediate- or high-risk PE. We did not include atrial fibrillation in our analysis and therefore our results may not be applicable to patients with BMI>40 kg·m−2 and atrial fibrillation.
In conclusion, we found that DOAC therapy does not put patients with morbid obesity at higher risk for recurrent VTE after intermediate- or high-risk PE compared to warfarin anticoagulation; we observed similar outcomes in obese and non-obese patients. Perfusion lung scanning did not suggest a difference in the rate of thrombus resolution, and echocardiography suggested similar rates of right ventricular recovery regardless of anticoagulation choice. In patients with PE, we believe that the available evidence makes DOAC therapy a reasonable option even in morbid obesity; we propose prospective clinical trials to address this directly.
Author contributions: D.J. Lachant, C. Bach, A. Fe, R.J. White and N.A. Lachant all contributed to the study design, analysis of the results and writing the manuscript, and approved the manuscript.
Conflict of interest: D.J. Lachant has nothing to disclose.
Conflict of interest: C. Bach has nothing to disclose.
Conflict of interest: A. Fe has nothing to disclose.
Conflict of interest: R.J. White has nothing to disclose.
Conflict of interest: N.A. Lachant has nothing to disclose. | WARFARIN SODIUM | DrugsGivenReaction | CC BY-NC | 33569503 | 19,037,050 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Liver injury'. | Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.
Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited.
We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure.
RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.
Learning points
Ventricular tachycardia (VT) storm in Anderson–Fabry disease (AFD) is due to re-entry around areas of fibrosis, and traditional principles for VT ablation can be used to acutely terminate the arrhythmia.
VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction and extensive late gadolinium enhancement are present.
Introduction
Anderson–Fabry disease (AFD) is a rare, X-linked storage disorder caused by deficiency of the enzyme α-galactosidase A resulting in accumulation of globotriaosylceramide in organs including the heart, kidneys, and nervous system.1 Lipid deposition, inflammation and fibrosis within the myocardial interstitium causes infiltrative hypertrophic cardiomyopathy and cardiac conduction tissue disease.2 The commonest arrhythmias in AFD are atrial fibrillation3,4 and ventricular tachycardia (VT).5–7 Here, we review the literature and report our experience of radiofrequency ablation (RFA) in three patients with AFD and drug-refractory VT.
Timeline
Case 1
May 2013 Initial presentation with presyncope. Monitoring: non-sustained ventricular tachycardia (NSVT). Cardiac magnetic resonance imaging (CMRI): left ventricular hypertrophy, left ventricular ejection fraction (LVEF) 61%.
July 2013 Anderson–Fabry disease (AFD) confirmed (serum alpha-galactosidase level 0.2 µmol/L/h; I117S mutation later identified). Enzyme replacement therapy started.
October 2013 Elective dual chamber implantable cardioverter-defibrillator (ICD) implantation.
September 2014 Echocardiography: LVEF 51%.
December 2015 Echocardiography: LVEF 35%.
May 2016 Admission following ICD shock delivery for sustained monomorphic ventricular tachycardia (SMVT). ICD reprogrammed.
May 2016 Further ICD therapy. SMVT and hypotension on admission. In-hospital cardiac arrest requiring cardiopulmonary resuscitation (CPR) with return of spontaneous circulation. Incessant ventricular tachycardia (VT) despite antiarrhythmics, overdrive pacing and anti-tachycardia pacing (ATP). Emergency radiofrequency VT ablation.
May 2016 Recurrent SMVT resistant to medical therapy. Second VT ablation. Polymorphic VT following ablation, requiring CPR and re-intubation.
May–July 2016 Recovery complicated by ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. Successfully rehabilitated and discharged 7 weeks after the second ablation.
August 2016 Palpitations at home. Device interrogation: VT treated with ATP.
September 2016 Admission with palpitations. SMVT on monitoring, responding to lignocaine. Beta-blocker dose increased.
September 2016 Palpitations at home. Three ICD shocks. Subsequent pulseless electrical activity arrest, CPR unsuccessful.
Case 2
May 2015 Initial presentation with syncope: SMVT, requiring direct current cardioversion. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 59%. Dual chamber ICD implantation. AFD confirmed (serum alpha-galactosidase level 0.3 µmol/L/h; P.N215S mutation).
June 2015 Enzyme replacement therapy started.
May 2016 Admission with palpitations and presyncope. Recurrent SMVT observed. Echocardiography: LVEF 45%.
May 2016 Inpatient VT ablation. Discharged 4 days later.
July–August 2018 Admission with heart failure and symptomatic atrial fibrillation (AF). Good response to diuretics. Acutely successful electrical cardioversion for AF.
June 2018 Two episodes of NSVT (each lasting 6–8 s) detected via ICD.
July 2019 Treated for refractory heart failure with palliative intent. No further VT.
September 2019 Died.
Case 3
December 2007 Abnormal preoperative electrocardiogram. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 61%.
February 2012 AFD confirmed (serum alpha-galactosidase level 0.45 µmol/L/h; N215S mutation identified). Enzyme replacement therapy started.
September 2016 Admission with SMVT leading to dual-chamber ICD implantation.
July 2018 Echocardiography: LVEF 35%.
November 2018 Admission following ICD shock delivery. Device interrogation: SMVT.
December 2018 Emergency external direct current cardioversion due to SMVT with hypotension.
December 2018 Acute kidney injury and acute liver injury secondary to VT-associated hypotension.
December 2018 Daily episodes of SMVT, resistant to antiarrhythmic therapy.
December 2018 Radiofrequency ablation of VT.
December 2018 Episodes of SMVT responding to ATP. Escalating doses of furosemide and dobutamine.
December 2018 Worsening heart failure with fluid overload and renal dysfunction. Decision to palliate: ICD therapies deactivated, medical therapy discontinued. Discharged home following day.
January 2019 Died.
Case series
Case 1
This 53-year-old man with a background of well-controlled asthma presented with exertional presyncope. Non-sustained VT (NSVT) was observed. Cardiac magnetic resonance imaging (CMRI) showed left ventricular hypertrophy (LVH) with a septal thickness of 24 mm, thinning of the basal inferolateral left ventricular wall, a left ventricular ejection fraction (LVEF) of 61%, and extensive mid-wall late gadolinium enhancement (LGE) of the mid and distal inferolateral left ventricle (LV) (Figure 1). Coronary angiography excluded obstructive coronary artery disease (CAD). A diagnosis of AFD was confirmed in July 2013 (I117S mutation). Enzyme replacement therapy (ERT) was commenced with intravenous (IV) agalsidase alfa (Replagal), and amiodarone 200 mg daily. A dual-chamber implantable cardioverter-defibrillator (ICD) was implanted. Over the next 18 months, LVEF declined to 35% despite angiotensin-converting enzyme inhibitor and beta blocker therapy. Pacing records showed a ventricular pacing burden of 1–2% during this time.
Figure 1 Cardiac magnetic resonance imaging in the three patients, prior to implantable cardioverter-defibrillator implantation.
Three years later, he had an episode of sustained monomorphic VT (SMVT), converted to sinus rhythm (Figure 2A) with a single ICD shock. He received another shock from his ICD 10 days later. His 12-lead electrocardiogram (ECG) during VT showed a rate of 175 b.p.m., a right bundle branch block (RBBB) pattern, and left-superior axis (Figure 3A). Despite an initial blood pressure (BP) of 65/37 mmHg, he lost cardiac output and required 20 min of cardiopulmonary resuscitation (CPR), with 15 internal and external shocks before return of spontaneous circulation. Despite treatment with IV amiodarone, lignocaine, carvedilol, heavy sedation with intubation and attempts at overdrive pacing, his VT was incessant with persistent hypotension and we proceeded to an emergency electrophysiological study (EPS).
Figure 2 Twelve-lead electrocardiogram during sinus rhythm. Case 1 (A); Case 2 (B); and Case 3 (C).
Figure 3 Twelve-lead electrocardiogram during VT. Case 1 (A): immediately before ventricular tachycardia ablation. Case 2 (B): on admission, 3 days prior to ventricular tachycardia ablation. Case 3 (C): 3 days after admission, shortly before external direct current cardioversion.
The VT terminated during catheter manipulation and was subsequently intermittent. Endocardial mapping of the LV was performed using a decapolar mapping catheter (Inquiry AFocus, EnSite Velocity™, Abbott). Mapping of the left ventricular substrate, activation, late potentials, and pace-mapping revealed areas of interest for ablation at the inferobasal left ventricular endocardium. RFA was performed from the site of earliest activation of VT in the LV forming a line of block from the scar to the mitral value annulus, incorporating the areas of interest (Flexability ablation catheter, 40-W power). Subsequent VT stimulation with three extras was negative. IV amiodarone was continued, and lignocaine stopped.
Three days later, he had recurrent SMVT of same morphology, resistant to re-initiation of lignocaine. A second EPS was performed, this time endocardially and epicardially (110 mm 16G Tuohy needle). Initially, we observed a paced rhythm with frequent monomorphic (right bundle, left superior axis) premature ventricular complexes (PVCs), of similar morphology to the initial VT. Endocardial and epicardial mapping of the PVCs was performed [EnSite Velocity™ Cardiac Mapping System (Abbott) using AFocus™ catheter]. Extensive epicardial scar was noted. The origin of the PVCs corresponded with an island of healthier tissue within scar on the basal epicardial inferoseptal LV. This was targeted with RFA, with abolition of the PVCs. Further VT (right bundle, left superior axis) was induced with right ventricular pacing, but due to haemodynamic instability it was not possible to map. Good pacemapping from an area of late potentials at the epicardial apical inferolateral sites was targeted for ablation. Pace mapping was also performed in the endocardial LV. ‘Good’ sites (11/12 match) were noted at the inferolateral apical LV and ablated. The procedure concluded once no further sites for ablation were identified. No further VT induction was attempted due to the very high risk of precipitating further haemodynamic decompensation.
Shortly after the procedure, he had polymorphic VT requiring ICD therapies, external defibrillation, CPR, dopamine and adrenaline infusions, and intra-aortic balloon pump insertion. Resuscitation was acutely successful and he was transferred to the intensive therapy unit.
Recovery was complicated by a ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. He was discharged 7 weeks after the ablation, requiring a stick to walk. He remained on oral amiodarone. Over the next 2 months, he had VT treated with anti-tachycardia pacing (ATP) and a second episode requiring a short admission for IV lignocaine.
Four months after the ablation procedures, he received three ICD shocks for SMVT, followed by pulseless electrical activity. CPR was unsuccessful.
Case 2
This 67-year-old man presented with presyncope on exercise due to VT, requiring direct current cardioversion (DCCV). CMRI at presentation demonstrated LVH (maximal septal thickness 22 mm), regional thinning and akinesia, LVEF of 59%, and full thickness LGE affecting the basal and mid-chamber inferior, inferolateral and anterolateral segments (Figure 1). A diagnosis of AFD was confirmed (P.N215S mutation), and Replagal started. He had no other past medical history of note, and coronary angiography excluded CAD. A dual chamber ICD was implanted in 2015. Device interrogation found a right ventricular (RV) pacing burden of 2–9%.
A year later, he represented with presyncope. The rhythm was SMVT at a rate of 161 b.p.m. (below the device programmed treatment zone), with RBBB morphology, and superior axis (Figure 3B). BP was 97/51 mmHg. Despite treatment with IV amiodarone, the rate increased and he was cardioverted via his ICD (Figure 2B). His bisoprolol dose was increased and oral amiodarone started. Echocardiography showed an LVEF of 45%. Over the next 3 days, recurrent NSVT without haemodynamic compromise was treated with IV amiodarone, lignocaine, and ATP.
EPS was performed 4 days after admission. Mapping of the LV was performed in sinus rhythm (EnSite Velocity mapping system, AFocus catheter, Abbott). Late potentials were seen in mid-inferolateral, mid-septal, and anteroapical sites. Scar mapping revealed large areas of dense scar in the inferolateral LV and the basal to mid-septal and anteroapical regions. Programmed electrical stimulation in the RV apex and various LV sites (up to three ventricular extrastimuli) did not induce VT. Pace-mapping was best at the mid-apical inferolateral regions. Ablation of the inferolateral, basal to mid-septal and anteroapical LV was undertaken. Shortly after the procedure, he had two episodes of NSVT, but no further episodes whilst an inpatient. He was discharged 4 days later with oral amiodarone and metoprolol. Amiodarone was discontinued in March 2017.
He remained stable for 2 years. Device interrogation between September 2016 and August 2019 demonstrated two episodes of NSVT, each lasting 6–8 s. In July 2018, he was hospitalized for 7 weeks due to decompensated heart failure in atrial fibrillation, responding to diuretics and DCCV. His LVEF had deteriorated to 38% and heart failure continued to progress despite medical treatment. A decision was made to treat this palliatively. He died in September 2019.
Case 3
This 69-year-old man with hypertension had an abnormal routine preoperative ECG (Figure 2C) in 2007 and was diagnosed with hypertrophic cardiomyopathy. CMRI showed asymmetrical LVH (24 mm) and LVEF of 61%. A diagnosis of AFD (N215S mutation) was confirmed in 2012, when ERT was started. An ICD was implanted after an episode of SMVT in 2016. Repeated CMRI revealed deterioration in left ventricular systolic function (LVEF 48%), with diffuse LGE in the basal to mid inferolateral LV ‘LV/RV hinge points’ and the left ventricular anteroseptum and apex (Figure 1). Coronary angiography excluded significant CAD. Echocardiography in July 2018 showed further deterioration in left ventricular systolic function (LVEF 35%), treated with standard heart failure therapy.
He presented in November 2018 after receiving shocks from his ICD. Device interrogation confirmed two episodes of SMVT, failing to respond to ATP, finally treated with shocks. RV pacing burden had been 0–8%, although the basal pacing rate was then increased from 50 to 80 b.p.m., and he was commenced on IV amiodarone. Three days later, an episode of SMVT (Figure 3C) with hypotension prompted emergency external DCCV. Over the next 9 days, he had daily episodes of SMVT, without haemodynamic compromise, responding to ATP. He was treated with IV lignocaine to control the SMVT and milrinone to treat persistent cardiogenic shock. Despite this, he had daily episodes of SMVT requiring ATP. He developed acute kidney and liver injuries, likely due to hypoperfusion during episodes of VT, although amiodarone was discontinued due to possible hepatotoxicity.
Three weeks into the admission, EPS was performed. VT induction was not attempted due to haemodynamic instability. Transseptal puncture and left ventricular mapping was performed during RV pacing, demonstrating extensive apical left ventricular scar (Figure 4). Pacemaps similar to the clinical VT (Figure 5A), and delayed potentials were recorded at the left ventricular apex (Figure 5B). Isolation of the left ventricular apex with loss of local pace capture was achieved with local impedance-guided RFA applications.
Figure 4 Bipolar voltage map and ablation lesions from ventricular tachycardia ablation (Case 3). The low voltage areas observed using conventional voltage criteria corresponded with late Gadolinium-enhanced areas seen with cardiac magnetic resonance (Figure 1, Case 3). There was mid-distal anteroseptal, apical, and posterolateral scar. Substrate-based ablation was performed guided by late potentials and pacemaps. Ventricular tachycardia was not inducible pre- or post-ablation. AP, antero-posterior; Bi, bipolar tissue voltage; Imp, impedance drop observed during radiofrequency ablation; LAO, left anterior oblique; LPO, left posterior oblique view.
Figure 5 Twelve-lead electrocardiogram (A) recorded during left ventricular pacing from an antero-apical site, demonstrating reasonable match with the clinical ventricular tachycardia (Figure 3C). Intracardiac electrograms (B) recorded during right ventricular pacing with the Pentarray (PENT) roving catheter (Biosense Webster) positioned in the left ventricle at the same apical site as the pace map displayed above. Delayed post-QRS potentials are seen in this area (arrows). CS, coronary sinus catheter.
Following EPS, lignocaine and milrinone were stopped. Further episodes of SMVT responding to ATP were observed over the next 3 days, but thereafter no VT was seen. Despite treatment with IV furosemide and dobutamine, he remained in cardiogenic shock. A joint decision was made to deactivate his ICD, discontinue medical therapy, and palliate. He died 11 days later.
Review of literature
Whilst multi-organ involvement is common in AFD, mortality is primarily caused by cardiac disease. A systematic review by Baig et al.8 identified 13 studies on ventricular arrhythmias and sudden cardiac death (SCD) in AFD. In this review, 75% of deaths were due to a cardiovascular condition and 62% of all deaths were reported as SCD events. The average prevalence of VT was reported as 15.3%. Factors associated with SCD included increasing age, LGE on CMRI, and NSVT.
We identified four case reports pertaining to the description of RFA of VT in AFD. Higashi et al.9 described the case of a 67-year-old man with an LVEF of 35% and a left lateral ventricle wall perfusion defect, presenting with VT storm resistant to anti-arrhythmic therapy. Epicardial activation mapping demonstrated a figure-of-eight re-entrant circuit on the lateral left ventricular wall. RFA to this region terminated the VT. Over a 24-month follow-up, recurrence of a non-ablated VT was observed, and the number of ICD shocks for VT decreased. In another study, Nakano et al.10 report on a 51-year-old man with an LVEF of 68%, presenting with SMVT. CMRI demonstrated high T2 signal in the basal epicardium and antero-septal endocardium. The patient underwent RFA of the left ventricular anterior-apical wall, with recurrence of the VT a few days after. A second ablation was performed but did not completely eradicate the VT. The patient was continued on long-term amiodarone and remained alive at 2 years, with no documented VT recurrence. A report by Ellis et al.11 described a 49-year-old man with AFD, LVEF 25–30%, permanent atrial fibrillation and complete heart block (with cardiac resynchronization therapy ICD), presenting with VT storm resistant to anti-arrhythmic therapy. EPS demonstrated a posterolateral site of origin near the mitral annulus, and RFA was performed at this site, with no VT subsequently inducible. Follow-up was limited to 3 months, without VT recurrence. In an abstract by Oder et al.,12 the authors describe the use of RFA in three patients with Fabry disease, two of whom experienced further VT episodes following the procedure and died due to end-stage heart failure.
With regards to guidance on ICD implantation in AFD, evidence is sparse. In a retrospective analysis of patients with AFD,13 several clinical factors were associated with ICD implantation, including increasing age, greater left ventricular mass, greater scar tissue, and larger atrial size. Importantly, only 28% of AFD patients with an ICD in this study had a Class 1 indication for implantation, highlighting the need for AFD-specific research and guidelines.
Discussion
Imaging
CMRI in our cohort showed extensive LGE, which was predominantly inferolateral mid-wall, patchy, extending from base to apex. Whilst the morphology of the VT on the 12-lead ECGs was variable, it did correspond with observed areas of LGE. In Case 1, an inferior basal septum origin, in Case 2, a lateral mid-chamber origin, and in Case 3, an apical wall origin.
All our patients had relatively stable slow SMVT (Figure 2) with rates between 150 and 180 min−1 and in one case the QRS had delayed intrinsicoid deflection, suggestive of epicardial breakout.
Ablation strategy
In our series, the mechanism of VT was re-entry around areas of fibrosis, and traditional principles for VT ablation were deemed appropriate. The substrate is transmural and the critical isthmus may be found endocardially but can be present anywhere within the myocardium. Despite extensive myocardial fibrosis in our cases, left ventricular walls remained hypertrophied. Accordingly, ablated areas were frequently in thickened myocardium, likely to hinder lesion transmurality. These factors suggest that a combined endocardial/epicardial approach may be helpful, although an endocardial-only approach was used in our most successful case who survived beyond three years.
In two of our cases, VT was not inducible at the end of the procedure (in the third, VT induction was not attempted due to haemodynamic instability). Therefore, inducibility does not appear to be a reliable marker of subsequent VT risk, so comprehensive treatment may involve complete substrate modification where possible.
Left ventricular function
Our experience suggests that VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction (LVSD) and extensive LGE are present. At the start of our case series, all patients had preserved LVEF, which later deteriorated after ICD implantation. Two had severe LVSD at the time of ablation; Case 1 who died 4 months following VT ablation, and Case 3 who died 2 weeks after. In contrast, Case 2 had moderate LVSD at the time of ablation, and survived more than 3 years following the procedure, although it must be acknowledged that prior to EPS, the patient had been stabilized on amiodarone which was continued for 10 months following the procedure. In our experience of over 175 patients with cardiac AFD, it appears that VT electrical storm in AFD patients is a marker of end-stage disease.
Conclusion
AFD can present with VT consistent with a re-entry mechanism. In our series of three patients with VT storm refractory to medical therapy, extensive infiltration and/or scar was demonstrated by LGE. Endocardial ± epicardial mapping demonstrated the arrhythmic substrate. However, RFA did not result in a significant prognostic benefit in two out of the three patients. In patients with AFD, VT storm is therefore likely a sign of end-stage disease.
Lead author biography
Dr Mark T. Mills is an academic clinical fellow and cardiology registrar in South Yorkshire, UK. He began his undergraduate training at the University of Sheffield, graduating with Honours in 2015. He subsequently completed a Masters in Cardiovascular Research at King’s College London. His research interests include cardiac electrophysiology, coronary physiology, and the impact of cardiac rhythm disturbance on coronary haemodynamics.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa529_Supplementary_Data Click here for additional data file.
Acknowledgements
We would like to thank Stacey Bates, cardiac physiologist at the Northern General Hospital, for her help during the electrophysiology studies and in preparing the figures for this case series.
Slide sets: A fully edited slide set detailing this case 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 image(s) and associated text has been obtained from the patients in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | AMIODARONE, DOBUTAMINE HYDROCHLORIDE, FUROSEMIDE, LIDOCAINE HYDROCHLORIDE, MILRINONE | DrugsGivenReaction | CC BY-NC | 33569526 | 20,893,199 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.
Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited.
We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure.
RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.
Learning points
Ventricular tachycardia (VT) storm in Anderson–Fabry disease (AFD) is due to re-entry around areas of fibrosis, and traditional principles for VT ablation can be used to acutely terminate the arrhythmia.
VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction and extensive late gadolinium enhancement are present.
Introduction
Anderson–Fabry disease (AFD) is a rare, X-linked storage disorder caused by deficiency of the enzyme α-galactosidase A resulting in accumulation of globotriaosylceramide in organs including the heart, kidneys, and nervous system.1 Lipid deposition, inflammation and fibrosis within the myocardial interstitium causes infiltrative hypertrophic cardiomyopathy and cardiac conduction tissue disease.2 The commonest arrhythmias in AFD are atrial fibrillation3,4 and ventricular tachycardia (VT).5–7 Here, we review the literature and report our experience of radiofrequency ablation (RFA) in three patients with AFD and drug-refractory VT.
Timeline
Case 1
May 2013 Initial presentation with presyncope. Monitoring: non-sustained ventricular tachycardia (NSVT). Cardiac magnetic resonance imaging (CMRI): left ventricular hypertrophy, left ventricular ejection fraction (LVEF) 61%.
July 2013 Anderson–Fabry disease (AFD) confirmed (serum alpha-galactosidase level 0.2 µmol/L/h; I117S mutation later identified). Enzyme replacement therapy started.
October 2013 Elective dual chamber implantable cardioverter-defibrillator (ICD) implantation.
September 2014 Echocardiography: LVEF 51%.
December 2015 Echocardiography: LVEF 35%.
May 2016 Admission following ICD shock delivery for sustained monomorphic ventricular tachycardia (SMVT). ICD reprogrammed.
May 2016 Further ICD therapy. SMVT and hypotension on admission. In-hospital cardiac arrest requiring cardiopulmonary resuscitation (CPR) with return of spontaneous circulation. Incessant ventricular tachycardia (VT) despite antiarrhythmics, overdrive pacing and anti-tachycardia pacing (ATP). Emergency radiofrequency VT ablation.
May 2016 Recurrent SMVT resistant to medical therapy. Second VT ablation. Polymorphic VT following ablation, requiring CPR and re-intubation.
May–July 2016 Recovery complicated by ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. Successfully rehabilitated and discharged 7 weeks after the second ablation.
August 2016 Palpitations at home. Device interrogation: VT treated with ATP.
September 2016 Admission with palpitations. SMVT on monitoring, responding to lignocaine. Beta-blocker dose increased.
September 2016 Palpitations at home. Three ICD shocks. Subsequent pulseless electrical activity arrest, CPR unsuccessful.
Case 2
May 2015 Initial presentation with syncope: SMVT, requiring direct current cardioversion. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 59%. Dual chamber ICD implantation. AFD confirmed (serum alpha-galactosidase level 0.3 µmol/L/h; P.N215S mutation).
June 2015 Enzyme replacement therapy started.
May 2016 Admission with palpitations and presyncope. Recurrent SMVT observed. Echocardiography: LVEF 45%.
May 2016 Inpatient VT ablation. Discharged 4 days later.
July–August 2018 Admission with heart failure and symptomatic atrial fibrillation (AF). Good response to diuretics. Acutely successful electrical cardioversion for AF.
June 2018 Two episodes of NSVT (each lasting 6–8 s) detected via ICD.
July 2019 Treated for refractory heart failure with palliative intent. No further VT.
September 2019 Died.
Case 3
December 2007 Abnormal preoperative electrocardiogram. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 61%.
February 2012 AFD confirmed (serum alpha-galactosidase level 0.45 µmol/L/h; N215S mutation identified). Enzyme replacement therapy started.
September 2016 Admission with SMVT leading to dual-chamber ICD implantation.
July 2018 Echocardiography: LVEF 35%.
November 2018 Admission following ICD shock delivery. Device interrogation: SMVT.
December 2018 Emergency external direct current cardioversion due to SMVT with hypotension.
December 2018 Acute kidney injury and acute liver injury secondary to VT-associated hypotension.
December 2018 Daily episodes of SMVT, resistant to antiarrhythmic therapy.
December 2018 Radiofrequency ablation of VT.
December 2018 Episodes of SMVT responding to ATP. Escalating doses of furosemide and dobutamine.
December 2018 Worsening heart failure with fluid overload and renal dysfunction. Decision to palliate: ICD therapies deactivated, medical therapy discontinued. Discharged home following day.
January 2019 Died.
Case series
Case 1
This 53-year-old man with a background of well-controlled asthma presented with exertional presyncope. Non-sustained VT (NSVT) was observed. Cardiac magnetic resonance imaging (CMRI) showed left ventricular hypertrophy (LVH) with a septal thickness of 24 mm, thinning of the basal inferolateral left ventricular wall, a left ventricular ejection fraction (LVEF) of 61%, and extensive mid-wall late gadolinium enhancement (LGE) of the mid and distal inferolateral left ventricle (LV) (Figure 1). Coronary angiography excluded obstructive coronary artery disease (CAD). A diagnosis of AFD was confirmed in July 2013 (I117S mutation). Enzyme replacement therapy (ERT) was commenced with intravenous (IV) agalsidase alfa (Replagal), and amiodarone 200 mg daily. A dual-chamber implantable cardioverter-defibrillator (ICD) was implanted. Over the next 18 months, LVEF declined to 35% despite angiotensin-converting enzyme inhibitor and beta blocker therapy. Pacing records showed a ventricular pacing burden of 1–2% during this time.
Figure 1 Cardiac magnetic resonance imaging in the three patients, prior to implantable cardioverter-defibrillator implantation.
Three years later, he had an episode of sustained monomorphic VT (SMVT), converted to sinus rhythm (Figure 2A) with a single ICD shock. He received another shock from his ICD 10 days later. His 12-lead electrocardiogram (ECG) during VT showed a rate of 175 b.p.m., a right bundle branch block (RBBB) pattern, and left-superior axis (Figure 3A). Despite an initial blood pressure (BP) of 65/37 mmHg, he lost cardiac output and required 20 min of cardiopulmonary resuscitation (CPR), with 15 internal and external shocks before return of spontaneous circulation. Despite treatment with IV amiodarone, lignocaine, carvedilol, heavy sedation with intubation and attempts at overdrive pacing, his VT was incessant with persistent hypotension and we proceeded to an emergency electrophysiological study (EPS).
Figure 2 Twelve-lead electrocardiogram during sinus rhythm. Case 1 (A); Case 2 (B); and Case 3 (C).
Figure 3 Twelve-lead electrocardiogram during VT. Case 1 (A): immediately before ventricular tachycardia ablation. Case 2 (B): on admission, 3 days prior to ventricular tachycardia ablation. Case 3 (C): 3 days after admission, shortly before external direct current cardioversion.
The VT terminated during catheter manipulation and was subsequently intermittent. Endocardial mapping of the LV was performed using a decapolar mapping catheter (Inquiry AFocus, EnSite Velocity™, Abbott). Mapping of the left ventricular substrate, activation, late potentials, and pace-mapping revealed areas of interest for ablation at the inferobasal left ventricular endocardium. RFA was performed from the site of earliest activation of VT in the LV forming a line of block from the scar to the mitral value annulus, incorporating the areas of interest (Flexability ablation catheter, 40-W power). Subsequent VT stimulation with three extras was negative. IV amiodarone was continued, and lignocaine stopped.
Three days later, he had recurrent SMVT of same morphology, resistant to re-initiation of lignocaine. A second EPS was performed, this time endocardially and epicardially (110 mm 16G Tuohy needle). Initially, we observed a paced rhythm with frequent monomorphic (right bundle, left superior axis) premature ventricular complexes (PVCs), of similar morphology to the initial VT. Endocardial and epicardial mapping of the PVCs was performed [EnSite Velocity™ Cardiac Mapping System (Abbott) using AFocus™ catheter]. Extensive epicardial scar was noted. The origin of the PVCs corresponded with an island of healthier tissue within scar on the basal epicardial inferoseptal LV. This was targeted with RFA, with abolition of the PVCs. Further VT (right bundle, left superior axis) was induced with right ventricular pacing, but due to haemodynamic instability it was not possible to map. Good pacemapping from an area of late potentials at the epicardial apical inferolateral sites was targeted for ablation. Pace mapping was also performed in the endocardial LV. ‘Good’ sites (11/12 match) were noted at the inferolateral apical LV and ablated. The procedure concluded once no further sites for ablation were identified. No further VT induction was attempted due to the very high risk of precipitating further haemodynamic decompensation.
Shortly after the procedure, he had polymorphic VT requiring ICD therapies, external defibrillation, CPR, dopamine and adrenaline infusions, and intra-aortic balloon pump insertion. Resuscitation was acutely successful and he was transferred to the intensive therapy unit.
Recovery was complicated by a ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. He was discharged 7 weeks after the ablation, requiring a stick to walk. He remained on oral amiodarone. Over the next 2 months, he had VT treated with anti-tachycardia pacing (ATP) and a second episode requiring a short admission for IV lignocaine.
Four months after the ablation procedures, he received three ICD shocks for SMVT, followed by pulseless electrical activity. CPR was unsuccessful.
Case 2
This 67-year-old man presented with presyncope on exercise due to VT, requiring direct current cardioversion (DCCV). CMRI at presentation demonstrated LVH (maximal septal thickness 22 mm), regional thinning and akinesia, LVEF of 59%, and full thickness LGE affecting the basal and mid-chamber inferior, inferolateral and anterolateral segments (Figure 1). A diagnosis of AFD was confirmed (P.N215S mutation), and Replagal started. He had no other past medical history of note, and coronary angiography excluded CAD. A dual chamber ICD was implanted in 2015. Device interrogation found a right ventricular (RV) pacing burden of 2–9%.
A year later, he represented with presyncope. The rhythm was SMVT at a rate of 161 b.p.m. (below the device programmed treatment zone), with RBBB morphology, and superior axis (Figure 3B). BP was 97/51 mmHg. Despite treatment with IV amiodarone, the rate increased and he was cardioverted via his ICD (Figure 2B). His bisoprolol dose was increased and oral amiodarone started. Echocardiography showed an LVEF of 45%. Over the next 3 days, recurrent NSVT without haemodynamic compromise was treated with IV amiodarone, lignocaine, and ATP.
EPS was performed 4 days after admission. Mapping of the LV was performed in sinus rhythm (EnSite Velocity mapping system, AFocus catheter, Abbott). Late potentials were seen in mid-inferolateral, mid-septal, and anteroapical sites. Scar mapping revealed large areas of dense scar in the inferolateral LV and the basal to mid-septal and anteroapical regions. Programmed electrical stimulation in the RV apex and various LV sites (up to three ventricular extrastimuli) did not induce VT. Pace-mapping was best at the mid-apical inferolateral regions. Ablation of the inferolateral, basal to mid-septal and anteroapical LV was undertaken. Shortly after the procedure, he had two episodes of NSVT, but no further episodes whilst an inpatient. He was discharged 4 days later with oral amiodarone and metoprolol. Amiodarone was discontinued in March 2017.
He remained stable for 2 years. Device interrogation between September 2016 and August 2019 demonstrated two episodes of NSVT, each lasting 6–8 s. In July 2018, he was hospitalized for 7 weeks due to decompensated heart failure in atrial fibrillation, responding to diuretics and DCCV. His LVEF had deteriorated to 38% and heart failure continued to progress despite medical treatment. A decision was made to treat this palliatively. He died in September 2019.
Case 3
This 69-year-old man with hypertension had an abnormal routine preoperative ECG (Figure 2C) in 2007 and was diagnosed with hypertrophic cardiomyopathy. CMRI showed asymmetrical LVH (24 mm) and LVEF of 61%. A diagnosis of AFD (N215S mutation) was confirmed in 2012, when ERT was started. An ICD was implanted after an episode of SMVT in 2016. Repeated CMRI revealed deterioration in left ventricular systolic function (LVEF 48%), with diffuse LGE in the basal to mid inferolateral LV ‘LV/RV hinge points’ and the left ventricular anteroseptum and apex (Figure 1). Coronary angiography excluded significant CAD. Echocardiography in July 2018 showed further deterioration in left ventricular systolic function (LVEF 35%), treated with standard heart failure therapy.
He presented in November 2018 after receiving shocks from his ICD. Device interrogation confirmed two episodes of SMVT, failing to respond to ATP, finally treated with shocks. RV pacing burden had been 0–8%, although the basal pacing rate was then increased from 50 to 80 b.p.m., and he was commenced on IV amiodarone. Three days later, an episode of SMVT (Figure 3C) with hypotension prompted emergency external DCCV. Over the next 9 days, he had daily episodes of SMVT, without haemodynamic compromise, responding to ATP. He was treated with IV lignocaine to control the SMVT and milrinone to treat persistent cardiogenic shock. Despite this, he had daily episodes of SMVT requiring ATP. He developed acute kidney and liver injuries, likely due to hypoperfusion during episodes of VT, although amiodarone was discontinued due to possible hepatotoxicity.
Three weeks into the admission, EPS was performed. VT induction was not attempted due to haemodynamic instability. Transseptal puncture and left ventricular mapping was performed during RV pacing, demonstrating extensive apical left ventricular scar (Figure 4). Pacemaps similar to the clinical VT (Figure 5A), and delayed potentials were recorded at the left ventricular apex (Figure 5B). Isolation of the left ventricular apex with loss of local pace capture was achieved with local impedance-guided RFA applications.
Figure 4 Bipolar voltage map and ablation lesions from ventricular tachycardia ablation (Case 3). The low voltage areas observed using conventional voltage criteria corresponded with late Gadolinium-enhanced areas seen with cardiac magnetic resonance (Figure 1, Case 3). There was mid-distal anteroseptal, apical, and posterolateral scar. Substrate-based ablation was performed guided by late potentials and pacemaps. Ventricular tachycardia was not inducible pre- or post-ablation. AP, antero-posterior; Bi, bipolar tissue voltage; Imp, impedance drop observed during radiofrequency ablation; LAO, left anterior oblique; LPO, left posterior oblique view.
Figure 5 Twelve-lead electrocardiogram (A) recorded during left ventricular pacing from an antero-apical site, demonstrating reasonable match with the clinical ventricular tachycardia (Figure 3C). Intracardiac electrograms (B) recorded during right ventricular pacing with the Pentarray (PENT) roving catheter (Biosense Webster) positioned in the left ventricle at the same apical site as the pace map displayed above. Delayed post-QRS potentials are seen in this area (arrows). CS, coronary sinus catheter.
Following EPS, lignocaine and milrinone were stopped. Further episodes of SMVT responding to ATP were observed over the next 3 days, but thereafter no VT was seen. Despite treatment with IV furosemide and dobutamine, he remained in cardiogenic shock. A joint decision was made to deactivate his ICD, discontinue medical therapy, and palliate. He died 11 days later.
Review of literature
Whilst multi-organ involvement is common in AFD, mortality is primarily caused by cardiac disease. A systematic review by Baig et al.8 identified 13 studies on ventricular arrhythmias and sudden cardiac death (SCD) in AFD. In this review, 75% of deaths were due to a cardiovascular condition and 62% of all deaths were reported as SCD events. The average prevalence of VT was reported as 15.3%. Factors associated with SCD included increasing age, LGE on CMRI, and NSVT.
We identified four case reports pertaining to the description of RFA of VT in AFD. Higashi et al.9 described the case of a 67-year-old man with an LVEF of 35% and a left lateral ventricle wall perfusion defect, presenting with VT storm resistant to anti-arrhythmic therapy. Epicardial activation mapping demonstrated a figure-of-eight re-entrant circuit on the lateral left ventricular wall. RFA to this region terminated the VT. Over a 24-month follow-up, recurrence of a non-ablated VT was observed, and the number of ICD shocks for VT decreased. In another study, Nakano et al.10 report on a 51-year-old man with an LVEF of 68%, presenting with SMVT. CMRI demonstrated high T2 signal in the basal epicardium and antero-septal endocardium. The patient underwent RFA of the left ventricular anterior-apical wall, with recurrence of the VT a few days after. A second ablation was performed but did not completely eradicate the VT. The patient was continued on long-term amiodarone and remained alive at 2 years, with no documented VT recurrence. A report by Ellis et al.11 described a 49-year-old man with AFD, LVEF 25–30%, permanent atrial fibrillation and complete heart block (with cardiac resynchronization therapy ICD), presenting with VT storm resistant to anti-arrhythmic therapy. EPS demonstrated a posterolateral site of origin near the mitral annulus, and RFA was performed at this site, with no VT subsequently inducible. Follow-up was limited to 3 months, without VT recurrence. In an abstract by Oder et al.,12 the authors describe the use of RFA in three patients with Fabry disease, two of whom experienced further VT episodes following the procedure and died due to end-stage heart failure.
With regards to guidance on ICD implantation in AFD, evidence is sparse. In a retrospective analysis of patients with AFD,13 several clinical factors were associated with ICD implantation, including increasing age, greater left ventricular mass, greater scar tissue, and larger atrial size. Importantly, only 28% of AFD patients with an ICD in this study had a Class 1 indication for implantation, highlighting the need for AFD-specific research and guidelines.
Discussion
Imaging
CMRI in our cohort showed extensive LGE, which was predominantly inferolateral mid-wall, patchy, extending from base to apex. Whilst the morphology of the VT on the 12-lead ECGs was variable, it did correspond with observed areas of LGE. In Case 1, an inferior basal septum origin, in Case 2, a lateral mid-chamber origin, and in Case 3, an apical wall origin.
All our patients had relatively stable slow SMVT (Figure 2) with rates between 150 and 180 min−1 and in one case the QRS had delayed intrinsicoid deflection, suggestive of epicardial breakout.
Ablation strategy
In our series, the mechanism of VT was re-entry around areas of fibrosis, and traditional principles for VT ablation were deemed appropriate. The substrate is transmural and the critical isthmus may be found endocardially but can be present anywhere within the myocardium. Despite extensive myocardial fibrosis in our cases, left ventricular walls remained hypertrophied. Accordingly, ablated areas were frequently in thickened myocardium, likely to hinder lesion transmurality. These factors suggest that a combined endocardial/epicardial approach may be helpful, although an endocardial-only approach was used in our most successful case who survived beyond three years.
In two of our cases, VT was not inducible at the end of the procedure (in the third, VT induction was not attempted due to haemodynamic instability). Therefore, inducibility does not appear to be a reliable marker of subsequent VT risk, so comprehensive treatment may involve complete substrate modification where possible.
Left ventricular function
Our experience suggests that VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction (LVSD) and extensive LGE are present. At the start of our case series, all patients had preserved LVEF, which later deteriorated after ICD implantation. Two had severe LVSD at the time of ablation; Case 1 who died 4 months following VT ablation, and Case 3 who died 2 weeks after. In contrast, Case 2 had moderate LVSD at the time of ablation, and survived more than 3 years following the procedure, although it must be acknowledged that prior to EPS, the patient had been stabilized on amiodarone which was continued for 10 months following the procedure. In our experience of over 175 patients with cardiac AFD, it appears that VT electrical storm in AFD patients is a marker of end-stage disease.
Conclusion
AFD can present with VT consistent with a re-entry mechanism. In our series of three patients with VT storm refractory to medical therapy, extensive infiltration and/or scar was demonstrated by LGE. Endocardial ± epicardial mapping demonstrated the arrhythmic substrate. However, RFA did not result in a significant prognostic benefit in two out of the three patients. In patients with AFD, VT storm is therefore likely a sign of end-stage disease.
Lead author biography
Dr Mark T. Mills is an academic clinical fellow and cardiology registrar in South Yorkshire, UK. He began his undergraduate training at the University of Sheffield, graduating with Honours in 2015. He subsequently completed a Masters in Cardiovascular Research at King’s College London. His research interests include cardiac electrophysiology, coronary physiology, and the impact of cardiac rhythm disturbance on coronary haemodynamics.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa529_Supplementary_Data Click here for additional data file.
Acknowledgements
We would like to thank Stacey Bates, cardiac physiologist at the Northern General Hospital, for her help during the electrophysiology studies and in preparing the figures for this case series.
Slide sets: A fully edited slide set detailing this case 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 image(s) and associated text has been obtained from the patients in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | AGALSIDASE ALFA, AMIODARONE, CARVEDILOL, LIDOCAINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33569526 | 20,807,708 | 2021-02 |
What was the administration route of drug 'AMIODARONE'? | Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.
Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited.
We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure.
RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.
Learning points
Ventricular tachycardia (VT) storm in Anderson–Fabry disease (AFD) is due to re-entry around areas of fibrosis, and traditional principles for VT ablation can be used to acutely terminate the arrhythmia.
VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction and extensive late gadolinium enhancement are present.
Introduction
Anderson–Fabry disease (AFD) is a rare, X-linked storage disorder caused by deficiency of the enzyme α-galactosidase A resulting in accumulation of globotriaosylceramide in organs including the heart, kidneys, and nervous system.1 Lipid deposition, inflammation and fibrosis within the myocardial interstitium causes infiltrative hypertrophic cardiomyopathy and cardiac conduction tissue disease.2 The commonest arrhythmias in AFD are atrial fibrillation3,4 and ventricular tachycardia (VT).5–7 Here, we review the literature and report our experience of radiofrequency ablation (RFA) in three patients with AFD and drug-refractory VT.
Timeline
Case 1
May 2013 Initial presentation with presyncope. Monitoring: non-sustained ventricular tachycardia (NSVT). Cardiac magnetic resonance imaging (CMRI): left ventricular hypertrophy, left ventricular ejection fraction (LVEF) 61%.
July 2013 Anderson–Fabry disease (AFD) confirmed (serum alpha-galactosidase level 0.2 µmol/L/h; I117S mutation later identified). Enzyme replacement therapy started.
October 2013 Elective dual chamber implantable cardioverter-defibrillator (ICD) implantation.
September 2014 Echocardiography: LVEF 51%.
December 2015 Echocardiography: LVEF 35%.
May 2016 Admission following ICD shock delivery for sustained monomorphic ventricular tachycardia (SMVT). ICD reprogrammed.
May 2016 Further ICD therapy. SMVT and hypotension on admission. In-hospital cardiac arrest requiring cardiopulmonary resuscitation (CPR) with return of spontaneous circulation. Incessant ventricular tachycardia (VT) despite antiarrhythmics, overdrive pacing and anti-tachycardia pacing (ATP). Emergency radiofrequency VT ablation.
May 2016 Recurrent SMVT resistant to medical therapy. Second VT ablation. Polymorphic VT following ablation, requiring CPR and re-intubation.
May–July 2016 Recovery complicated by ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. Successfully rehabilitated and discharged 7 weeks after the second ablation.
August 2016 Palpitations at home. Device interrogation: VT treated with ATP.
September 2016 Admission with palpitations. SMVT on monitoring, responding to lignocaine. Beta-blocker dose increased.
September 2016 Palpitations at home. Three ICD shocks. Subsequent pulseless electrical activity arrest, CPR unsuccessful.
Case 2
May 2015 Initial presentation with syncope: SMVT, requiring direct current cardioversion. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 59%. Dual chamber ICD implantation. AFD confirmed (serum alpha-galactosidase level 0.3 µmol/L/h; P.N215S mutation).
June 2015 Enzyme replacement therapy started.
May 2016 Admission with palpitations and presyncope. Recurrent SMVT observed. Echocardiography: LVEF 45%.
May 2016 Inpatient VT ablation. Discharged 4 days later.
July–August 2018 Admission with heart failure and symptomatic atrial fibrillation (AF). Good response to diuretics. Acutely successful electrical cardioversion for AF.
June 2018 Two episodes of NSVT (each lasting 6–8 s) detected via ICD.
July 2019 Treated for refractory heart failure with palliative intent. No further VT.
September 2019 Died.
Case 3
December 2007 Abnormal preoperative electrocardiogram. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 61%.
February 2012 AFD confirmed (serum alpha-galactosidase level 0.45 µmol/L/h; N215S mutation identified). Enzyme replacement therapy started.
September 2016 Admission with SMVT leading to dual-chamber ICD implantation.
July 2018 Echocardiography: LVEF 35%.
November 2018 Admission following ICD shock delivery. Device interrogation: SMVT.
December 2018 Emergency external direct current cardioversion due to SMVT with hypotension.
December 2018 Acute kidney injury and acute liver injury secondary to VT-associated hypotension.
December 2018 Daily episodes of SMVT, resistant to antiarrhythmic therapy.
December 2018 Radiofrequency ablation of VT.
December 2018 Episodes of SMVT responding to ATP. Escalating doses of furosemide and dobutamine.
December 2018 Worsening heart failure with fluid overload and renal dysfunction. Decision to palliate: ICD therapies deactivated, medical therapy discontinued. Discharged home following day.
January 2019 Died.
Case series
Case 1
This 53-year-old man with a background of well-controlled asthma presented with exertional presyncope. Non-sustained VT (NSVT) was observed. Cardiac magnetic resonance imaging (CMRI) showed left ventricular hypertrophy (LVH) with a septal thickness of 24 mm, thinning of the basal inferolateral left ventricular wall, a left ventricular ejection fraction (LVEF) of 61%, and extensive mid-wall late gadolinium enhancement (LGE) of the mid and distal inferolateral left ventricle (LV) (Figure 1). Coronary angiography excluded obstructive coronary artery disease (CAD). A diagnosis of AFD was confirmed in July 2013 (I117S mutation). Enzyme replacement therapy (ERT) was commenced with intravenous (IV) agalsidase alfa (Replagal), and amiodarone 200 mg daily. A dual-chamber implantable cardioverter-defibrillator (ICD) was implanted. Over the next 18 months, LVEF declined to 35% despite angiotensin-converting enzyme inhibitor and beta blocker therapy. Pacing records showed a ventricular pacing burden of 1–2% during this time.
Figure 1 Cardiac magnetic resonance imaging in the three patients, prior to implantable cardioverter-defibrillator implantation.
Three years later, he had an episode of sustained monomorphic VT (SMVT), converted to sinus rhythm (Figure 2A) with a single ICD shock. He received another shock from his ICD 10 days later. His 12-lead electrocardiogram (ECG) during VT showed a rate of 175 b.p.m., a right bundle branch block (RBBB) pattern, and left-superior axis (Figure 3A). Despite an initial blood pressure (BP) of 65/37 mmHg, he lost cardiac output and required 20 min of cardiopulmonary resuscitation (CPR), with 15 internal and external shocks before return of spontaneous circulation. Despite treatment with IV amiodarone, lignocaine, carvedilol, heavy sedation with intubation and attempts at overdrive pacing, his VT was incessant with persistent hypotension and we proceeded to an emergency electrophysiological study (EPS).
Figure 2 Twelve-lead electrocardiogram during sinus rhythm. Case 1 (A); Case 2 (B); and Case 3 (C).
Figure 3 Twelve-lead electrocardiogram during VT. Case 1 (A): immediately before ventricular tachycardia ablation. Case 2 (B): on admission, 3 days prior to ventricular tachycardia ablation. Case 3 (C): 3 days after admission, shortly before external direct current cardioversion.
The VT terminated during catheter manipulation and was subsequently intermittent. Endocardial mapping of the LV was performed using a decapolar mapping catheter (Inquiry AFocus, EnSite Velocity™, Abbott). Mapping of the left ventricular substrate, activation, late potentials, and pace-mapping revealed areas of interest for ablation at the inferobasal left ventricular endocardium. RFA was performed from the site of earliest activation of VT in the LV forming a line of block from the scar to the mitral value annulus, incorporating the areas of interest (Flexability ablation catheter, 40-W power). Subsequent VT stimulation with three extras was negative. IV amiodarone was continued, and lignocaine stopped.
Three days later, he had recurrent SMVT of same morphology, resistant to re-initiation of lignocaine. A second EPS was performed, this time endocardially and epicardially (110 mm 16G Tuohy needle). Initially, we observed a paced rhythm with frequent monomorphic (right bundle, left superior axis) premature ventricular complexes (PVCs), of similar morphology to the initial VT. Endocardial and epicardial mapping of the PVCs was performed [EnSite Velocity™ Cardiac Mapping System (Abbott) using AFocus™ catheter]. Extensive epicardial scar was noted. The origin of the PVCs corresponded with an island of healthier tissue within scar on the basal epicardial inferoseptal LV. This was targeted with RFA, with abolition of the PVCs. Further VT (right bundle, left superior axis) was induced with right ventricular pacing, but due to haemodynamic instability it was not possible to map. Good pacemapping from an area of late potentials at the epicardial apical inferolateral sites was targeted for ablation. Pace mapping was also performed in the endocardial LV. ‘Good’ sites (11/12 match) were noted at the inferolateral apical LV and ablated. The procedure concluded once no further sites for ablation were identified. No further VT induction was attempted due to the very high risk of precipitating further haemodynamic decompensation.
Shortly after the procedure, he had polymorphic VT requiring ICD therapies, external defibrillation, CPR, dopamine and adrenaline infusions, and intra-aortic balloon pump insertion. Resuscitation was acutely successful and he was transferred to the intensive therapy unit.
Recovery was complicated by a ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. He was discharged 7 weeks after the ablation, requiring a stick to walk. He remained on oral amiodarone. Over the next 2 months, he had VT treated with anti-tachycardia pacing (ATP) and a second episode requiring a short admission for IV lignocaine.
Four months after the ablation procedures, he received three ICD shocks for SMVT, followed by pulseless electrical activity. CPR was unsuccessful.
Case 2
This 67-year-old man presented with presyncope on exercise due to VT, requiring direct current cardioversion (DCCV). CMRI at presentation demonstrated LVH (maximal septal thickness 22 mm), regional thinning and akinesia, LVEF of 59%, and full thickness LGE affecting the basal and mid-chamber inferior, inferolateral and anterolateral segments (Figure 1). A diagnosis of AFD was confirmed (P.N215S mutation), and Replagal started. He had no other past medical history of note, and coronary angiography excluded CAD. A dual chamber ICD was implanted in 2015. Device interrogation found a right ventricular (RV) pacing burden of 2–9%.
A year later, he represented with presyncope. The rhythm was SMVT at a rate of 161 b.p.m. (below the device programmed treatment zone), with RBBB morphology, and superior axis (Figure 3B). BP was 97/51 mmHg. Despite treatment with IV amiodarone, the rate increased and he was cardioverted via his ICD (Figure 2B). His bisoprolol dose was increased and oral amiodarone started. Echocardiography showed an LVEF of 45%. Over the next 3 days, recurrent NSVT without haemodynamic compromise was treated with IV amiodarone, lignocaine, and ATP.
EPS was performed 4 days after admission. Mapping of the LV was performed in sinus rhythm (EnSite Velocity mapping system, AFocus catheter, Abbott). Late potentials were seen in mid-inferolateral, mid-septal, and anteroapical sites. Scar mapping revealed large areas of dense scar in the inferolateral LV and the basal to mid-septal and anteroapical regions. Programmed electrical stimulation in the RV apex and various LV sites (up to three ventricular extrastimuli) did not induce VT. Pace-mapping was best at the mid-apical inferolateral regions. Ablation of the inferolateral, basal to mid-septal and anteroapical LV was undertaken. Shortly after the procedure, he had two episodes of NSVT, but no further episodes whilst an inpatient. He was discharged 4 days later with oral amiodarone and metoprolol. Amiodarone was discontinued in March 2017.
He remained stable for 2 years. Device interrogation between September 2016 and August 2019 demonstrated two episodes of NSVT, each lasting 6–8 s. In July 2018, he was hospitalized for 7 weeks due to decompensated heart failure in atrial fibrillation, responding to diuretics and DCCV. His LVEF had deteriorated to 38% and heart failure continued to progress despite medical treatment. A decision was made to treat this palliatively. He died in September 2019.
Case 3
This 69-year-old man with hypertension had an abnormal routine preoperative ECG (Figure 2C) in 2007 and was diagnosed with hypertrophic cardiomyopathy. CMRI showed asymmetrical LVH (24 mm) and LVEF of 61%. A diagnosis of AFD (N215S mutation) was confirmed in 2012, when ERT was started. An ICD was implanted after an episode of SMVT in 2016. Repeated CMRI revealed deterioration in left ventricular systolic function (LVEF 48%), with diffuse LGE in the basal to mid inferolateral LV ‘LV/RV hinge points’ and the left ventricular anteroseptum and apex (Figure 1). Coronary angiography excluded significant CAD. Echocardiography in July 2018 showed further deterioration in left ventricular systolic function (LVEF 35%), treated with standard heart failure therapy.
He presented in November 2018 after receiving shocks from his ICD. Device interrogation confirmed two episodes of SMVT, failing to respond to ATP, finally treated with shocks. RV pacing burden had been 0–8%, although the basal pacing rate was then increased from 50 to 80 b.p.m., and he was commenced on IV amiodarone. Three days later, an episode of SMVT (Figure 3C) with hypotension prompted emergency external DCCV. Over the next 9 days, he had daily episodes of SMVT, without haemodynamic compromise, responding to ATP. He was treated with IV lignocaine to control the SMVT and milrinone to treat persistent cardiogenic shock. Despite this, he had daily episodes of SMVT requiring ATP. He developed acute kidney and liver injuries, likely due to hypoperfusion during episodes of VT, although amiodarone was discontinued due to possible hepatotoxicity.
Three weeks into the admission, EPS was performed. VT induction was not attempted due to haemodynamic instability. Transseptal puncture and left ventricular mapping was performed during RV pacing, demonstrating extensive apical left ventricular scar (Figure 4). Pacemaps similar to the clinical VT (Figure 5A), and delayed potentials were recorded at the left ventricular apex (Figure 5B). Isolation of the left ventricular apex with loss of local pace capture was achieved with local impedance-guided RFA applications.
Figure 4 Bipolar voltage map and ablation lesions from ventricular tachycardia ablation (Case 3). The low voltage areas observed using conventional voltage criteria corresponded with late Gadolinium-enhanced areas seen with cardiac magnetic resonance (Figure 1, Case 3). There was mid-distal anteroseptal, apical, and posterolateral scar. Substrate-based ablation was performed guided by late potentials and pacemaps. Ventricular tachycardia was not inducible pre- or post-ablation. AP, antero-posterior; Bi, bipolar tissue voltage; Imp, impedance drop observed during radiofrequency ablation; LAO, left anterior oblique; LPO, left posterior oblique view.
Figure 5 Twelve-lead electrocardiogram (A) recorded during left ventricular pacing from an antero-apical site, demonstrating reasonable match with the clinical ventricular tachycardia (Figure 3C). Intracardiac electrograms (B) recorded during right ventricular pacing with the Pentarray (PENT) roving catheter (Biosense Webster) positioned in the left ventricle at the same apical site as the pace map displayed above. Delayed post-QRS potentials are seen in this area (arrows). CS, coronary sinus catheter.
Following EPS, lignocaine and milrinone were stopped. Further episodes of SMVT responding to ATP were observed over the next 3 days, but thereafter no VT was seen. Despite treatment with IV furosemide and dobutamine, he remained in cardiogenic shock. A joint decision was made to deactivate his ICD, discontinue medical therapy, and palliate. He died 11 days later.
Review of literature
Whilst multi-organ involvement is common in AFD, mortality is primarily caused by cardiac disease. A systematic review by Baig et al.8 identified 13 studies on ventricular arrhythmias and sudden cardiac death (SCD) in AFD. In this review, 75% of deaths were due to a cardiovascular condition and 62% of all deaths were reported as SCD events. The average prevalence of VT was reported as 15.3%. Factors associated with SCD included increasing age, LGE on CMRI, and NSVT.
We identified four case reports pertaining to the description of RFA of VT in AFD. Higashi et al.9 described the case of a 67-year-old man with an LVEF of 35% and a left lateral ventricle wall perfusion defect, presenting with VT storm resistant to anti-arrhythmic therapy. Epicardial activation mapping demonstrated a figure-of-eight re-entrant circuit on the lateral left ventricular wall. RFA to this region terminated the VT. Over a 24-month follow-up, recurrence of a non-ablated VT was observed, and the number of ICD shocks for VT decreased. In another study, Nakano et al.10 report on a 51-year-old man with an LVEF of 68%, presenting with SMVT. CMRI demonstrated high T2 signal in the basal epicardium and antero-septal endocardium. The patient underwent RFA of the left ventricular anterior-apical wall, with recurrence of the VT a few days after. A second ablation was performed but did not completely eradicate the VT. The patient was continued on long-term amiodarone and remained alive at 2 years, with no documented VT recurrence. A report by Ellis et al.11 described a 49-year-old man with AFD, LVEF 25–30%, permanent atrial fibrillation and complete heart block (with cardiac resynchronization therapy ICD), presenting with VT storm resistant to anti-arrhythmic therapy. EPS demonstrated a posterolateral site of origin near the mitral annulus, and RFA was performed at this site, with no VT subsequently inducible. Follow-up was limited to 3 months, without VT recurrence. In an abstract by Oder et al.,12 the authors describe the use of RFA in three patients with Fabry disease, two of whom experienced further VT episodes following the procedure and died due to end-stage heart failure.
With regards to guidance on ICD implantation in AFD, evidence is sparse. In a retrospective analysis of patients with AFD,13 several clinical factors were associated with ICD implantation, including increasing age, greater left ventricular mass, greater scar tissue, and larger atrial size. Importantly, only 28% of AFD patients with an ICD in this study had a Class 1 indication for implantation, highlighting the need for AFD-specific research and guidelines.
Discussion
Imaging
CMRI in our cohort showed extensive LGE, which was predominantly inferolateral mid-wall, patchy, extending from base to apex. Whilst the morphology of the VT on the 12-lead ECGs was variable, it did correspond with observed areas of LGE. In Case 1, an inferior basal septum origin, in Case 2, a lateral mid-chamber origin, and in Case 3, an apical wall origin.
All our patients had relatively stable slow SMVT (Figure 2) with rates between 150 and 180 min−1 and in one case the QRS had delayed intrinsicoid deflection, suggestive of epicardial breakout.
Ablation strategy
In our series, the mechanism of VT was re-entry around areas of fibrosis, and traditional principles for VT ablation were deemed appropriate. The substrate is transmural and the critical isthmus may be found endocardially but can be present anywhere within the myocardium. Despite extensive myocardial fibrosis in our cases, left ventricular walls remained hypertrophied. Accordingly, ablated areas were frequently in thickened myocardium, likely to hinder lesion transmurality. These factors suggest that a combined endocardial/epicardial approach may be helpful, although an endocardial-only approach was used in our most successful case who survived beyond three years.
In two of our cases, VT was not inducible at the end of the procedure (in the third, VT induction was not attempted due to haemodynamic instability). Therefore, inducibility does not appear to be a reliable marker of subsequent VT risk, so comprehensive treatment may involve complete substrate modification where possible.
Left ventricular function
Our experience suggests that VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction (LVSD) and extensive LGE are present. At the start of our case series, all patients had preserved LVEF, which later deteriorated after ICD implantation. Two had severe LVSD at the time of ablation; Case 1 who died 4 months following VT ablation, and Case 3 who died 2 weeks after. In contrast, Case 2 had moderate LVSD at the time of ablation, and survived more than 3 years following the procedure, although it must be acknowledged that prior to EPS, the patient had been stabilized on amiodarone which was continued for 10 months following the procedure. In our experience of over 175 patients with cardiac AFD, it appears that VT electrical storm in AFD patients is a marker of end-stage disease.
Conclusion
AFD can present with VT consistent with a re-entry mechanism. In our series of three patients with VT storm refractory to medical therapy, extensive infiltration and/or scar was demonstrated by LGE. Endocardial ± epicardial mapping demonstrated the arrhythmic substrate. However, RFA did not result in a significant prognostic benefit in two out of the three patients. In patients with AFD, VT storm is therefore likely a sign of end-stage disease.
Lead author biography
Dr Mark T. Mills is an academic clinical fellow and cardiology registrar in South Yorkshire, UK. He began his undergraduate training at the University of Sheffield, graduating with Honours in 2015. He subsequently completed a Masters in Cardiovascular Research at King’s College London. His research interests include cardiac electrophysiology, coronary physiology, and the impact of cardiac rhythm disturbance on coronary haemodynamics.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa529_Supplementary_Data Click here for additional data file.
Acknowledgements
We would like to thank Stacey Bates, cardiac physiologist at the Northern General Hospital, for her help during the electrophysiology studies and in preparing the figures for this case series.
Slide sets: A fully edited slide set detailing this case 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 image(s) and associated text has been obtained from the patients in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33569526 | 20,807,708 | 2021-02 |
What was the administration route of drug 'CARVEDILOL'? | Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.
Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited.
We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure.
RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.
Learning points
Ventricular tachycardia (VT) storm in Anderson–Fabry disease (AFD) is due to re-entry around areas of fibrosis, and traditional principles for VT ablation can be used to acutely terminate the arrhythmia.
VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction and extensive late gadolinium enhancement are present.
Introduction
Anderson–Fabry disease (AFD) is a rare, X-linked storage disorder caused by deficiency of the enzyme α-galactosidase A resulting in accumulation of globotriaosylceramide in organs including the heart, kidneys, and nervous system.1 Lipid deposition, inflammation and fibrosis within the myocardial interstitium causes infiltrative hypertrophic cardiomyopathy and cardiac conduction tissue disease.2 The commonest arrhythmias in AFD are atrial fibrillation3,4 and ventricular tachycardia (VT).5–7 Here, we review the literature and report our experience of radiofrequency ablation (RFA) in three patients with AFD and drug-refractory VT.
Timeline
Case 1
May 2013 Initial presentation with presyncope. Monitoring: non-sustained ventricular tachycardia (NSVT). Cardiac magnetic resonance imaging (CMRI): left ventricular hypertrophy, left ventricular ejection fraction (LVEF) 61%.
July 2013 Anderson–Fabry disease (AFD) confirmed (serum alpha-galactosidase level 0.2 µmol/L/h; I117S mutation later identified). Enzyme replacement therapy started.
October 2013 Elective dual chamber implantable cardioverter-defibrillator (ICD) implantation.
September 2014 Echocardiography: LVEF 51%.
December 2015 Echocardiography: LVEF 35%.
May 2016 Admission following ICD shock delivery for sustained monomorphic ventricular tachycardia (SMVT). ICD reprogrammed.
May 2016 Further ICD therapy. SMVT and hypotension on admission. In-hospital cardiac arrest requiring cardiopulmonary resuscitation (CPR) with return of spontaneous circulation. Incessant ventricular tachycardia (VT) despite antiarrhythmics, overdrive pacing and anti-tachycardia pacing (ATP). Emergency radiofrequency VT ablation.
May 2016 Recurrent SMVT resistant to medical therapy. Second VT ablation. Polymorphic VT following ablation, requiring CPR and re-intubation.
May–July 2016 Recovery complicated by ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. Successfully rehabilitated and discharged 7 weeks after the second ablation.
August 2016 Palpitations at home. Device interrogation: VT treated with ATP.
September 2016 Admission with palpitations. SMVT on monitoring, responding to lignocaine. Beta-blocker dose increased.
September 2016 Palpitations at home. Three ICD shocks. Subsequent pulseless electrical activity arrest, CPR unsuccessful.
Case 2
May 2015 Initial presentation with syncope: SMVT, requiring direct current cardioversion. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 59%. Dual chamber ICD implantation. AFD confirmed (serum alpha-galactosidase level 0.3 µmol/L/h; P.N215S mutation).
June 2015 Enzyme replacement therapy started.
May 2016 Admission with palpitations and presyncope. Recurrent SMVT observed. Echocardiography: LVEF 45%.
May 2016 Inpatient VT ablation. Discharged 4 days later.
July–August 2018 Admission with heart failure and symptomatic atrial fibrillation (AF). Good response to diuretics. Acutely successful electrical cardioversion for AF.
June 2018 Two episodes of NSVT (each lasting 6–8 s) detected via ICD.
July 2019 Treated for refractory heart failure with palliative intent. No further VT.
September 2019 Died.
Case 3
December 2007 Abnormal preoperative electrocardiogram. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 61%.
February 2012 AFD confirmed (serum alpha-galactosidase level 0.45 µmol/L/h; N215S mutation identified). Enzyme replacement therapy started.
September 2016 Admission with SMVT leading to dual-chamber ICD implantation.
July 2018 Echocardiography: LVEF 35%.
November 2018 Admission following ICD shock delivery. Device interrogation: SMVT.
December 2018 Emergency external direct current cardioversion due to SMVT with hypotension.
December 2018 Acute kidney injury and acute liver injury secondary to VT-associated hypotension.
December 2018 Daily episodes of SMVT, resistant to antiarrhythmic therapy.
December 2018 Radiofrequency ablation of VT.
December 2018 Episodes of SMVT responding to ATP. Escalating doses of furosemide and dobutamine.
December 2018 Worsening heart failure with fluid overload and renal dysfunction. Decision to palliate: ICD therapies deactivated, medical therapy discontinued. Discharged home following day.
January 2019 Died.
Case series
Case 1
This 53-year-old man with a background of well-controlled asthma presented with exertional presyncope. Non-sustained VT (NSVT) was observed. Cardiac magnetic resonance imaging (CMRI) showed left ventricular hypertrophy (LVH) with a septal thickness of 24 mm, thinning of the basal inferolateral left ventricular wall, a left ventricular ejection fraction (LVEF) of 61%, and extensive mid-wall late gadolinium enhancement (LGE) of the mid and distal inferolateral left ventricle (LV) (Figure 1). Coronary angiography excluded obstructive coronary artery disease (CAD). A diagnosis of AFD was confirmed in July 2013 (I117S mutation). Enzyme replacement therapy (ERT) was commenced with intravenous (IV) agalsidase alfa (Replagal), and amiodarone 200 mg daily. A dual-chamber implantable cardioverter-defibrillator (ICD) was implanted. Over the next 18 months, LVEF declined to 35% despite angiotensin-converting enzyme inhibitor and beta blocker therapy. Pacing records showed a ventricular pacing burden of 1–2% during this time.
Figure 1 Cardiac magnetic resonance imaging in the three patients, prior to implantable cardioverter-defibrillator implantation.
Three years later, he had an episode of sustained monomorphic VT (SMVT), converted to sinus rhythm (Figure 2A) with a single ICD shock. He received another shock from his ICD 10 days later. His 12-lead electrocardiogram (ECG) during VT showed a rate of 175 b.p.m., a right bundle branch block (RBBB) pattern, and left-superior axis (Figure 3A). Despite an initial blood pressure (BP) of 65/37 mmHg, he lost cardiac output and required 20 min of cardiopulmonary resuscitation (CPR), with 15 internal and external shocks before return of spontaneous circulation. Despite treatment with IV amiodarone, lignocaine, carvedilol, heavy sedation with intubation and attempts at overdrive pacing, his VT was incessant with persistent hypotension and we proceeded to an emergency electrophysiological study (EPS).
Figure 2 Twelve-lead electrocardiogram during sinus rhythm. Case 1 (A); Case 2 (B); and Case 3 (C).
Figure 3 Twelve-lead electrocardiogram during VT. Case 1 (A): immediately before ventricular tachycardia ablation. Case 2 (B): on admission, 3 days prior to ventricular tachycardia ablation. Case 3 (C): 3 days after admission, shortly before external direct current cardioversion.
The VT terminated during catheter manipulation and was subsequently intermittent. Endocardial mapping of the LV was performed using a decapolar mapping catheter (Inquiry AFocus, EnSite Velocity™, Abbott). Mapping of the left ventricular substrate, activation, late potentials, and pace-mapping revealed areas of interest for ablation at the inferobasal left ventricular endocardium. RFA was performed from the site of earliest activation of VT in the LV forming a line of block from the scar to the mitral value annulus, incorporating the areas of interest (Flexability ablation catheter, 40-W power). Subsequent VT stimulation with three extras was negative. IV amiodarone was continued, and lignocaine stopped.
Three days later, he had recurrent SMVT of same morphology, resistant to re-initiation of lignocaine. A second EPS was performed, this time endocardially and epicardially (110 mm 16G Tuohy needle). Initially, we observed a paced rhythm with frequent monomorphic (right bundle, left superior axis) premature ventricular complexes (PVCs), of similar morphology to the initial VT. Endocardial and epicardial mapping of the PVCs was performed [EnSite Velocity™ Cardiac Mapping System (Abbott) using AFocus™ catheter]. Extensive epicardial scar was noted. The origin of the PVCs corresponded with an island of healthier tissue within scar on the basal epicardial inferoseptal LV. This was targeted with RFA, with abolition of the PVCs. Further VT (right bundle, left superior axis) was induced with right ventricular pacing, but due to haemodynamic instability it was not possible to map. Good pacemapping from an area of late potentials at the epicardial apical inferolateral sites was targeted for ablation. Pace mapping was also performed in the endocardial LV. ‘Good’ sites (11/12 match) were noted at the inferolateral apical LV and ablated. The procedure concluded once no further sites for ablation were identified. No further VT induction was attempted due to the very high risk of precipitating further haemodynamic decompensation.
Shortly after the procedure, he had polymorphic VT requiring ICD therapies, external defibrillation, CPR, dopamine and adrenaline infusions, and intra-aortic balloon pump insertion. Resuscitation was acutely successful and he was transferred to the intensive therapy unit.
Recovery was complicated by a ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. He was discharged 7 weeks after the ablation, requiring a stick to walk. He remained on oral amiodarone. Over the next 2 months, he had VT treated with anti-tachycardia pacing (ATP) and a second episode requiring a short admission for IV lignocaine.
Four months after the ablation procedures, he received three ICD shocks for SMVT, followed by pulseless electrical activity. CPR was unsuccessful.
Case 2
This 67-year-old man presented with presyncope on exercise due to VT, requiring direct current cardioversion (DCCV). CMRI at presentation demonstrated LVH (maximal septal thickness 22 mm), regional thinning and akinesia, LVEF of 59%, and full thickness LGE affecting the basal and mid-chamber inferior, inferolateral and anterolateral segments (Figure 1). A diagnosis of AFD was confirmed (P.N215S mutation), and Replagal started. He had no other past medical history of note, and coronary angiography excluded CAD. A dual chamber ICD was implanted in 2015. Device interrogation found a right ventricular (RV) pacing burden of 2–9%.
A year later, he represented with presyncope. The rhythm was SMVT at a rate of 161 b.p.m. (below the device programmed treatment zone), with RBBB morphology, and superior axis (Figure 3B). BP was 97/51 mmHg. Despite treatment with IV amiodarone, the rate increased and he was cardioverted via his ICD (Figure 2B). His bisoprolol dose was increased and oral amiodarone started. Echocardiography showed an LVEF of 45%. Over the next 3 days, recurrent NSVT without haemodynamic compromise was treated with IV amiodarone, lignocaine, and ATP.
EPS was performed 4 days after admission. Mapping of the LV was performed in sinus rhythm (EnSite Velocity mapping system, AFocus catheter, Abbott). Late potentials were seen in mid-inferolateral, mid-septal, and anteroapical sites. Scar mapping revealed large areas of dense scar in the inferolateral LV and the basal to mid-septal and anteroapical regions. Programmed electrical stimulation in the RV apex and various LV sites (up to three ventricular extrastimuli) did not induce VT. Pace-mapping was best at the mid-apical inferolateral regions. Ablation of the inferolateral, basal to mid-septal and anteroapical LV was undertaken. Shortly after the procedure, he had two episodes of NSVT, but no further episodes whilst an inpatient. He was discharged 4 days later with oral amiodarone and metoprolol. Amiodarone was discontinued in March 2017.
He remained stable for 2 years. Device interrogation between September 2016 and August 2019 demonstrated two episodes of NSVT, each lasting 6–8 s. In July 2018, he was hospitalized for 7 weeks due to decompensated heart failure in atrial fibrillation, responding to diuretics and DCCV. His LVEF had deteriorated to 38% and heart failure continued to progress despite medical treatment. A decision was made to treat this palliatively. He died in September 2019.
Case 3
This 69-year-old man with hypertension had an abnormal routine preoperative ECG (Figure 2C) in 2007 and was diagnosed with hypertrophic cardiomyopathy. CMRI showed asymmetrical LVH (24 mm) and LVEF of 61%. A diagnosis of AFD (N215S mutation) was confirmed in 2012, when ERT was started. An ICD was implanted after an episode of SMVT in 2016. Repeated CMRI revealed deterioration in left ventricular systolic function (LVEF 48%), with diffuse LGE in the basal to mid inferolateral LV ‘LV/RV hinge points’ and the left ventricular anteroseptum and apex (Figure 1). Coronary angiography excluded significant CAD. Echocardiography in July 2018 showed further deterioration in left ventricular systolic function (LVEF 35%), treated with standard heart failure therapy.
He presented in November 2018 after receiving shocks from his ICD. Device interrogation confirmed two episodes of SMVT, failing to respond to ATP, finally treated with shocks. RV pacing burden had been 0–8%, although the basal pacing rate was then increased from 50 to 80 b.p.m., and he was commenced on IV amiodarone. Three days later, an episode of SMVT (Figure 3C) with hypotension prompted emergency external DCCV. Over the next 9 days, he had daily episodes of SMVT, without haemodynamic compromise, responding to ATP. He was treated with IV lignocaine to control the SMVT and milrinone to treat persistent cardiogenic shock. Despite this, he had daily episodes of SMVT requiring ATP. He developed acute kidney and liver injuries, likely due to hypoperfusion during episodes of VT, although amiodarone was discontinued due to possible hepatotoxicity.
Three weeks into the admission, EPS was performed. VT induction was not attempted due to haemodynamic instability. Transseptal puncture and left ventricular mapping was performed during RV pacing, demonstrating extensive apical left ventricular scar (Figure 4). Pacemaps similar to the clinical VT (Figure 5A), and delayed potentials were recorded at the left ventricular apex (Figure 5B). Isolation of the left ventricular apex with loss of local pace capture was achieved with local impedance-guided RFA applications.
Figure 4 Bipolar voltage map and ablation lesions from ventricular tachycardia ablation (Case 3). The low voltage areas observed using conventional voltage criteria corresponded with late Gadolinium-enhanced areas seen with cardiac magnetic resonance (Figure 1, Case 3). There was mid-distal anteroseptal, apical, and posterolateral scar. Substrate-based ablation was performed guided by late potentials and pacemaps. Ventricular tachycardia was not inducible pre- or post-ablation. AP, antero-posterior; Bi, bipolar tissue voltage; Imp, impedance drop observed during radiofrequency ablation; LAO, left anterior oblique; LPO, left posterior oblique view.
Figure 5 Twelve-lead electrocardiogram (A) recorded during left ventricular pacing from an antero-apical site, demonstrating reasonable match with the clinical ventricular tachycardia (Figure 3C). Intracardiac electrograms (B) recorded during right ventricular pacing with the Pentarray (PENT) roving catheter (Biosense Webster) positioned in the left ventricle at the same apical site as the pace map displayed above. Delayed post-QRS potentials are seen in this area (arrows). CS, coronary sinus catheter.
Following EPS, lignocaine and milrinone were stopped. Further episodes of SMVT responding to ATP were observed over the next 3 days, but thereafter no VT was seen. Despite treatment with IV furosemide and dobutamine, he remained in cardiogenic shock. A joint decision was made to deactivate his ICD, discontinue medical therapy, and palliate. He died 11 days later.
Review of literature
Whilst multi-organ involvement is common in AFD, mortality is primarily caused by cardiac disease. A systematic review by Baig et al.8 identified 13 studies on ventricular arrhythmias and sudden cardiac death (SCD) in AFD. In this review, 75% of deaths were due to a cardiovascular condition and 62% of all deaths were reported as SCD events. The average prevalence of VT was reported as 15.3%. Factors associated with SCD included increasing age, LGE on CMRI, and NSVT.
We identified four case reports pertaining to the description of RFA of VT in AFD. Higashi et al.9 described the case of a 67-year-old man with an LVEF of 35% and a left lateral ventricle wall perfusion defect, presenting with VT storm resistant to anti-arrhythmic therapy. Epicardial activation mapping demonstrated a figure-of-eight re-entrant circuit on the lateral left ventricular wall. RFA to this region terminated the VT. Over a 24-month follow-up, recurrence of a non-ablated VT was observed, and the number of ICD shocks for VT decreased. In another study, Nakano et al.10 report on a 51-year-old man with an LVEF of 68%, presenting with SMVT. CMRI demonstrated high T2 signal in the basal epicardium and antero-septal endocardium. The patient underwent RFA of the left ventricular anterior-apical wall, with recurrence of the VT a few days after. A second ablation was performed but did not completely eradicate the VT. The patient was continued on long-term amiodarone and remained alive at 2 years, with no documented VT recurrence. A report by Ellis et al.11 described a 49-year-old man with AFD, LVEF 25–30%, permanent atrial fibrillation and complete heart block (with cardiac resynchronization therapy ICD), presenting with VT storm resistant to anti-arrhythmic therapy. EPS demonstrated a posterolateral site of origin near the mitral annulus, and RFA was performed at this site, with no VT subsequently inducible. Follow-up was limited to 3 months, without VT recurrence. In an abstract by Oder et al.,12 the authors describe the use of RFA in three patients with Fabry disease, two of whom experienced further VT episodes following the procedure and died due to end-stage heart failure.
With regards to guidance on ICD implantation in AFD, evidence is sparse. In a retrospective analysis of patients with AFD,13 several clinical factors were associated with ICD implantation, including increasing age, greater left ventricular mass, greater scar tissue, and larger atrial size. Importantly, only 28% of AFD patients with an ICD in this study had a Class 1 indication for implantation, highlighting the need for AFD-specific research and guidelines.
Discussion
Imaging
CMRI in our cohort showed extensive LGE, which was predominantly inferolateral mid-wall, patchy, extending from base to apex. Whilst the morphology of the VT on the 12-lead ECGs was variable, it did correspond with observed areas of LGE. In Case 1, an inferior basal septum origin, in Case 2, a lateral mid-chamber origin, and in Case 3, an apical wall origin.
All our patients had relatively stable slow SMVT (Figure 2) with rates between 150 and 180 min−1 and in one case the QRS had delayed intrinsicoid deflection, suggestive of epicardial breakout.
Ablation strategy
In our series, the mechanism of VT was re-entry around areas of fibrosis, and traditional principles for VT ablation were deemed appropriate. The substrate is transmural and the critical isthmus may be found endocardially but can be present anywhere within the myocardium. Despite extensive myocardial fibrosis in our cases, left ventricular walls remained hypertrophied. Accordingly, ablated areas were frequently in thickened myocardium, likely to hinder lesion transmurality. These factors suggest that a combined endocardial/epicardial approach may be helpful, although an endocardial-only approach was used in our most successful case who survived beyond three years.
In two of our cases, VT was not inducible at the end of the procedure (in the third, VT induction was not attempted due to haemodynamic instability). Therefore, inducibility does not appear to be a reliable marker of subsequent VT risk, so comprehensive treatment may involve complete substrate modification where possible.
Left ventricular function
Our experience suggests that VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction (LVSD) and extensive LGE are present. At the start of our case series, all patients had preserved LVEF, which later deteriorated after ICD implantation. Two had severe LVSD at the time of ablation; Case 1 who died 4 months following VT ablation, and Case 3 who died 2 weeks after. In contrast, Case 2 had moderate LVSD at the time of ablation, and survived more than 3 years following the procedure, although it must be acknowledged that prior to EPS, the patient had been stabilized on amiodarone which was continued for 10 months following the procedure. In our experience of over 175 patients with cardiac AFD, it appears that VT electrical storm in AFD patients is a marker of end-stage disease.
Conclusion
AFD can present with VT consistent with a re-entry mechanism. In our series of three patients with VT storm refractory to medical therapy, extensive infiltration and/or scar was demonstrated by LGE. Endocardial ± epicardial mapping demonstrated the arrhythmic substrate. However, RFA did not result in a significant prognostic benefit in two out of the three patients. In patients with AFD, VT storm is therefore likely a sign of end-stage disease.
Lead author biography
Dr Mark T. Mills is an academic clinical fellow and cardiology registrar in South Yorkshire, UK. He began his undergraduate training at the University of Sheffield, graduating with Honours in 2015. He subsequently completed a Masters in Cardiovascular Research at King’s College London. His research interests include cardiac electrophysiology, coronary physiology, and the impact of cardiac rhythm disturbance on coronary haemodynamics.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa529_Supplementary_Data Click here for additional data file.
Acknowledgements
We would like to thank Stacey Bates, cardiac physiologist at the Northern General Hospital, for her help during the electrophysiology studies and in preparing the figures for this case series.
Slide sets: A fully edited slide set detailing this case 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 image(s) and associated text has been obtained from the patients in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33569526 | 20,807,708 | 2021-02 |
What was the administration route of drug 'LIDOCAINE HYDROCHLORIDE'? | Radiofrequency ablation of ventricular tachycardia in Anderson-Fabry disease: a case series.
Cardiac involvement in Anderson-Fabry disease (AFD) can lead to arrhythmia, including ventricular tachycardia (VT). The literature on radiofrequency ablation (RFA) for the treatment of VT in AFD disease is limited.
We discuss RFA of drug-refractory VT electrical storm in three males with AFD. The first patient (53 years old) had extensive involvement of the inferolateral left ventricle (LV) demonstrated with cardiac magnetic resonance imaging (CMRI), with a left ventricular ejection fraction (LVEF) of 35%. Two VT ablation procedures were performed. At the first procedure, the inferobasal endocardial LV was ablated. Furthermore, VT prompted a second ablation, where epicardial and endocardial sites were ablated. The acute arrhythmia burden was controlled but he died 4 months later despite appropriate implantable cardioverter-defibrillator therapies for VT. The second patient (67 years old) had full-thickness inferolateral involvement demonstrated with CMRI and LVEF of 45%. RFA of several endocardial left ventricular sites was performed. Over a 3-year follow-up, only brief non-sustained VT was identified, but he subsequently died of cardiac failure. Our third patient (69 years old), had an LVEF of 35%. He had RFA of endocardial left ventricular apical disease, but died 3 weeks later of cardiac failure.
RFA of drug-refractory VT in AFD is feasible using standard electrophysiological mapping and ablation techniques, although the added clinical benefit is of questionable value. VT storm in the context of AFD may be a marker of end-stage disease.
Learning points
Ventricular tachycardia (VT) storm in Anderson–Fabry disease (AFD) is due to re-entry around areas of fibrosis, and traditional principles for VT ablation can be used to acutely terminate the arrhythmia.
VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction and extensive late gadolinium enhancement are present.
Introduction
Anderson–Fabry disease (AFD) is a rare, X-linked storage disorder caused by deficiency of the enzyme α-galactosidase A resulting in accumulation of globotriaosylceramide in organs including the heart, kidneys, and nervous system.1 Lipid deposition, inflammation and fibrosis within the myocardial interstitium causes infiltrative hypertrophic cardiomyopathy and cardiac conduction tissue disease.2 The commonest arrhythmias in AFD are atrial fibrillation3,4 and ventricular tachycardia (VT).5–7 Here, we review the literature and report our experience of radiofrequency ablation (RFA) in three patients with AFD and drug-refractory VT.
Timeline
Case 1
May 2013 Initial presentation with presyncope. Monitoring: non-sustained ventricular tachycardia (NSVT). Cardiac magnetic resonance imaging (CMRI): left ventricular hypertrophy, left ventricular ejection fraction (LVEF) 61%.
July 2013 Anderson–Fabry disease (AFD) confirmed (serum alpha-galactosidase level 0.2 µmol/L/h; I117S mutation later identified). Enzyme replacement therapy started.
October 2013 Elective dual chamber implantable cardioverter-defibrillator (ICD) implantation.
September 2014 Echocardiography: LVEF 51%.
December 2015 Echocardiography: LVEF 35%.
May 2016 Admission following ICD shock delivery for sustained monomorphic ventricular tachycardia (SMVT). ICD reprogrammed.
May 2016 Further ICD therapy. SMVT and hypotension on admission. In-hospital cardiac arrest requiring cardiopulmonary resuscitation (CPR) with return of spontaneous circulation. Incessant ventricular tachycardia (VT) despite antiarrhythmics, overdrive pacing and anti-tachycardia pacing (ATP). Emergency radiofrequency VT ablation.
May 2016 Recurrent SMVT resistant to medical therapy. Second VT ablation. Polymorphic VT following ablation, requiring CPR and re-intubation.
May–July 2016 Recovery complicated by ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. Successfully rehabilitated and discharged 7 weeks after the second ablation.
August 2016 Palpitations at home. Device interrogation: VT treated with ATP.
September 2016 Admission with palpitations. SMVT on monitoring, responding to lignocaine. Beta-blocker dose increased.
September 2016 Palpitations at home. Three ICD shocks. Subsequent pulseless electrical activity arrest, CPR unsuccessful.
Case 2
May 2015 Initial presentation with syncope: SMVT, requiring direct current cardioversion. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 59%. Dual chamber ICD implantation. AFD confirmed (serum alpha-galactosidase level 0.3 µmol/L/h; P.N215S mutation).
June 2015 Enzyme replacement therapy started.
May 2016 Admission with palpitations and presyncope. Recurrent SMVT observed. Echocardiography: LVEF 45%.
May 2016 Inpatient VT ablation. Discharged 4 days later.
July–August 2018 Admission with heart failure and symptomatic atrial fibrillation (AF). Good response to diuretics. Acutely successful electrical cardioversion for AF.
June 2018 Two episodes of NSVT (each lasting 6–8 s) detected via ICD.
July 2019 Treated for refractory heart failure with palliative intent. No further VT.
September 2019 Died.
Case 3
December 2007 Abnormal preoperative electrocardiogram. Hypertrophic cardiomyopathy diagnosed on CMRI. LVEF 61%.
February 2012 AFD confirmed (serum alpha-galactosidase level 0.45 µmol/L/h; N215S mutation identified). Enzyme replacement therapy started.
September 2016 Admission with SMVT leading to dual-chamber ICD implantation.
July 2018 Echocardiography: LVEF 35%.
November 2018 Admission following ICD shock delivery. Device interrogation: SMVT.
December 2018 Emergency external direct current cardioversion due to SMVT with hypotension.
December 2018 Acute kidney injury and acute liver injury secondary to VT-associated hypotension.
December 2018 Daily episodes of SMVT, resistant to antiarrhythmic therapy.
December 2018 Radiofrequency ablation of VT.
December 2018 Episodes of SMVT responding to ATP. Escalating doses of furosemide and dobutamine.
December 2018 Worsening heart failure with fluid overload and renal dysfunction. Decision to palliate: ICD therapies deactivated, medical therapy discontinued. Discharged home following day.
January 2019 Died.
Case series
Case 1
This 53-year-old man with a background of well-controlled asthma presented with exertional presyncope. Non-sustained VT (NSVT) was observed. Cardiac magnetic resonance imaging (CMRI) showed left ventricular hypertrophy (LVH) with a septal thickness of 24 mm, thinning of the basal inferolateral left ventricular wall, a left ventricular ejection fraction (LVEF) of 61%, and extensive mid-wall late gadolinium enhancement (LGE) of the mid and distal inferolateral left ventricle (LV) (Figure 1). Coronary angiography excluded obstructive coronary artery disease (CAD). A diagnosis of AFD was confirmed in July 2013 (I117S mutation). Enzyme replacement therapy (ERT) was commenced with intravenous (IV) agalsidase alfa (Replagal), and amiodarone 200 mg daily. A dual-chamber implantable cardioverter-defibrillator (ICD) was implanted. Over the next 18 months, LVEF declined to 35% despite angiotensin-converting enzyme inhibitor and beta blocker therapy. Pacing records showed a ventricular pacing burden of 1–2% during this time.
Figure 1 Cardiac magnetic resonance imaging in the three patients, prior to implantable cardioverter-defibrillator implantation.
Three years later, he had an episode of sustained monomorphic VT (SMVT), converted to sinus rhythm (Figure 2A) with a single ICD shock. He received another shock from his ICD 10 days later. His 12-lead electrocardiogram (ECG) during VT showed a rate of 175 b.p.m., a right bundle branch block (RBBB) pattern, and left-superior axis (Figure 3A). Despite an initial blood pressure (BP) of 65/37 mmHg, he lost cardiac output and required 20 min of cardiopulmonary resuscitation (CPR), with 15 internal and external shocks before return of spontaneous circulation. Despite treatment with IV amiodarone, lignocaine, carvedilol, heavy sedation with intubation and attempts at overdrive pacing, his VT was incessant with persistent hypotension and we proceeded to an emergency electrophysiological study (EPS).
Figure 2 Twelve-lead electrocardiogram during sinus rhythm. Case 1 (A); Case 2 (B); and Case 3 (C).
Figure 3 Twelve-lead electrocardiogram during VT. Case 1 (A): immediately before ventricular tachycardia ablation. Case 2 (B): on admission, 3 days prior to ventricular tachycardia ablation. Case 3 (C): 3 days after admission, shortly before external direct current cardioversion.
The VT terminated during catheter manipulation and was subsequently intermittent. Endocardial mapping of the LV was performed using a decapolar mapping catheter (Inquiry AFocus, EnSite Velocity™, Abbott). Mapping of the left ventricular substrate, activation, late potentials, and pace-mapping revealed areas of interest for ablation at the inferobasal left ventricular endocardium. RFA was performed from the site of earliest activation of VT in the LV forming a line of block from the scar to the mitral value annulus, incorporating the areas of interest (Flexability ablation catheter, 40-W power). Subsequent VT stimulation with three extras was negative. IV amiodarone was continued, and lignocaine stopped.
Three days later, he had recurrent SMVT of same morphology, resistant to re-initiation of lignocaine. A second EPS was performed, this time endocardially and epicardially (110 mm 16G Tuohy needle). Initially, we observed a paced rhythm with frequent monomorphic (right bundle, left superior axis) premature ventricular complexes (PVCs), of similar morphology to the initial VT. Endocardial and epicardial mapping of the PVCs was performed [EnSite Velocity™ Cardiac Mapping System (Abbott) using AFocus™ catheter]. Extensive epicardial scar was noted. The origin of the PVCs corresponded with an island of healthier tissue within scar on the basal epicardial inferoseptal LV. This was targeted with RFA, with abolition of the PVCs. Further VT (right bundle, left superior axis) was induced with right ventricular pacing, but due to haemodynamic instability it was not possible to map. Good pacemapping from an area of late potentials at the epicardial apical inferolateral sites was targeted for ablation. Pace mapping was also performed in the endocardial LV. ‘Good’ sites (11/12 match) were noted at the inferolateral apical LV and ablated. The procedure concluded once no further sites for ablation were identified. No further VT induction was attempted due to the very high risk of precipitating further haemodynamic decompensation.
Shortly after the procedure, he had polymorphic VT requiring ICD therapies, external defibrillation, CPR, dopamine and adrenaline infusions, and intra-aortic balloon pump insertion. Resuscitation was acutely successful and he was transferred to the intensive therapy unit.
Recovery was complicated by a ventilator-associated pneumonia, prolonged mechanical ventilation (21 days) and a stroke. He was discharged 7 weeks after the ablation, requiring a stick to walk. He remained on oral amiodarone. Over the next 2 months, he had VT treated with anti-tachycardia pacing (ATP) and a second episode requiring a short admission for IV lignocaine.
Four months after the ablation procedures, he received three ICD shocks for SMVT, followed by pulseless electrical activity. CPR was unsuccessful.
Case 2
This 67-year-old man presented with presyncope on exercise due to VT, requiring direct current cardioversion (DCCV). CMRI at presentation demonstrated LVH (maximal septal thickness 22 mm), regional thinning and akinesia, LVEF of 59%, and full thickness LGE affecting the basal and mid-chamber inferior, inferolateral and anterolateral segments (Figure 1). A diagnosis of AFD was confirmed (P.N215S mutation), and Replagal started. He had no other past medical history of note, and coronary angiography excluded CAD. A dual chamber ICD was implanted in 2015. Device interrogation found a right ventricular (RV) pacing burden of 2–9%.
A year later, he represented with presyncope. The rhythm was SMVT at a rate of 161 b.p.m. (below the device programmed treatment zone), with RBBB morphology, and superior axis (Figure 3B). BP was 97/51 mmHg. Despite treatment with IV amiodarone, the rate increased and he was cardioverted via his ICD (Figure 2B). His bisoprolol dose was increased and oral amiodarone started. Echocardiography showed an LVEF of 45%. Over the next 3 days, recurrent NSVT without haemodynamic compromise was treated with IV amiodarone, lignocaine, and ATP.
EPS was performed 4 days after admission. Mapping of the LV was performed in sinus rhythm (EnSite Velocity mapping system, AFocus catheter, Abbott). Late potentials were seen in mid-inferolateral, mid-septal, and anteroapical sites. Scar mapping revealed large areas of dense scar in the inferolateral LV and the basal to mid-septal and anteroapical regions. Programmed electrical stimulation in the RV apex and various LV sites (up to three ventricular extrastimuli) did not induce VT. Pace-mapping was best at the mid-apical inferolateral regions. Ablation of the inferolateral, basal to mid-septal and anteroapical LV was undertaken. Shortly after the procedure, he had two episodes of NSVT, but no further episodes whilst an inpatient. He was discharged 4 days later with oral amiodarone and metoprolol. Amiodarone was discontinued in March 2017.
He remained stable for 2 years. Device interrogation between September 2016 and August 2019 demonstrated two episodes of NSVT, each lasting 6–8 s. In July 2018, he was hospitalized for 7 weeks due to decompensated heart failure in atrial fibrillation, responding to diuretics and DCCV. His LVEF had deteriorated to 38% and heart failure continued to progress despite medical treatment. A decision was made to treat this palliatively. He died in September 2019.
Case 3
This 69-year-old man with hypertension had an abnormal routine preoperative ECG (Figure 2C) in 2007 and was diagnosed with hypertrophic cardiomyopathy. CMRI showed asymmetrical LVH (24 mm) and LVEF of 61%. A diagnosis of AFD (N215S mutation) was confirmed in 2012, when ERT was started. An ICD was implanted after an episode of SMVT in 2016. Repeated CMRI revealed deterioration in left ventricular systolic function (LVEF 48%), with diffuse LGE in the basal to mid inferolateral LV ‘LV/RV hinge points’ and the left ventricular anteroseptum and apex (Figure 1). Coronary angiography excluded significant CAD. Echocardiography in July 2018 showed further deterioration in left ventricular systolic function (LVEF 35%), treated with standard heart failure therapy.
He presented in November 2018 after receiving shocks from his ICD. Device interrogation confirmed two episodes of SMVT, failing to respond to ATP, finally treated with shocks. RV pacing burden had been 0–8%, although the basal pacing rate was then increased from 50 to 80 b.p.m., and he was commenced on IV amiodarone. Three days later, an episode of SMVT (Figure 3C) with hypotension prompted emergency external DCCV. Over the next 9 days, he had daily episodes of SMVT, without haemodynamic compromise, responding to ATP. He was treated with IV lignocaine to control the SMVT and milrinone to treat persistent cardiogenic shock. Despite this, he had daily episodes of SMVT requiring ATP. He developed acute kidney and liver injuries, likely due to hypoperfusion during episodes of VT, although amiodarone was discontinued due to possible hepatotoxicity.
Three weeks into the admission, EPS was performed. VT induction was not attempted due to haemodynamic instability. Transseptal puncture and left ventricular mapping was performed during RV pacing, demonstrating extensive apical left ventricular scar (Figure 4). Pacemaps similar to the clinical VT (Figure 5A), and delayed potentials were recorded at the left ventricular apex (Figure 5B). Isolation of the left ventricular apex with loss of local pace capture was achieved with local impedance-guided RFA applications.
Figure 4 Bipolar voltage map and ablation lesions from ventricular tachycardia ablation (Case 3). The low voltage areas observed using conventional voltage criteria corresponded with late Gadolinium-enhanced areas seen with cardiac magnetic resonance (Figure 1, Case 3). There was mid-distal anteroseptal, apical, and posterolateral scar. Substrate-based ablation was performed guided by late potentials and pacemaps. Ventricular tachycardia was not inducible pre- or post-ablation. AP, antero-posterior; Bi, bipolar tissue voltage; Imp, impedance drop observed during radiofrequency ablation; LAO, left anterior oblique; LPO, left posterior oblique view.
Figure 5 Twelve-lead electrocardiogram (A) recorded during left ventricular pacing from an antero-apical site, demonstrating reasonable match with the clinical ventricular tachycardia (Figure 3C). Intracardiac electrograms (B) recorded during right ventricular pacing with the Pentarray (PENT) roving catheter (Biosense Webster) positioned in the left ventricle at the same apical site as the pace map displayed above. Delayed post-QRS potentials are seen in this area (arrows). CS, coronary sinus catheter.
Following EPS, lignocaine and milrinone were stopped. Further episodes of SMVT responding to ATP were observed over the next 3 days, but thereafter no VT was seen. Despite treatment with IV furosemide and dobutamine, he remained in cardiogenic shock. A joint decision was made to deactivate his ICD, discontinue medical therapy, and palliate. He died 11 days later.
Review of literature
Whilst multi-organ involvement is common in AFD, mortality is primarily caused by cardiac disease. A systematic review by Baig et al.8 identified 13 studies on ventricular arrhythmias and sudden cardiac death (SCD) in AFD. In this review, 75% of deaths were due to a cardiovascular condition and 62% of all deaths were reported as SCD events. The average prevalence of VT was reported as 15.3%. Factors associated with SCD included increasing age, LGE on CMRI, and NSVT.
We identified four case reports pertaining to the description of RFA of VT in AFD. Higashi et al.9 described the case of a 67-year-old man with an LVEF of 35% and a left lateral ventricle wall perfusion defect, presenting with VT storm resistant to anti-arrhythmic therapy. Epicardial activation mapping demonstrated a figure-of-eight re-entrant circuit on the lateral left ventricular wall. RFA to this region terminated the VT. Over a 24-month follow-up, recurrence of a non-ablated VT was observed, and the number of ICD shocks for VT decreased. In another study, Nakano et al.10 report on a 51-year-old man with an LVEF of 68%, presenting with SMVT. CMRI demonstrated high T2 signal in the basal epicardium and antero-septal endocardium. The patient underwent RFA of the left ventricular anterior-apical wall, with recurrence of the VT a few days after. A second ablation was performed but did not completely eradicate the VT. The patient was continued on long-term amiodarone and remained alive at 2 years, with no documented VT recurrence. A report by Ellis et al.11 described a 49-year-old man with AFD, LVEF 25–30%, permanent atrial fibrillation and complete heart block (with cardiac resynchronization therapy ICD), presenting with VT storm resistant to anti-arrhythmic therapy. EPS demonstrated a posterolateral site of origin near the mitral annulus, and RFA was performed at this site, with no VT subsequently inducible. Follow-up was limited to 3 months, without VT recurrence. In an abstract by Oder et al.,12 the authors describe the use of RFA in three patients with Fabry disease, two of whom experienced further VT episodes following the procedure and died due to end-stage heart failure.
With regards to guidance on ICD implantation in AFD, evidence is sparse. In a retrospective analysis of patients with AFD,13 several clinical factors were associated with ICD implantation, including increasing age, greater left ventricular mass, greater scar tissue, and larger atrial size. Importantly, only 28% of AFD patients with an ICD in this study had a Class 1 indication for implantation, highlighting the need for AFD-specific research and guidelines.
Discussion
Imaging
CMRI in our cohort showed extensive LGE, which was predominantly inferolateral mid-wall, patchy, extending from base to apex. Whilst the morphology of the VT on the 12-lead ECGs was variable, it did correspond with observed areas of LGE. In Case 1, an inferior basal septum origin, in Case 2, a lateral mid-chamber origin, and in Case 3, an apical wall origin.
All our patients had relatively stable slow SMVT (Figure 2) with rates between 150 and 180 min−1 and in one case the QRS had delayed intrinsicoid deflection, suggestive of epicardial breakout.
Ablation strategy
In our series, the mechanism of VT was re-entry around areas of fibrosis, and traditional principles for VT ablation were deemed appropriate. The substrate is transmural and the critical isthmus may be found endocardially but can be present anywhere within the myocardium. Despite extensive myocardial fibrosis in our cases, left ventricular walls remained hypertrophied. Accordingly, ablated areas were frequently in thickened myocardium, likely to hinder lesion transmurality. These factors suggest that a combined endocardial/epicardial approach may be helpful, although an endocardial-only approach was used in our most successful case who survived beyond three years.
In two of our cases, VT was not inducible at the end of the procedure (in the third, VT induction was not attempted due to haemodynamic instability). Therefore, inducibility does not appear to be a reliable marker of subsequent VT risk, so comprehensive treatment may involve complete substrate modification where possible.
Left ventricular function
Our experience suggests that VT resistant to medical therapy in patients with AFD is likely to represent end-stage disease when severe left ventricular systolic dysfunction (LVSD) and extensive LGE are present. At the start of our case series, all patients had preserved LVEF, which later deteriorated after ICD implantation. Two had severe LVSD at the time of ablation; Case 1 who died 4 months following VT ablation, and Case 3 who died 2 weeks after. In contrast, Case 2 had moderate LVSD at the time of ablation, and survived more than 3 years following the procedure, although it must be acknowledged that prior to EPS, the patient had been stabilized on amiodarone which was continued for 10 months following the procedure. In our experience of over 175 patients with cardiac AFD, it appears that VT electrical storm in AFD patients is a marker of end-stage disease.
Conclusion
AFD can present with VT consistent with a re-entry mechanism. In our series of three patients with VT storm refractory to medical therapy, extensive infiltration and/or scar was demonstrated by LGE. Endocardial ± epicardial mapping demonstrated the arrhythmic substrate. However, RFA did not result in a significant prognostic benefit in two out of the three patients. In patients with AFD, VT storm is therefore likely a sign of end-stage disease.
Lead author biography
Dr Mark T. Mills is an academic clinical fellow and cardiology registrar in South Yorkshire, UK. He began his undergraduate training at the University of Sheffield, graduating with Honours in 2015. He subsequently completed a Masters in Cardiovascular Research at King’s College London. His research interests include cardiac electrophysiology, coronary physiology, and the impact of cardiac rhythm disturbance on coronary haemodynamics.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
ytaa529_Supplementary_Data Click here for additional data file.
Acknowledgements
We would like to thank Stacey Bates, cardiac physiologist at the Northern General Hospital, for her help during the electrophysiology studies and in preparing the figures for this case series.
Slide sets: A fully edited slide set detailing this case 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 image(s) and associated text has been obtained from the patients in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33569526 | 20,807,708 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrial fibrillation'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE, ATORVASTATIN, BISOPROLOL, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN TOSYLATE, FERROUS FUMARATE, FUROSEMIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM BROMIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33569535 | 19,039,396 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyskinesia'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperreflexia'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertonia'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malaise'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myoclonus'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | ALLOPURINOL, AMIODARONE HYDROCHLORIDE, ATORVASTATIN, BISOPROLOL FUMARATE, BUDESONIDE\FORMOTEROL, DIGOXIN, EDOXABAN, FERROUS FUMARATE, FUROSEMIDE, GLICLAZIDE, LANSOPRAZOLE, METFORMIN HYDROCHLORIDE, MIRTAZAPINE, UMECLIDINIUM | DrugsGivenReaction | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the administration route of drug 'BUDESONIDE\FORMOTEROL'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Respiratory (inhalation) | DrugAdministrationRoute | CC BY | 33569535 | 19,989,574 | 2021-02 |
What was the administration route of drug 'DIGOXIN'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33569535 | 20,077,901 | 2021-02 |
What was the administration route of drug 'UMECLIDINIUM BROMIDE'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Respiratory (inhalation) | DrugAdministrationRoute | CC BY | 33569535 | 19,989,574 | 2021-02 |
What was the administration route of drug 'UMECLIDINIUM'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Respiratory (inhalation) | DrugAdministrationRoute | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Atrial fibrillation'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,039,396 | 2021-02 |
What was the outcome of reaction 'Chorea'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,989,574 | 2021-02 |
What was the outcome of reaction 'Diarrhoea'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Dyskinesia'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Fatigue'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Hyperkalaemia'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Hyperreflexia'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Hypertonia'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Malaise'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Myoclonus'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
What was the outcome of reaction 'Toxicity to various agents'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,989,574 | 2021-02 |
What was the outcome of reaction 'Vomiting'? | Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.
Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation.
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence.
We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.
Learning points
Chorea is a rare complication of digoxin toxicity.
This condition is managed acutely with dopamine blocking agents, but mainstay of treatment is reversal of digoxin and supportive care.
Those with prior established infarct of the basal ganglia may be more likely to develop this complication.
Introduction
Chorea is a rare movement disorder characterized by its involuntary, rapid, and irregular movements. It sometimes resembles purposeful motion and can be described as ‘dance-like’, hence is derived from the Ancient Greek word meaning ‘dance’. Although rare, causes of this phenomenon are extensive, including vascular, endocrine, drug-related, inflammatory, or genetic causes. In patients with atrial fibrillation, this phenomenon is commonly secondary to cardio-embolic stroke.1
Digoxin has a narrow therapeutic window, and serum toxicity has well-recognized effects on the central nervous system such as encephalopathy, hallucinations, seizures, dysphagia, dysphonia, and visual disturbances.2 Chorea, however, is an exceedingly rare side effect of digoxin toxicity, described only three times in the literature since 1984.3–5 The typical presentation occurs as a transient bilateral chorea, in the setting of digitalis toxicity, which resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms.
Timeline
Timeline Admission Within 24 h 72 h 1 month
Movements Normal Bilateral chorea Chorea resolved Normal
Digoxin level Toxic Toxic Normalized Bisoprolol used as an alternative.
Renal function Acute kidney injury (AKI) on chronic kidney disease (CKD) AKI on CKD Baseline CKD Baseline CKD
Case presentation
A 78-year-old lady presented to the emergency department with a 4-week history of intermittent diarrhoea and vomiting in addition to fatigue and malaise. This began after she completed a course of antibiotics, which were prescribed by her general practitioner to treat a urinary tract infection.
She was an ex-smoker and had a past medical history of atrial fibrillation (AF), chronic kidney disease, chronic obstructive pulmonary disease, gout, type-2 diabetes mellitus.
On admission, our patient was regularly taking edoxaban 30 mg once daily (o.d.), digoxin 125 micrograms (mcg) o.d., bisoprolol 5 mg o.d., amiodarone 200 mg o.d., allopurinol 100 mg o.d., ferrous fumarate 305 mg o.d., lansoprazole 30 mg o.d., metformin 500 mg three times daily, gliclazide (modified release) 30 mg o.d., furosemide 40 mg o.d., atorvastatin 20 mg o.d., budesonide/formoterol 200 mcg/6 mcg inhaled twice daily, umeclidinium 55 mcg inhaled o.d., mirtazapine 30 mg o.d., in addition to nutritional supplementation.
Observations on arrival found a heart rate of 40 beats per minute, with a blood pressure of 103/57. Respiratory rate was 24 with an oxygen saturation of 92% on room air. She was apyrexial. She had cool peripheries with an otherwise normal examination.
Serial electrocardiograms demonstrated bradycardic AF (see Figure 1), with a ventricular rate between 32 and 52 b.p.m. T-wave inversion with down-sloping ST depression was present in leads II, III, aVF, and V3–V6. Serology showed an acute kidney injury (AKI) with hyperkalaemia [creatinine 396 µmol/L (44–80 µmol/L), eGFR 10 mL/min/1.73 m2 and potassium 6.2 mmol/L]. Digoxin levels were markedly elevated at 8.1 nmol/L (0.8–1.2).
Figure 1 Electrocardiogram of patient on admission to the emergency department. This demonstrates slow atrial fibrillation with diffuse down-sloping ST segments in-keeping with digoxin toxicity.
C-reactive protein was 3.8 mg/L (0–5). Her liver function tests showed total bilirubin 4.9 µmol/L (2.0–21), alkaline phosphatase 99 IU/L (30–130), gamma GT 114 U/L (6–42), and albumin 42 g/L (35–50).
Other bloods included venous blood gas: pH 7.42 (7.35–7.45), lactate 4.4 mmol/L (0.0–1.3), glucose 5.2 mmol/L (3.6–5.3). Full blood count: haemoglobin 12.2 (12–15), white cell count 9.9 × 109/L (4–10), platelets 263 × 109/L (150–400). Electrolyte screen: sodium 144 mmol/L (135–145), magnesium 0.57 mmol/L (0.7–1.0), calcium 2.59 mmol/L (2.2–2.6), phosphorus 1.1 mmol/L (0.8–1.5).
Echocardiography was done the following day and demonstrated no regional wall motion abnormality, with good ejection fraction (50%) and normal valves
In terms of medications administered, in the first 24 h of her admission, our patient received management for hyperkalaemia [i.e. 10 mL of 10% calcium gluconate intravenously (IV), with 10 units actrapid in 50 mL of 50% dextrose IV infusion], five vials of digoxin FAB, resuscitation with NaCl 0.9% IV, magnesium sulfate 2 g IV, and an IV dobutamine infusion.
She was administered with intravenous digoxin specific antibody (FAB), treated for hyperkalaemia (6.2 mmol/L), commenced on fluid resuscitation, and transferred to the coronary care unit (CCU) for cardiac monitoring. While in the CCU, she was noted to develop generalized symmetrical choreiform movements. She had not been treated with any neuroleptic medications or any other drugs. Examination revealed myoclonus in the fingers and dyskinetic movements of the oral muscles and tongue. Diffuse hypertonia and hyper-reflexia were present. An urgent computerized tomography brain scan showed no new abnormalities but demonstrated old established basal ganglia infarcts bilaterally.
Magnetic resonance imaging would be the preferred method of investigation in this setting; however, this was not acutely available in our centre.
She was reviewed by neurology and commenced on 0.5 mg of haloperidol twice daily. Her clinical state improved in correlation with supportive measures for haemodynamics and renal function.
Symptoms of chorea resolved fully as digoxin levels normalized without recurrence even after cessation of haloperidol, and the patient was discharged home after 5 days. The absence of chorea was confirmed at a virtual clinic 1 month after her discharge.
Discussion
We have identified three reported cases of digoxin-induced chorea, published since 1984.3–5 Two cases involved bilateral choreiform movements, in the setting of acute toxicity—one case secondary to reduced clearance following AKI, as with our patient. The movements were transient, resolving within a few days of treatment of the toxicity. Typical antipsychotics such as haloperidol were used with good effect in the acute setting, and successful weaning occurred if digoxin levels were no longer elevated. When one case was revisited 2 years later, no recurrence of chorea had occurred.4
A second case involved a 7-year-old girl with congenital heart disease, who was initiated on 125 micrograms of digoxin twice daily, and developed choreiform movements when her digoxin level rose to 3.8 ng/mL. This disappeared when levels fell to 1.5 ng/mL and recurred when she was re-trialled on the drug with levels rising to 2.5 ng/mL. Symptoms fully resolved when digoxin was discontinued and blood levels fell back to the normal range.5
The final case was unique to the others as hemi-chorea was noted. The author described a 76-year-old lady who newly commenced digoxin in the setting of new AF and heart failure. Despite ceasing digoxin, the chorea did not fully resolve, even after 1 week. The author adds that acute ischaemic stroke could not be excluded as the cause.3
Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity, resolves within a few days of normalization of digoxin levels and is associated with no other focal neurological signs or symptoms. As digoxin is used for rate control in AF, patients are at an increased risk of cardio-embolic stroke, and this is a leading differential diagnosis if the symptoms are unilateral or the symptoms do not fully resolve soon after resolution of toxicity.6
Of note, amiodarone has been demonstrated to cause neuromuscular side effects such as ataxia and generalized hyper-reflexia when at toxic levels. This, however, has been described as taking 2–6 months to resolve, and does not clinically fit the choreiform movements at rest exhibited by our patient.7,8
All of the patient’s regular medications except for inhalers, anticoagulation, and nutritional supplements were held in the first 24 h. Although mirtazapine is known to cause psychomotor agitation and other forms of hyperkinesia when reduced clearance is present, there are no published reports of mirtazapine toxicity causing chorea.9,10 There were also no identifiable agents that are known to induce chorea upon their withdrawal.
The cause of digoxin-related chorea is not known, however, it has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.11 As demonstrated with our patient’s neuroimaging, there were old bilateral infarcts of the basal ganglia. This established parenchymal loss may have acted as a predisposing factor to developing chorea in the setting of digoxin toxicity.
Due to the narrow therapeutic window, digoxin therapy needs to be monitored more strictly in those who are at risk of digitalis toxicity, such as in the setting of chronic kidney disease. It is also important to fully educate patients to be vigilant of the side effects of digoxin and to present themselves to a healthcare professional in a timely manner to avoid haemodynamic compromise.
Lead author biography
Dr James Mannion, MB BCh BAO, is a cardiology Senior House Officer, working in University Hospital Waterford, in the south-east of Ireland. He is currently enjoying his second year of his Basic Specialist Training programme and hopes to go onto Higher Specialist Training in cardiology and thereafter electrophysiology.
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 guidelines.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab022_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33569535 | 19,992,634 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Pharmacotherapy Management for COVID-19 and Cardiac Safety: A Data Mining Approach for Pharmacovigilance Evidence from the FDA Adverse Event Reporting System (FAERS).
BACKGROUND
Several pharmacological agents, such as chloroquine/hydroxychloroquine, have been promoted for COVID-19 treatment or pre-exposure prophylaxis. However, no comprehensive evaluation of the safety of these possible agents is available, and is urgently needed.
OBJECTIVE
The purpose of this study was to investigate the risks of cardiac adverse events associated with the possible pharmacotherapies for COVID-19, including certain antimalarial, antiviral, and antibiotic drugs.
METHODS
We conduced retrospective pharmacovigilance analyses of the US Food and Drug Administration Adverse Event Reporting System database. The reporting odds ratio (ROR), a data mining algorithm commonly used in pharmacovigilance assessment, was generated to quantify the detection signal of adverse events.
RESULTS
Among individuals without coronavirus infection from 2015 Q1 to 2020 Q1, increased risks for cardiac disorders were found for antiviral agents such as chloroquine/hydroxychloroquine (ROR: 1.68; 95% confidence interval [CI] 1.66-1.70), lopinavir/ritonavir (ROR: 1.52; 95% CI 1.39-1.66), and antibiotics such as azithromycin (ROR: 1.37; 95% CI 1.30-1.44) and ceftriaxone (ROR: 1.92; 95% CI 1.80-2.05). Increased serious cardiac adverse events, including myocardial infarction, arrhythmia, and cardiac arrest, were also reported for these drugs. Further analyses of individuals with coronavirus infections revealed that 40% of individuals receiving chloroquine/hydroxychloroquine reported serious cardiac adverse events. Two cases resulted in QT prolongations and one case resulted in cardiac arrest. Chloroquine/hydroxychloroquine and azithromycin contributed to all the QT prolongation and cardiac arrest cases.
CONCLUSIONS
The current pharmacotherapies for COVID-19 are associated with increased risks of cardiac adverse events. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. Clinicians should closely monitor patients with COVID-19, especially those at high risk, using chloroquine/hydroxychloroquine and azithromycin.
Key Points
Chloroquine/hydroxychloroquine may have contributed to a large proportion of cardiac disorders for COVID-19 treatment or pre-exposure prophylaxis.
The cardiac risks associated with the pharmacotherapies seem to be further elevated in patients with coronavirus infection, and close monitoring of cardiac risks is needed.
The potential pharmacotherapies are associated with serious cardiac adverse events, such as myocardial infarction, arrhythmia, and cardiac arrest.
Introduction
Over five million cases of Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], were reported worldwide as of 21 May, 2020 [2]. A large majority of individuals with COVID-19 have reported experiencing mild-to-moderate symptoms, including fever, cough, and fatigue [3], most of which do not require medical attention. However, COVID-19 can cause severe complications or even death in older adults or high-risk patients with concurrent chronic diseases [3]. Currently, there is no proven effective treatment against COVID-19. Infection control measures and supportive care, for example, supplemental oxygen and mechanical ventilatory support, are the main management strategies recommended by the current COVID-19 Treatment Guidelines [4]. With the rapid growth of the COVID-19 pandemic, there is an urgent need to identify existing medications deemed to be safe and effective with acceptable side effects, to attenuate infections and prevent severe complications in individuals with COVID-19.
Currently, three antiviral drugs—remdesivir, hydroxychloroquine, and chloroquine—have received emergency use authorization from the US Food and Drug Administration (FDA) in May 2020 [5]. These three drugs demonstrated antiviral properties against SARS-CoV-2 in an early in-vitro study [6]. Chloroquines showed benefits in patients hospitalized with COVID-19, based on two small clinical studies [7, 8]. Thereafter, on 23 March, 2020, the FDA allowed the emergency use of chloroquines in confirmed COVID-19 cases who were hospitalized. However, more recent research demonstrated no benefits of using chloroquines in treating COVID-19 infection [9, 10]. In addition to remdesivir, several antiviral agents such as lopinavir/ritonavir have been tested while showing uncertain benefits in treating COVID-19 [4]. The combined use of antiviral agents and antibiotics, such as azithromycin and fluoroquinolones, has also been reported with mixed results.
While COVID-19 is the disease that primarily manifests in the respiratory system [11], cardiac disorders, such as coronary artery disease (CAD), heart failure (HF), and cerebrovascular disease, are common in hospitalized individuals with COVID-19 [3]. One potential mechanism is that myocardial cells have strong receptor angiotensin-converting enzyme II expression, which could be the target of SARS-CoV-2 infection [12]. Other possible explanations include hypoxia and microthrombi, which cause vascular damage [13]. Considering the potential cardiac risks associated with some antiviral agents, however, pharmacotherapy may also play a role in the elevated risk of cardiac adverse events (AEs) observed in individuals with COVID-19. For example, chloroquine and hydroxychloroquine have long been proven to increase the risk of torsade de pointes (TdP) and cause QT prolongation [14], which further increases the patient’s susceptibility to adverse cardiovascular outcomes and death during aggressive responses to COVID-19 infections. Risks of ventricular arrhythmia and cardiac arrests are also complicated by the incremental effects of azithromycin. After the emergence of severe cardiac AEs associated with hydroxychloroquine and chloroquine, the FDA cautioned against the use of investigational drugs outside the setting of a health system or clinical trial to avoid possible cardiovascular damage.
With the rapid growth of the COVID-19 pandemic and current promotion of certain pharmacological agents for COVID-19 treatments or pre-exposure prophylaxis, evidence on the cardiac risks of these possible therapies is urgently needed for clinicians to make informed decisions related to the benefits and risks of pharmacotherapies [15]. Therefore, the objective of this study was to investigate the association between the possible pharmacotherapies for COVID-19 and the risks of cardiac AEs.
Methods
Study Design and Data Source
We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. The AEs reported for the potential pharmacotherapies for COVID-19 were extracted and queried from the first quarter of 2015 through the first quarter of 2020. We included the study period from 2015 and forward because the goal of the study was to investigate the risks of cardiac AEs associated with the possible pharmacotherapies for COVID-19. Therefore, although the medications may not be used for COVID-19 before the end of 2019, the potential risks may still be possible for other indications and are worthy of evaluation. In addition, the FAERS data were limited since the COVID-19 pandemic, therefore, we included data from 2015 and forwards to evaluate the safety of the therapies. These drugs were commonly used in clinical settings or under investigation to treat patients with COVID-19 [16].
The FAERS is a post-marketing surveillance system that collects spontaneous AEs reported directly from consumers, healthcare professionals, pharmaceutical companies, or others [17]. The database contains nearly 20 million reports from 1969 to March 2020 [17]. The database contains detailed information on patient demographics, indications, medication use, outcomes, and sources of reports. All AEs were coded using Preferred Terms (PTs) in the Medical Dictionary for Regulatory Activities terminology [18]. The Medical Dictionary for Regulatory Activities hierarchy consists of five levels, from specific to broad categories. These coded terms are arranged in a hierarchy of five categories. The “System Organ Classes”, grouped by disease etiology, manifestation site, or purpose, are the high-level group terms. The PTs, describing the disease symptoms or diagnosis, an indication, laboratory results, and procedures, are the low-level group terms and were used in the FAERS database [18].
Identification of Exposures
We searched the FAERS database to identify reports involving drug generic names, including chloroquine, hydroxychloroquine, lopinavir, ritonavir, ribavirin, umifenovir, tocilizumab, sarilumab, darunavir, favipiravir, azithromycin, moxifloxacin, ceftriaxone, piperacetazine, tazobactam, ampicillin, sulbactam, and tobramycin. A clinical pharmacist also reviewed the medications identified by the search queries. Oseltamivir was not included in the analysis because it was an investigational drug and not permitted for use outside of clinical trials. Drugs coded as suspect or concomitant use were also examined. For AEs reported in the first quarter of 2020, we further limited to those reports with coronavirus infection, to identify individuals with COVID-19.
Identification of Cardiac Disorder
To search for cardiac-related terms, we used the following PTs, including myocardial infarction, tachycardia, bradycardia, palpitations, cardiac failure, cardiac arrest, coronary artery disease, atrial fibrillation, and arrhythmia [19]. To understand the risks of overall cardiac AEs, we also searched the PTs listed under the System Organ Class of cardiac disorders in the Medical Dictionary for Regulatory Activities [18].
Identification of Coronavirus Infection
To identify patients with COVID-19, we searched reports involving “coronavirus infection” or “coronavirus test positive”, in the first quarter of 2020. To test this data mining strategy, we also compared the number of individuals with coronavirus infection from 2015 Q1 through 2019 Q4. The number of individuals was fewer than 40. In the first quarter of 2020, there were 311 individuals with coronavirus infection. Given the substantial increase in the number of infections, most of them should have COVID-19.
Data Analyses
To evaluate the risk of drug-associated AEs, we calculated the reporting odds ratio (ROR) [20], the data mining algorithm commonly used in a pharmacovigilance assessment. The RORs were calculated in the contingency 2 × 2 table, as described elsewhere [20]. We calculated the ROR for each drug of interest. If the lower bound of the 95% confidence interval (CI) of a ROR is greater than the threshold of 1.0, then the signal of an AE is considered as significant, or the detected AE is associated with a statistically significantly higher number of reports following the use of the drug of interest, compared with those reports following the use of all other drugs [20].
Results
Individuals Without Coronavirus Infection
In the FAERS database from 2015 Q1 to 2020 Q1, a total of 6.12 million reports were identified. The number of individuals reporting the use of each drug was 347,034 for chloroquine/hydroxychloroquine, 7506 for lopinavir/ritonavir, 38,810 for ribavirin, 5615 for darunavir, 38,049 for tocilizumab/sarilumab, 10 for umifenovir, 11 for favipiravir, 26,093 for azithromycin, 8838 for moxifloxacin, 12,595 for ceftriaxone, 1478 for piperacetazine/tazobactam, 351 for ampicillin/sulbactam, and 11,456 for tobramycin (Fig. 1a).Fig. 1 Frequency of cardiac disorders in the FDA Adverse Event Reporting System 2015 Q1 to 2020 Q1. a Demonstrates the proportion of cardiac disorders among individuals without coronavirus indications. b Demonstrates the proportion of cardiac disorders among individuals with coronavirus indications. AEs adverse events, CQ chloroquine, HCQ hydroxychloroquine, Sulbacta sulbactam, Tazo tazobactam
Of 6.12 million reports, 288,232 reports of cardiac AEs were indented. Table 1 compared basic characteristics of FAERS reports. The total number of cardiac AEs were 24,618 (Fig. 1a, 7.09%) for chloroquine/hydroxychloroquine, 501 (6.67%) for lopinavir/ritonavir, 1311 (3.38%) for ribavirin, 279 (4.97%) for darunavir, 1683 (4.42%) for tocilizumab/sarilumab, 2 (20%) for umifenovir, 2 (18.18%) for favipiravir, 1582 (6.06%) for azithromycin, 839 (9.49%) for moxifloxacin, 1045 (8.30%) for ceftriaxone, 131 (8.86%) for piperacetazine/tazobactam, 21 (5.98%) for ampicillin/sulbactam, and 239 (2.09%) for tobramycin, respectively.Table 1 Patient characteristics in the FDA Adverse Event Reporting System (FAERS) database 2015 Q1 to 2020 Q1
Characteristics Without coronavirus infection With coronavirus infectiona
No cardiac disorders
n (%) Cardiac disorders
n (%) P value No cardiac disorders
n (%) Cardiac disorders
n (%) P value
Age, years < 0.0001 < 0.0001
0–17 7371 (2.56) 17,990 (2.94) 11 (3.86) 10 (38.46)
18–44 35,932 (12.47) 691,341 (11.31) 38 (13.33) 3 (11.54)
45–64 64,994 (22.55) 1,170,182 (19.14) 56 (19.65) 3 (11.54)
65–75 42,702 (14.82) 649,677 (10.62) 31 (10.88) 2 (7.69)
75 and over 40,274 (13.97) 540,490 (8.84) 13 (4.56) 4 (15.38)
Unknown 96,959 (33.64) 2,883,488 (47.15) 136 (47.72) 4 (15.38)
Sex < 0.0001 0.120
Female 142,923 (49.59) 3,308,570 (54.1) 116 (40.70) 16 (61.54)
Male 116,680 (40.48) 2,026,205 (33.13) 133 (46.67) 8 (30.77)
Unknown 28,629 (9.93) 780,393 (12.76) 36 (12.63) 2 (7.69)
Year <0.0001
2015 49,631 (17.22) 1,038,146 (16.98)
2016 48,839 (16.94) 1,055,895 (17.27)
2017 51,771 (17.96) 1,090,998 (17.84)
2018 60,304 (20.92) 1,290,049 (21.1)
2019 61,198 (21.23) 1,285,828 (21.03)
2020 16,489 (5.72) 354,252 (5.79) 285 (100) 26 (100)
Country < 0.0001 0.0357
USA 145,599 (50.51) 4,461,211 (72.95) 136 (47.72) 18 (69.23)
Non-USA 142,633 (49.49) 1,653,957 (27.05) 149 (52.28) 8 (30.77)
Reporter’s type of occupation < 0.0001 0.0584
Consumer 112,593 (39.06) 3,034,172 (49.62) 113 (39.65) 4 (15.38)
Lawyer 5266 (1.83) 81,556 (1.33) 0 (0.00) 0 (0.00)
Physician 71,291 (24.73) 1,260,021 (20.6) 94 (32.98) 10 (38.46)
Other health professional 71,276 (24.73) 1,121,967 (18.35) 50 (17.54) 7 (26.92)
Pharmacist 19,830 (6.88) 453,270 (7.41) 15 (5.26) 4 (15.38)
Unknown 7976 (2.77) 164,182 (2.68) 0 (0.00) 1 (3.85)
aReports identified with “Coronavirus infection” in the FAERS from 1 January to 31 March, 2020
For chloroquine/hydroxychloroquine, the most frequently reported cardiac AaEs were palpitations (Fig. 2a, n = 3079), cardiac failure (n = 3129), myocardial infarction [MI] (n = 2964), tachycardia (n = 2859), and atrial fibrillation [AF] (n = 2441). The RORs (95% CI) associated with chloroquine/hydroxychloroquine were statistically significant, including 1.68 (1.66–1.70) for overall cardiac disorders, 1.35 (1.28–1.42) for cardiac arrest, 1.45 (1.40–1.50) for MI, 1.73 (1.66–1.80) for tachycardia, 1.77 (1.67–1.87) for arrhythmia, 1.79 (1.70–1.88) for bradycardia, 1.80 (1.73–1.86) for cardiac failure, and 2.28 (2.05–2.53) for CAD. When chloroquine/hydroxychloroquine concomitantly with azithromycin, the RORs were still significant (Fig. 2b). This finding was also consistent with previous findings that azithromycin may be associated with increased cardiac risks [25, 26, 28]. Taken together, close monitoring for QTc prolongation is necessary for patients who are female, older, have a history of HF, or use chloroquine/hydroxychloroquine with azithromycin.Fig. 2 Reporting odds ratio (ROR) of cardiac adverse events among individuals without coronavirus infection. The ROR and the 95% confidence interval (CI) of each cardiac adverse event following the use of a chloroquine/hydroxychloroquine (CQ/HCQ), b CQ/HCQ plus azithromycin, c lopinavir/ritonavir, d ribavirin, e darunavir, f tocilizumab/sarilumab, g azithromycin, h ceftriaxone, i moxifloxacin, j piperacetazine/tazobactam, and k ampicillin\sulbactam are provided in the adjacent tables. Note that the vertical red bar shows the line of ROR = 1. RORs (95% CI) in bold represent the significant signals of cardiac adverse events. Data source: FDA Adverse Event Reporting System 2015 Q1–2020 Q1
As shown in Fig. 2c, the most frequently reported cardiac AEs for lopinavir/ritonavir were cardiac failure (n = 82), MI (n = 77), palpitations (n = 56), tachycardia (n = 44), and AF (n = 44). The significant ROR signals were 1.52 (1.39–1.66) for overall cardiac disorders, 1.70 (1.36–2.13) for MI, 2.23 (1.63–3.06) for arrhythmia, 2.19 (1.63–2.95) for bradycardia, 2.09 (1.68–2.60) for cardiac failure, and 1.57 (1.17–2.11) for AF. The signal for palpitations was detected for ribavirin (Fig. 2d, ROR = 1.18, 95% CI 1.04–1.35). For darunavir (Fig. 2e), the ROR signals for MI and CAD were 2.95 (2.42–3.60) and 4.72 (2.79–7.98), respectively. For tocilizumab/sarilumab (Fig. 2f), the ROR signal for MI was 1.45 (1.30–1.62). For umifenovir and favipiravir, the number of events was too small to calculate RORs. For azithromycin only, the most frequently reported cardiac AEs were tachycardia (Fig. 2g, n = 212), palpitations (n = 197), AF (n = 172), and cardiac failure (n = 163). The RORs (95% CI) was 1.37 (1.30–1.44) for overall cardiac disorders, 1.51 (1.26–1.80) for cardiac arrest, 1.64 (1.44–1.88) for tachycardia, 1.45 (1.26–1.67) for palpitations, 1.26 (1.02–1.55) for arrhythmia, 1.51 (1.23–1.86) for bradycardia, 1.19 (1.02–1.39) for cardiac failure, and 1.77 (1.52–2.06) for CAD, respectively. For ceftriaxone (Fig. 2h), the significant ROR signals were 1.92 (1.80–2.05) for overall cardiac disorders, 4.50 (3.88–5.23) for cardiac arrests, 3.43 (2.99–3.93) for tachycardia, 1.39 (1.03–1.90) for arrhythmia, 2.65 (2.15–3.27) for bradycardia, 1.67 (1.38–2.02) for cardiac failure, and 1.77 (1.42–2.19) for AF, respectively. For moxifloxacin (Fig. 2i), the RORs (95% CI) were 2.23 (2.08–2.39) for overall cardiac disorders, 1.88 (1.43–2.47) for cardiac arrest, 2.32 (1.91–2.82) for tachycardia, 3.32 (2.61–4.22) for arrhythmia, 1.52 (1.10–2.11) for bradycardia, 1.86 (1.51–2.30) for cardiac failure, 1.51 (1.15–2.00) for AF, and 2.56 (1.45–4.52) for CAD. For piperacetazine/tazobactam (Fig. 2j), the significant ROR signals were 2.06 (1.72–2.47) for overall cardiac disorders, 3.70 (2.29–5.96) for cardiac arrest, 5.15 (3.71–7.13) for tachycardia, 1.77 (0.84–3.72) for bradycardia, 3.26 (2.20–4.84) for AF, and 4.39 (2.93–6.58) for CAD. The signal for cardiac failure was detected for ampicillin/sulbactam (Fig. 2k, ROR = 2.74, 95% CI 1.13–6.62).
Individuals with Coronavirus Infection
During the first quarter of 2020, a total of 311 individuals with coronavirus infection were identified. The number of patients reporting the use of the following drugs were 16 for chloroquine/hydroxychloroquine (Fig. 1b), 43 for lopinavir/ritonavir, 7 for ribavirin, 1 for darunavir, 1 for tocilizumab/sarilumab, 7 for umifenovir, 4 for azithromycin, 3 for moxifloxacin, 8 for ceftriaxone, and 2 for tobramycin, respectively. Among them, six drugs were reported with cardiac AEs, including chloroquine/hydroxychloroquine (n = 5, 31.25%), lopinavir/ritonavir (n = 1, 2.33%), ribavirin (n = 1, 14.29%), umifenovir (n = 1, 14.29%), azithromycin (n = 2, 50.00%), and ceftriaxone (n = 1, 12.50%).
Of 311 individuals with coronavirus infections, 26 patients reported cardiac AEs. As shown in Table 1, ten or 38.5% of individuals were dominantly aged under 17 years (p < 0.001). For chloroquine/hydroxychloroquine, as shown in Fig. 3a, the most frequently reported cardiac AEs included cardiac arrest (n = 1), tachycardia (n = 2), and QT prolongation (n = 2). When chloroquine/hydroxychloroquine was combined with azithromycin, cardiac arrest and QT prolongation were reported (Fig. 3b). Two cases of QT prolongation were reported for individuals using chloroquine/hydroxychloroquine.Fig. 3 Reporting odds ratio (ROR) of cardiac adverse events among individuals with coronavirus infection. Individuals with Preferred Terms of “Coronavirus infection”. The ROR and the 95% confidence interval (CI) of each cardiac adverse event following the use of a chloroquine/hydroxychloroquine (CQ/HCQ), b CQ/HCQ plus azithromycin, c lopinavir/ritonavir, d ribavirin, e umifenovir, f azithromycin, and g ceftriaxone are provided in the adjacent tables. Note that the vertical red bar shows the line of ROR = 1. RORs (95% CI) in bold represent the significant signals of cardiac adverse events. Data source: FDA Adverse Event Reporting System 2020 Q1
Cardiac arrest (n = 1) and tachycardia (n = 1) were reported for azithromycin with strong signals (Fig. 3f). For ceftriaxone, the two cases of cardiac AEs were tachycardia and cardiac arrest (Fig. 3g). The signals of cardiac AEs were not strong for lopinavir/ritonavir (n = 1), ribavirin (n = 1), and umifenovir (n = 1).
Discussion
This study found that the existing potential pharmacotherapies are associated with increased risks of overall cardiac disorders. We also found that nearly half of the individuals with coronavirus infections reported cardiac disorders following pharmacotherapies. In particular, chloroquine/hydroxychloroquine was reported to develop serious cardiac AEs, including tachycardia, cardiac arrest, and QT prolonged in the overall sample. In addition, individuals with coronavirus infections had further elevated risks of cardiac disorders compared with the overall sample. We also observed variations in the cardiac safety profiles of the pharmacotherapies available for patients with COVID-19. Therefore, in clinical practice, clinicians should be aware of the elevated cardiac AEs in patients with COVID-19 and weigh up both the benefits and harms of the therapies. Continued pharmacovigilance is needed on cardiac disorders of other possible pharmacotherapies for COVID-19 to improve patient health outcomes.
The increased cardiac risks reported in patients with COVID-19 using chloroquine/hydroxychloroquine and azithromycin can be explained by drug-induced QTc prolongation, a measure of delayed ventricular repolarization [21]. It can be fatal enough to result in sudden death. Excessive QTc prolongation with a corrected interval >500 ms can predispose the myocardium to the development of early arrhythmia, which in turn can trigger re-entrant tachycardia as the deadly Tdp. As a surrogate marker for developing Tdp, QTc prolongation has been an established side effect of class I and III anti-arrhythmic medications. This analysis revealed that azithromycin and hydroxychloroquine were associated with QT prolongations and cardiac arrest, consistent with a recent multi-national cohort study, in which chloroquine/hydroxychloroquine with or without azithromycin increased the risks of arrhythmias and in-hospital mortality.
Hydroxychloroquine specifically was consistent with increased risks of arrhythmia-related events such as palpitations, tachycardia, and a further complication of AF. For antiretrovirals used for COVID-19, most cardiac AEs are statistically significant in the group of lopinavir/ritonavir, especially for high-risk individuals with pre-existing cardiac injury or comorbidities such as HF and prior MI, resulting in its early stop in 13.8% of patients because of unfavorable reactions. In comparison with lopinavir/ritonavir, other antiretrovirals are not as prominent while it is important to weigh the risk-benefit ratio when selecting the best therapy. For instance, darunavir should be avoided in individuals with a history of CAD or prior MI as it significantly increases the risks of cardiac deterioration. Selected antibacterial agents for the treatment of COVID-19 have not shown promising outcomes but significantly increased risks of developing unwanted cardiac AEs. These findings strongly suggest caution in the use of certain medications with respect to cardiac adverse risks, particularly those patients at a high risk of cardiac disorders, either for COVID-19 treatment or pre-exposure prophylaxis.
Frequently used azithromycin and moxifloxacin have consistently shown increased risks of cardiovascular damage and mortality, especially among elderly individuals with pneumonia [23]. While beta-lactams such as ceftriaxone and zosyn cause more harms than benefits in patients who are more likely to experience tachycardia, and have symptoms of AF, HF, and cardiac arrest [24]. The risk of developing TdP is not solely based upon one medication but a cumulative effect of multiple risk factors such as female sex, increasing age, genetic disposition, and the use of multiple medications that can prolong QTc intervals, affect the metabolism of another QTc-prolonging drug, or cause renal/hepatic dysfunction [25, 26]. Hence, it is important to evaluate the patient demographic and clinical profile before administering possible pharmacotherapies for COVID-19 to minimize cardiac disorders.
In addition to drug-induced cardiac AEs, SARS-CoV-2 itself may cause heart inflammation, and is notorious in worsening pre-existing cardiovascular conditions in patients with myocarditis, HF, and arrhythmia [11]. Different etiologies of acute cardiac injury resulting from COVID-19 may include right-sided HF secondary to hypoxia-mediated pulmonary hypertension, worsening of coronary perfusion due to reduced oxygen-blood saturation, and most severely, a hyperacute systematic inflammatory response syndrome like sepsis, especially seen in older patients with multiple underlying chronic diseases admitted to the intensive care units. Moreover, a problem concerning potassium levels has arisen in patients with COVID-19 as a result of the interaction of SARS-CoV2 with the renal artery stenosis system [27]. Hypokalemia is known to increase the susceptibility of patients to arrhythmia and heart rhythm irregularities. Here, we found that chloroquine/hydroxychloroquine was associated with higher risks of cardiac arrhythmias. Therefore, it is recommended for the management of arrhythmia to optimize electrolyte concentrations through appropriate supplementation and fluids, avoiding high-risk medications, and closely monitoring the electrocardiograms of patients taking QTc-prolonging agents.
This study has some strengths worth mentioning. The FAERS database includes a large amount of cardiac AEs of possible pharmacotherapies for COVID-19 reported worldwide. This enables researchers to examine cardiac AEs and compare to those in patients with COVID-19. This study further provides early signals for health professionals regarding adverse cardiovascular reactions during the selection of specific medications to be utilized or placed in future guidelines while ensuring maximal efficacy and patient safety. Onsite clinical judgment and incorporation of individualized patient factors are also important for optimizing treatment outcomes for patients with COVID-19.
This study possesses some limitations that should be considered. First, most case reports submitted were based upon personal observations and did not have a commonly agreed pathological pattern and treatment preference, leading to inconsistent data quality and potentially incomplete reports with missing information. Second, the reporting to the FAERS database is voluntary and can be easily biased. Depending on the variable criteria used for the selection of events, some cases may not be interpreted as incidence and can be omitted. Third, the sample size of patients with COVID-19 was relatively limited owing to the unavailability of the latest data in the FAERS database. Fourth, we could not exclude the possibility of unmeasured confounding factors, such as disease severity and coexisting conditions and complications, which may over- or under-estimate the association with potential pharmacotherapies and the risk of cardiac AEs. Hence, further studies are needed to make a causal link between drug exposure and cardiac AEs. Last, we cannot exclude the possibility that some patients with coronavirus infection actually had other conditions, such as influenza, rather than COVID-19. By comparing the number of individuals in the previous quarters, more than 90% of individuals identified in the 2020 Q1 are expected to have COVID-19.
Conclusions
The current pharmacotherapies for COVID-19, particularly chloroquine/hydroxychloroquine and azithromycin, are associated with increased risks of cardiac AEs. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. The choice of pharmacotherapy should be based on demographic and clinical profiles. Cardiac monitoring should be employed for patients with COVID-19, especially those at high risk.
Appendix
See Tables Table 2 List of preferred terms
Preferred terms
Acute coronary syndrome
Aortic valve disease
Asystole
Atrial fibrillation
Atrial flutter
Atrioventricular block complete
Atrioventricular block first degree
Cardiac arrest
Chest pain—cardiac
Conduction disorder
Constrictive pericarditis
Heart failure
Left ventricular systolic dysfunction
Mitral valve disease
Mobitz (type) II atrioventricular block
Mobitz type I
Myocardial infarction
Myocarditis
Palpitations
Paroxysmal atrial tachycardia
Pericardial effusion
Pericardial tamponade
Pericarditis
Pulmonary valve disease
Restrictive cardiomyopathy
Right ventricular dysfunction
Sick sinus syndrome
Sinus bradycardia
Sinus tachycardia
Supraventricular tachycardia
Tricuspid valve disease
Ventricular arrhythmia
Ventricular fibrillation
Ventricular tachycardia
Wolff-Parkinson-White syndrome
2 and Table 3 Number of individuals with coronavirus infection in the FDA Adverse Event Reporting System database, 2015 Q1–2020 Q1
Quarter Number of individuals with coronavirus infection
2020Q4 311
2019Q4 32
2019Q3 36
2019Q2 37
2019Q1 43
2018Q4 38
2018Q3 40
2018Q2 40
2018Q1 39
2017Q4 12
2017Q3 9
2017Q2 21
2017Q1 23
2016Q4 14
2016Q3 10
2016Q2 9
2016Q1 7
2015Q4 2
2015Q3 0
2015Q2 6
2015Q1 6
3.
Declarations
Funding
This research did not receive any funding.
Conflicts of Interest/Competing interest
Jing Yuan, Minghui Li, Xiaoqiang Xiang, Tai-Ying Lee, Gang Lv, Yiqun Yu, Bing Han, and Z. Kevin Lu have no conflicts of interest that are directly relevant to the content of this article.
Ethics approval
This research does not involve human subjects. It is not required to obtain institutional review board approval.
Consent to participate
Not applicable.
Consent for Publication
Not applicable.
Availability of data and material
Data are available upon reasonable request.
Code availability
SAS codes are available upon reasonable request.
Authors’ contributions
Concept and design: JY, ML, XX, ZKL. Acquisition, analysis, or interpretation of data: JY, ZKL, GL, XX, ML. Drafting of the manuscript: JY, ZKL, GL, ML. Critical revision of the manuscript for important intellectual content: JY, ZKL, GL, ML, YY, BH, XX. Statistical analysis: JY, ML. Administrative, technical, or material support: ZKL, XX, BH. Supervision: ZKL, XX, BH.
Jing Yuan, Minghui Li, Yiqun Yu, Bing Han have contributed equally to the article. | AZITHROMYCIN ANHYDROUS | DrugsGivenReaction | CC BY-NC | 33569736 | 18,935,191 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Pharmacotherapy Management for COVID-19 and Cardiac Safety: A Data Mining Approach for Pharmacovigilance Evidence from the FDA Adverse Event Reporting System (FAERS).
BACKGROUND
Several pharmacological agents, such as chloroquine/hydroxychloroquine, have been promoted for COVID-19 treatment or pre-exposure prophylaxis. However, no comprehensive evaluation of the safety of these possible agents is available, and is urgently needed.
OBJECTIVE
The purpose of this study was to investigate the risks of cardiac adverse events associated with the possible pharmacotherapies for COVID-19, including certain antimalarial, antiviral, and antibiotic drugs.
METHODS
We conduced retrospective pharmacovigilance analyses of the US Food and Drug Administration Adverse Event Reporting System database. The reporting odds ratio (ROR), a data mining algorithm commonly used in pharmacovigilance assessment, was generated to quantify the detection signal of adverse events.
RESULTS
Among individuals without coronavirus infection from 2015 Q1 to 2020 Q1, increased risks for cardiac disorders were found for antiviral agents such as chloroquine/hydroxychloroquine (ROR: 1.68; 95% confidence interval [CI] 1.66-1.70), lopinavir/ritonavir (ROR: 1.52; 95% CI 1.39-1.66), and antibiotics such as azithromycin (ROR: 1.37; 95% CI 1.30-1.44) and ceftriaxone (ROR: 1.92; 95% CI 1.80-2.05). Increased serious cardiac adverse events, including myocardial infarction, arrhythmia, and cardiac arrest, were also reported for these drugs. Further analyses of individuals with coronavirus infections revealed that 40% of individuals receiving chloroquine/hydroxychloroquine reported serious cardiac adverse events. Two cases resulted in QT prolongations and one case resulted in cardiac arrest. Chloroquine/hydroxychloroquine and azithromycin contributed to all the QT prolongation and cardiac arrest cases.
CONCLUSIONS
The current pharmacotherapies for COVID-19 are associated with increased risks of cardiac adverse events. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. Clinicians should closely monitor patients with COVID-19, especially those at high risk, using chloroquine/hydroxychloroquine and azithromycin.
Key Points
Chloroquine/hydroxychloroquine may have contributed to a large proportion of cardiac disorders for COVID-19 treatment or pre-exposure prophylaxis.
The cardiac risks associated with the pharmacotherapies seem to be further elevated in patients with coronavirus infection, and close monitoring of cardiac risks is needed.
The potential pharmacotherapies are associated with serious cardiac adverse events, such as myocardial infarction, arrhythmia, and cardiac arrest.
Introduction
Over five million cases of Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], were reported worldwide as of 21 May, 2020 [2]. A large majority of individuals with COVID-19 have reported experiencing mild-to-moderate symptoms, including fever, cough, and fatigue [3], most of which do not require medical attention. However, COVID-19 can cause severe complications or even death in older adults or high-risk patients with concurrent chronic diseases [3]. Currently, there is no proven effective treatment against COVID-19. Infection control measures and supportive care, for example, supplemental oxygen and mechanical ventilatory support, are the main management strategies recommended by the current COVID-19 Treatment Guidelines [4]. With the rapid growth of the COVID-19 pandemic, there is an urgent need to identify existing medications deemed to be safe and effective with acceptable side effects, to attenuate infections and prevent severe complications in individuals with COVID-19.
Currently, three antiviral drugs—remdesivir, hydroxychloroquine, and chloroquine—have received emergency use authorization from the US Food and Drug Administration (FDA) in May 2020 [5]. These three drugs demonstrated antiviral properties against SARS-CoV-2 in an early in-vitro study [6]. Chloroquines showed benefits in patients hospitalized with COVID-19, based on two small clinical studies [7, 8]. Thereafter, on 23 March, 2020, the FDA allowed the emergency use of chloroquines in confirmed COVID-19 cases who were hospitalized. However, more recent research demonstrated no benefits of using chloroquines in treating COVID-19 infection [9, 10]. In addition to remdesivir, several antiviral agents such as lopinavir/ritonavir have been tested while showing uncertain benefits in treating COVID-19 [4]. The combined use of antiviral agents and antibiotics, such as azithromycin and fluoroquinolones, has also been reported with mixed results.
While COVID-19 is the disease that primarily manifests in the respiratory system [11], cardiac disorders, such as coronary artery disease (CAD), heart failure (HF), and cerebrovascular disease, are common in hospitalized individuals with COVID-19 [3]. One potential mechanism is that myocardial cells have strong receptor angiotensin-converting enzyme II expression, which could be the target of SARS-CoV-2 infection [12]. Other possible explanations include hypoxia and microthrombi, which cause vascular damage [13]. Considering the potential cardiac risks associated with some antiviral agents, however, pharmacotherapy may also play a role in the elevated risk of cardiac adverse events (AEs) observed in individuals with COVID-19. For example, chloroquine and hydroxychloroquine have long been proven to increase the risk of torsade de pointes (TdP) and cause QT prolongation [14], which further increases the patient’s susceptibility to adverse cardiovascular outcomes and death during aggressive responses to COVID-19 infections. Risks of ventricular arrhythmia and cardiac arrests are also complicated by the incremental effects of azithromycin. After the emergence of severe cardiac AEs associated with hydroxychloroquine and chloroquine, the FDA cautioned against the use of investigational drugs outside the setting of a health system or clinical trial to avoid possible cardiovascular damage.
With the rapid growth of the COVID-19 pandemic and current promotion of certain pharmacological agents for COVID-19 treatments or pre-exposure prophylaxis, evidence on the cardiac risks of these possible therapies is urgently needed for clinicians to make informed decisions related to the benefits and risks of pharmacotherapies [15]. Therefore, the objective of this study was to investigate the association between the possible pharmacotherapies for COVID-19 and the risks of cardiac AEs.
Methods
Study Design and Data Source
We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. The AEs reported for the potential pharmacotherapies for COVID-19 were extracted and queried from the first quarter of 2015 through the first quarter of 2020. We included the study period from 2015 and forward because the goal of the study was to investigate the risks of cardiac AEs associated with the possible pharmacotherapies for COVID-19. Therefore, although the medications may not be used for COVID-19 before the end of 2019, the potential risks may still be possible for other indications and are worthy of evaluation. In addition, the FAERS data were limited since the COVID-19 pandemic, therefore, we included data from 2015 and forwards to evaluate the safety of the therapies. These drugs were commonly used in clinical settings or under investigation to treat patients with COVID-19 [16].
The FAERS is a post-marketing surveillance system that collects spontaneous AEs reported directly from consumers, healthcare professionals, pharmaceutical companies, or others [17]. The database contains nearly 20 million reports from 1969 to March 2020 [17]. The database contains detailed information on patient demographics, indications, medication use, outcomes, and sources of reports. All AEs were coded using Preferred Terms (PTs) in the Medical Dictionary for Regulatory Activities terminology [18]. The Medical Dictionary for Regulatory Activities hierarchy consists of five levels, from specific to broad categories. These coded terms are arranged in a hierarchy of five categories. The “System Organ Classes”, grouped by disease etiology, manifestation site, or purpose, are the high-level group terms. The PTs, describing the disease symptoms or diagnosis, an indication, laboratory results, and procedures, are the low-level group terms and were used in the FAERS database [18].
Identification of Exposures
We searched the FAERS database to identify reports involving drug generic names, including chloroquine, hydroxychloroquine, lopinavir, ritonavir, ribavirin, umifenovir, tocilizumab, sarilumab, darunavir, favipiravir, azithromycin, moxifloxacin, ceftriaxone, piperacetazine, tazobactam, ampicillin, sulbactam, and tobramycin. A clinical pharmacist also reviewed the medications identified by the search queries. Oseltamivir was not included in the analysis because it was an investigational drug and not permitted for use outside of clinical trials. Drugs coded as suspect or concomitant use were also examined. For AEs reported in the first quarter of 2020, we further limited to those reports with coronavirus infection, to identify individuals with COVID-19.
Identification of Cardiac Disorder
To search for cardiac-related terms, we used the following PTs, including myocardial infarction, tachycardia, bradycardia, palpitations, cardiac failure, cardiac arrest, coronary artery disease, atrial fibrillation, and arrhythmia [19]. To understand the risks of overall cardiac AEs, we also searched the PTs listed under the System Organ Class of cardiac disorders in the Medical Dictionary for Regulatory Activities [18].
Identification of Coronavirus Infection
To identify patients with COVID-19, we searched reports involving “coronavirus infection” or “coronavirus test positive”, in the first quarter of 2020. To test this data mining strategy, we also compared the number of individuals with coronavirus infection from 2015 Q1 through 2019 Q4. The number of individuals was fewer than 40. In the first quarter of 2020, there were 311 individuals with coronavirus infection. Given the substantial increase in the number of infections, most of them should have COVID-19.
Data Analyses
To evaluate the risk of drug-associated AEs, we calculated the reporting odds ratio (ROR) [20], the data mining algorithm commonly used in a pharmacovigilance assessment. The RORs were calculated in the contingency 2 × 2 table, as described elsewhere [20]. We calculated the ROR for each drug of interest. If the lower bound of the 95% confidence interval (CI) of a ROR is greater than the threshold of 1.0, then the signal of an AE is considered as significant, or the detected AE is associated with a statistically significantly higher number of reports following the use of the drug of interest, compared with those reports following the use of all other drugs [20].
Results
Individuals Without Coronavirus Infection
In the FAERS database from 2015 Q1 to 2020 Q1, a total of 6.12 million reports were identified. The number of individuals reporting the use of each drug was 347,034 for chloroquine/hydroxychloroquine, 7506 for lopinavir/ritonavir, 38,810 for ribavirin, 5615 for darunavir, 38,049 for tocilizumab/sarilumab, 10 for umifenovir, 11 for favipiravir, 26,093 for azithromycin, 8838 for moxifloxacin, 12,595 for ceftriaxone, 1478 for piperacetazine/tazobactam, 351 for ampicillin/sulbactam, and 11,456 for tobramycin (Fig. 1a).Fig. 1 Frequency of cardiac disorders in the FDA Adverse Event Reporting System 2015 Q1 to 2020 Q1. a Demonstrates the proportion of cardiac disorders among individuals without coronavirus indications. b Demonstrates the proportion of cardiac disorders among individuals with coronavirus indications. AEs adverse events, CQ chloroquine, HCQ hydroxychloroquine, Sulbacta sulbactam, Tazo tazobactam
Of 6.12 million reports, 288,232 reports of cardiac AEs were indented. Table 1 compared basic characteristics of FAERS reports. The total number of cardiac AEs were 24,618 (Fig. 1a, 7.09%) for chloroquine/hydroxychloroquine, 501 (6.67%) for lopinavir/ritonavir, 1311 (3.38%) for ribavirin, 279 (4.97%) for darunavir, 1683 (4.42%) for tocilizumab/sarilumab, 2 (20%) for umifenovir, 2 (18.18%) for favipiravir, 1582 (6.06%) for azithromycin, 839 (9.49%) for moxifloxacin, 1045 (8.30%) for ceftriaxone, 131 (8.86%) for piperacetazine/tazobactam, 21 (5.98%) for ampicillin/sulbactam, and 239 (2.09%) for tobramycin, respectively.Table 1 Patient characteristics in the FDA Adverse Event Reporting System (FAERS) database 2015 Q1 to 2020 Q1
Characteristics Without coronavirus infection With coronavirus infectiona
No cardiac disorders
n (%) Cardiac disorders
n (%) P value No cardiac disorders
n (%) Cardiac disorders
n (%) P value
Age, years < 0.0001 < 0.0001
0–17 7371 (2.56) 17,990 (2.94) 11 (3.86) 10 (38.46)
18–44 35,932 (12.47) 691,341 (11.31) 38 (13.33) 3 (11.54)
45–64 64,994 (22.55) 1,170,182 (19.14) 56 (19.65) 3 (11.54)
65–75 42,702 (14.82) 649,677 (10.62) 31 (10.88) 2 (7.69)
75 and over 40,274 (13.97) 540,490 (8.84) 13 (4.56) 4 (15.38)
Unknown 96,959 (33.64) 2,883,488 (47.15) 136 (47.72) 4 (15.38)
Sex < 0.0001 0.120
Female 142,923 (49.59) 3,308,570 (54.1) 116 (40.70) 16 (61.54)
Male 116,680 (40.48) 2,026,205 (33.13) 133 (46.67) 8 (30.77)
Unknown 28,629 (9.93) 780,393 (12.76) 36 (12.63) 2 (7.69)
Year <0.0001
2015 49,631 (17.22) 1,038,146 (16.98)
2016 48,839 (16.94) 1,055,895 (17.27)
2017 51,771 (17.96) 1,090,998 (17.84)
2018 60,304 (20.92) 1,290,049 (21.1)
2019 61,198 (21.23) 1,285,828 (21.03)
2020 16,489 (5.72) 354,252 (5.79) 285 (100) 26 (100)
Country < 0.0001 0.0357
USA 145,599 (50.51) 4,461,211 (72.95) 136 (47.72) 18 (69.23)
Non-USA 142,633 (49.49) 1,653,957 (27.05) 149 (52.28) 8 (30.77)
Reporter’s type of occupation < 0.0001 0.0584
Consumer 112,593 (39.06) 3,034,172 (49.62) 113 (39.65) 4 (15.38)
Lawyer 5266 (1.83) 81,556 (1.33) 0 (0.00) 0 (0.00)
Physician 71,291 (24.73) 1,260,021 (20.6) 94 (32.98) 10 (38.46)
Other health professional 71,276 (24.73) 1,121,967 (18.35) 50 (17.54) 7 (26.92)
Pharmacist 19,830 (6.88) 453,270 (7.41) 15 (5.26) 4 (15.38)
Unknown 7976 (2.77) 164,182 (2.68) 0 (0.00) 1 (3.85)
aReports identified with “Coronavirus infection” in the FAERS from 1 January to 31 March, 2020
For chloroquine/hydroxychloroquine, the most frequently reported cardiac AaEs were palpitations (Fig. 2a, n = 3079), cardiac failure (n = 3129), myocardial infarction [MI] (n = 2964), tachycardia (n = 2859), and atrial fibrillation [AF] (n = 2441). The RORs (95% CI) associated with chloroquine/hydroxychloroquine were statistically significant, including 1.68 (1.66–1.70) for overall cardiac disorders, 1.35 (1.28–1.42) for cardiac arrest, 1.45 (1.40–1.50) for MI, 1.73 (1.66–1.80) for tachycardia, 1.77 (1.67–1.87) for arrhythmia, 1.79 (1.70–1.88) for bradycardia, 1.80 (1.73–1.86) for cardiac failure, and 2.28 (2.05–2.53) for CAD. When chloroquine/hydroxychloroquine concomitantly with azithromycin, the RORs were still significant (Fig. 2b). This finding was also consistent with previous findings that azithromycin may be associated with increased cardiac risks [25, 26, 28]. Taken together, close monitoring for QTc prolongation is necessary for patients who are female, older, have a history of HF, or use chloroquine/hydroxychloroquine with azithromycin.Fig. 2 Reporting odds ratio (ROR) of cardiac adverse events among individuals without coronavirus infection. The ROR and the 95% confidence interval (CI) of each cardiac adverse event following the use of a chloroquine/hydroxychloroquine (CQ/HCQ), b CQ/HCQ plus azithromycin, c lopinavir/ritonavir, d ribavirin, e darunavir, f tocilizumab/sarilumab, g azithromycin, h ceftriaxone, i moxifloxacin, j piperacetazine/tazobactam, and k ampicillin\sulbactam are provided in the adjacent tables. Note that the vertical red bar shows the line of ROR = 1. RORs (95% CI) in bold represent the significant signals of cardiac adverse events. Data source: FDA Adverse Event Reporting System 2015 Q1–2020 Q1
As shown in Fig. 2c, the most frequently reported cardiac AEs for lopinavir/ritonavir were cardiac failure (n = 82), MI (n = 77), palpitations (n = 56), tachycardia (n = 44), and AF (n = 44). The significant ROR signals were 1.52 (1.39–1.66) for overall cardiac disorders, 1.70 (1.36–2.13) for MI, 2.23 (1.63–3.06) for arrhythmia, 2.19 (1.63–2.95) for bradycardia, 2.09 (1.68–2.60) for cardiac failure, and 1.57 (1.17–2.11) for AF. The signal for palpitations was detected for ribavirin (Fig. 2d, ROR = 1.18, 95% CI 1.04–1.35). For darunavir (Fig. 2e), the ROR signals for MI and CAD were 2.95 (2.42–3.60) and 4.72 (2.79–7.98), respectively. For tocilizumab/sarilumab (Fig. 2f), the ROR signal for MI was 1.45 (1.30–1.62). For umifenovir and favipiravir, the number of events was too small to calculate RORs. For azithromycin only, the most frequently reported cardiac AEs were tachycardia (Fig. 2g, n = 212), palpitations (n = 197), AF (n = 172), and cardiac failure (n = 163). The RORs (95% CI) was 1.37 (1.30–1.44) for overall cardiac disorders, 1.51 (1.26–1.80) for cardiac arrest, 1.64 (1.44–1.88) for tachycardia, 1.45 (1.26–1.67) for palpitations, 1.26 (1.02–1.55) for arrhythmia, 1.51 (1.23–1.86) for bradycardia, 1.19 (1.02–1.39) for cardiac failure, and 1.77 (1.52–2.06) for CAD, respectively. For ceftriaxone (Fig. 2h), the significant ROR signals were 1.92 (1.80–2.05) for overall cardiac disorders, 4.50 (3.88–5.23) for cardiac arrests, 3.43 (2.99–3.93) for tachycardia, 1.39 (1.03–1.90) for arrhythmia, 2.65 (2.15–3.27) for bradycardia, 1.67 (1.38–2.02) for cardiac failure, and 1.77 (1.42–2.19) for AF, respectively. For moxifloxacin (Fig. 2i), the RORs (95% CI) were 2.23 (2.08–2.39) for overall cardiac disorders, 1.88 (1.43–2.47) for cardiac arrest, 2.32 (1.91–2.82) for tachycardia, 3.32 (2.61–4.22) for arrhythmia, 1.52 (1.10–2.11) for bradycardia, 1.86 (1.51–2.30) for cardiac failure, 1.51 (1.15–2.00) for AF, and 2.56 (1.45–4.52) for CAD. For piperacetazine/tazobactam (Fig. 2j), the significant ROR signals were 2.06 (1.72–2.47) for overall cardiac disorders, 3.70 (2.29–5.96) for cardiac arrest, 5.15 (3.71–7.13) for tachycardia, 1.77 (0.84–3.72) for bradycardia, 3.26 (2.20–4.84) for AF, and 4.39 (2.93–6.58) for CAD. The signal for cardiac failure was detected for ampicillin/sulbactam (Fig. 2k, ROR = 2.74, 95% CI 1.13–6.62).
Individuals with Coronavirus Infection
During the first quarter of 2020, a total of 311 individuals with coronavirus infection were identified. The number of patients reporting the use of the following drugs were 16 for chloroquine/hydroxychloroquine (Fig. 1b), 43 for lopinavir/ritonavir, 7 for ribavirin, 1 for darunavir, 1 for tocilizumab/sarilumab, 7 for umifenovir, 4 for azithromycin, 3 for moxifloxacin, 8 for ceftriaxone, and 2 for tobramycin, respectively. Among them, six drugs were reported with cardiac AEs, including chloroquine/hydroxychloroquine (n = 5, 31.25%), lopinavir/ritonavir (n = 1, 2.33%), ribavirin (n = 1, 14.29%), umifenovir (n = 1, 14.29%), azithromycin (n = 2, 50.00%), and ceftriaxone (n = 1, 12.50%).
Of 311 individuals with coronavirus infections, 26 patients reported cardiac AEs. As shown in Table 1, ten or 38.5% of individuals were dominantly aged under 17 years (p < 0.001). For chloroquine/hydroxychloroquine, as shown in Fig. 3a, the most frequently reported cardiac AEs included cardiac arrest (n = 1), tachycardia (n = 2), and QT prolongation (n = 2). When chloroquine/hydroxychloroquine was combined with azithromycin, cardiac arrest and QT prolongation were reported (Fig. 3b). Two cases of QT prolongation were reported for individuals using chloroquine/hydroxychloroquine.Fig. 3 Reporting odds ratio (ROR) of cardiac adverse events among individuals with coronavirus infection. Individuals with Preferred Terms of “Coronavirus infection”. The ROR and the 95% confidence interval (CI) of each cardiac adverse event following the use of a chloroquine/hydroxychloroquine (CQ/HCQ), b CQ/HCQ plus azithromycin, c lopinavir/ritonavir, d ribavirin, e umifenovir, f azithromycin, and g ceftriaxone are provided in the adjacent tables. Note that the vertical red bar shows the line of ROR = 1. RORs (95% CI) in bold represent the significant signals of cardiac adverse events. Data source: FDA Adverse Event Reporting System 2020 Q1
Cardiac arrest (n = 1) and tachycardia (n = 1) were reported for azithromycin with strong signals (Fig. 3f). For ceftriaxone, the two cases of cardiac AEs were tachycardia and cardiac arrest (Fig. 3g). The signals of cardiac AEs were not strong for lopinavir/ritonavir (n = 1), ribavirin (n = 1), and umifenovir (n = 1).
Discussion
This study found that the existing potential pharmacotherapies are associated with increased risks of overall cardiac disorders. We also found that nearly half of the individuals with coronavirus infections reported cardiac disorders following pharmacotherapies. In particular, chloroquine/hydroxychloroquine was reported to develop serious cardiac AEs, including tachycardia, cardiac arrest, and QT prolonged in the overall sample. In addition, individuals with coronavirus infections had further elevated risks of cardiac disorders compared with the overall sample. We also observed variations in the cardiac safety profiles of the pharmacotherapies available for patients with COVID-19. Therefore, in clinical practice, clinicians should be aware of the elevated cardiac AEs in patients with COVID-19 and weigh up both the benefits and harms of the therapies. Continued pharmacovigilance is needed on cardiac disorders of other possible pharmacotherapies for COVID-19 to improve patient health outcomes.
The increased cardiac risks reported in patients with COVID-19 using chloroquine/hydroxychloroquine and azithromycin can be explained by drug-induced QTc prolongation, a measure of delayed ventricular repolarization [21]. It can be fatal enough to result in sudden death. Excessive QTc prolongation with a corrected interval >500 ms can predispose the myocardium to the development of early arrhythmia, which in turn can trigger re-entrant tachycardia as the deadly Tdp. As a surrogate marker for developing Tdp, QTc prolongation has been an established side effect of class I and III anti-arrhythmic medications. This analysis revealed that azithromycin and hydroxychloroquine were associated with QT prolongations and cardiac arrest, consistent with a recent multi-national cohort study, in which chloroquine/hydroxychloroquine with or without azithromycin increased the risks of arrhythmias and in-hospital mortality.
Hydroxychloroquine specifically was consistent with increased risks of arrhythmia-related events such as palpitations, tachycardia, and a further complication of AF. For antiretrovirals used for COVID-19, most cardiac AEs are statistically significant in the group of lopinavir/ritonavir, especially for high-risk individuals with pre-existing cardiac injury or comorbidities such as HF and prior MI, resulting in its early stop in 13.8% of patients because of unfavorable reactions. In comparison with lopinavir/ritonavir, other antiretrovirals are not as prominent while it is important to weigh the risk-benefit ratio when selecting the best therapy. For instance, darunavir should be avoided in individuals with a history of CAD or prior MI as it significantly increases the risks of cardiac deterioration. Selected antibacterial agents for the treatment of COVID-19 have not shown promising outcomes but significantly increased risks of developing unwanted cardiac AEs. These findings strongly suggest caution in the use of certain medications with respect to cardiac adverse risks, particularly those patients at a high risk of cardiac disorders, either for COVID-19 treatment or pre-exposure prophylaxis.
Frequently used azithromycin and moxifloxacin have consistently shown increased risks of cardiovascular damage and mortality, especially among elderly individuals with pneumonia [23]. While beta-lactams such as ceftriaxone and zosyn cause more harms than benefits in patients who are more likely to experience tachycardia, and have symptoms of AF, HF, and cardiac arrest [24]. The risk of developing TdP is not solely based upon one medication but a cumulative effect of multiple risk factors such as female sex, increasing age, genetic disposition, and the use of multiple medications that can prolong QTc intervals, affect the metabolism of another QTc-prolonging drug, or cause renal/hepatic dysfunction [25, 26]. Hence, it is important to evaluate the patient demographic and clinical profile before administering possible pharmacotherapies for COVID-19 to minimize cardiac disorders.
In addition to drug-induced cardiac AEs, SARS-CoV-2 itself may cause heart inflammation, and is notorious in worsening pre-existing cardiovascular conditions in patients with myocarditis, HF, and arrhythmia [11]. Different etiologies of acute cardiac injury resulting from COVID-19 may include right-sided HF secondary to hypoxia-mediated pulmonary hypertension, worsening of coronary perfusion due to reduced oxygen-blood saturation, and most severely, a hyperacute systematic inflammatory response syndrome like sepsis, especially seen in older patients with multiple underlying chronic diseases admitted to the intensive care units. Moreover, a problem concerning potassium levels has arisen in patients with COVID-19 as a result of the interaction of SARS-CoV2 with the renal artery stenosis system [27]. Hypokalemia is known to increase the susceptibility of patients to arrhythmia and heart rhythm irregularities. Here, we found that chloroquine/hydroxychloroquine was associated with higher risks of cardiac arrhythmias. Therefore, it is recommended for the management of arrhythmia to optimize electrolyte concentrations through appropriate supplementation and fluids, avoiding high-risk medications, and closely monitoring the electrocardiograms of patients taking QTc-prolonging agents.
This study has some strengths worth mentioning. The FAERS database includes a large amount of cardiac AEs of possible pharmacotherapies for COVID-19 reported worldwide. This enables researchers to examine cardiac AEs and compare to those in patients with COVID-19. This study further provides early signals for health professionals regarding adverse cardiovascular reactions during the selection of specific medications to be utilized or placed in future guidelines while ensuring maximal efficacy and patient safety. Onsite clinical judgment and incorporation of individualized patient factors are also important for optimizing treatment outcomes for patients with COVID-19.
This study possesses some limitations that should be considered. First, most case reports submitted were based upon personal observations and did not have a commonly agreed pathological pattern and treatment preference, leading to inconsistent data quality and potentially incomplete reports with missing information. Second, the reporting to the FAERS database is voluntary and can be easily biased. Depending on the variable criteria used for the selection of events, some cases may not be interpreted as incidence and can be omitted. Third, the sample size of patients with COVID-19 was relatively limited owing to the unavailability of the latest data in the FAERS database. Fourth, we could not exclude the possibility of unmeasured confounding factors, such as disease severity and coexisting conditions and complications, which may over- or under-estimate the association with potential pharmacotherapies and the risk of cardiac AEs. Hence, further studies are needed to make a causal link between drug exposure and cardiac AEs. Last, we cannot exclude the possibility that some patients with coronavirus infection actually had other conditions, such as influenza, rather than COVID-19. By comparing the number of individuals in the previous quarters, more than 90% of individuals identified in the 2020 Q1 are expected to have COVID-19.
Conclusions
The current pharmacotherapies for COVID-19, particularly chloroquine/hydroxychloroquine and azithromycin, are associated with increased risks of cardiac AEs. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. The choice of pharmacotherapy should be based on demographic and clinical profiles. Cardiac monitoring should be employed for patients with COVID-19, especially those at high risk.
Appendix
See Tables Table 2 List of preferred terms
Preferred terms
Acute coronary syndrome
Aortic valve disease
Asystole
Atrial fibrillation
Atrial flutter
Atrioventricular block complete
Atrioventricular block first degree
Cardiac arrest
Chest pain—cardiac
Conduction disorder
Constrictive pericarditis
Heart failure
Left ventricular systolic dysfunction
Mitral valve disease
Mobitz (type) II atrioventricular block
Mobitz type I
Myocardial infarction
Myocarditis
Palpitations
Paroxysmal atrial tachycardia
Pericardial effusion
Pericardial tamponade
Pericarditis
Pulmonary valve disease
Restrictive cardiomyopathy
Right ventricular dysfunction
Sick sinus syndrome
Sinus bradycardia
Sinus tachycardia
Supraventricular tachycardia
Tricuspid valve disease
Ventricular arrhythmia
Ventricular fibrillation
Ventricular tachycardia
Wolff-Parkinson-White syndrome
2 and Table 3 Number of individuals with coronavirus infection in the FDA Adverse Event Reporting System database, 2015 Q1–2020 Q1
Quarter Number of individuals with coronavirus infection
2020Q4 311
2019Q4 32
2019Q3 36
2019Q2 37
2019Q1 43
2018Q4 38
2018Q3 40
2018Q2 40
2018Q1 39
2017Q4 12
2017Q3 9
2017Q2 21
2017Q1 23
2016Q4 14
2016Q3 10
2016Q2 9
2016Q1 7
2015Q4 2
2015Q3 0
2015Q2 6
2015Q1 6
3.
Declarations
Funding
This research did not receive any funding.
Conflicts of Interest/Competing interest
Jing Yuan, Minghui Li, Xiaoqiang Xiang, Tai-Ying Lee, Gang Lv, Yiqun Yu, Bing Han, and Z. Kevin Lu have no conflicts of interest that are directly relevant to the content of this article.
Ethics approval
This research does not involve human subjects. It is not required to obtain institutional review board approval.
Consent to participate
Not applicable.
Consent for Publication
Not applicable.
Availability of data and material
Data are available upon reasonable request.
Code availability
SAS codes are available upon reasonable request.
Authors’ contributions
Concept and design: JY, ML, XX, ZKL. Acquisition, analysis, or interpretation of data: JY, ZKL, GL, XX, ML. Drafting of the manuscript: JY, ZKL, GL, ML. Critical revision of the manuscript for important intellectual content: JY, ZKL, GL, ML, YY, BH, XX. Statistical analysis: JY, ML. Administrative, technical, or material support: ZKL, XX, BH. Supervision: ZKL, XX, BH.
Jing Yuan, Minghui Li, Yiqun Yu, Bing Han have contributed equally to the article. | AZITHROMYCIN ANHYDROUS | DrugsGivenReaction | CC BY-NC | 33569736 | 18,935,191 | 2021-06 |
What was the outcome of reaction 'Product use in unapproved indication'? | Pharmacotherapy Management for COVID-19 and Cardiac Safety: A Data Mining Approach for Pharmacovigilance Evidence from the FDA Adverse Event Reporting System (FAERS).
BACKGROUND
Several pharmacological agents, such as chloroquine/hydroxychloroquine, have been promoted for COVID-19 treatment or pre-exposure prophylaxis. However, no comprehensive evaluation of the safety of these possible agents is available, and is urgently needed.
OBJECTIVE
The purpose of this study was to investigate the risks of cardiac adverse events associated with the possible pharmacotherapies for COVID-19, including certain antimalarial, antiviral, and antibiotic drugs.
METHODS
We conduced retrospective pharmacovigilance analyses of the US Food and Drug Administration Adverse Event Reporting System database. The reporting odds ratio (ROR), a data mining algorithm commonly used in pharmacovigilance assessment, was generated to quantify the detection signal of adverse events.
RESULTS
Among individuals without coronavirus infection from 2015 Q1 to 2020 Q1, increased risks for cardiac disorders were found for antiviral agents such as chloroquine/hydroxychloroquine (ROR: 1.68; 95% confidence interval [CI] 1.66-1.70), lopinavir/ritonavir (ROR: 1.52; 95% CI 1.39-1.66), and antibiotics such as azithromycin (ROR: 1.37; 95% CI 1.30-1.44) and ceftriaxone (ROR: 1.92; 95% CI 1.80-2.05). Increased serious cardiac adverse events, including myocardial infarction, arrhythmia, and cardiac arrest, were also reported for these drugs. Further analyses of individuals with coronavirus infections revealed that 40% of individuals receiving chloroquine/hydroxychloroquine reported serious cardiac adverse events. Two cases resulted in QT prolongations and one case resulted in cardiac arrest. Chloroquine/hydroxychloroquine and azithromycin contributed to all the QT prolongation and cardiac arrest cases.
CONCLUSIONS
The current pharmacotherapies for COVID-19 are associated with increased risks of cardiac adverse events. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. Clinicians should closely monitor patients with COVID-19, especially those at high risk, using chloroquine/hydroxychloroquine and azithromycin.
Key Points
Chloroquine/hydroxychloroquine may have contributed to a large proportion of cardiac disorders for COVID-19 treatment or pre-exposure prophylaxis.
The cardiac risks associated with the pharmacotherapies seem to be further elevated in patients with coronavirus infection, and close monitoring of cardiac risks is needed.
The potential pharmacotherapies are associated with serious cardiac adverse events, such as myocardial infarction, arrhythmia, and cardiac arrest.
Introduction
Over five million cases of Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], were reported worldwide as of 21 May, 2020 [2]. A large majority of individuals with COVID-19 have reported experiencing mild-to-moderate symptoms, including fever, cough, and fatigue [3], most of which do not require medical attention. However, COVID-19 can cause severe complications or even death in older adults or high-risk patients with concurrent chronic diseases [3]. Currently, there is no proven effective treatment against COVID-19. Infection control measures and supportive care, for example, supplemental oxygen and mechanical ventilatory support, are the main management strategies recommended by the current COVID-19 Treatment Guidelines [4]. With the rapid growth of the COVID-19 pandemic, there is an urgent need to identify existing medications deemed to be safe and effective with acceptable side effects, to attenuate infections and prevent severe complications in individuals with COVID-19.
Currently, three antiviral drugs—remdesivir, hydroxychloroquine, and chloroquine—have received emergency use authorization from the US Food and Drug Administration (FDA) in May 2020 [5]. These three drugs demonstrated antiviral properties against SARS-CoV-2 in an early in-vitro study [6]. Chloroquines showed benefits in patients hospitalized with COVID-19, based on two small clinical studies [7, 8]. Thereafter, on 23 March, 2020, the FDA allowed the emergency use of chloroquines in confirmed COVID-19 cases who were hospitalized. However, more recent research demonstrated no benefits of using chloroquines in treating COVID-19 infection [9, 10]. In addition to remdesivir, several antiviral agents such as lopinavir/ritonavir have been tested while showing uncertain benefits in treating COVID-19 [4]. The combined use of antiviral agents and antibiotics, such as azithromycin and fluoroquinolones, has also been reported with mixed results.
While COVID-19 is the disease that primarily manifests in the respiratory system [11], cardiac disorders, such as coronary artery disease (CAD), heart failure (HF), and cerebrovascular disease, are common in hospitalized individuals with COVID-19 [3]. One potential mechanism is that myocardial cells have strong receptor angiotensin-converting enzyme II expression, which could be the target of SARS-CoV-2 infection [12]. Other possible explanations include hypoxia and microthrombi, which cause vascular damage [13]. Considering the potential cardiac risks associated with some antiviral agents, however, pharmacotherapy may also play a role in the elevated risk of cardiac adverse events (AEs) observed in individuals with COVID-19. For example, chloroquine and hydroxychloroquine have long been proven to increase the risk of torsade de pointes (TdP) and cause QT prolongation [14], which further increases the patient’s susceptibility to adverse cardiovascular outcomes and death during aggressive responses to COVID-19 infections. Risks of ventricular arrhythmia and cardiac arrests are also complicated by the incremental effects of azithromycin. After the emergence of severe cardiac AEs associated with hydroxychloroquine and chloroquine, the FDA cautioned against the use of investigational drugs outside the setting of a health system or clinical trial to avoid possible cardiovascular damage.
With the rapid growth of the COVID-19 pandemic and current promotion of certain pharmacological agents for COVID-19 treatments or pre-exposure prophylaxis, evidence on the cardiac risks of these possible therapies is urgently needed for clinicians to make informed decisions related to the benefits and risks of pharmacotherapies [15]. Therefore, the objective of this study was to investigate the association between the possible pharmacotherapies for COVID-19 and the risks of cardiac AEs.
Methods
Study Design and Data Source
We conducted a retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. The AEs reported for the potential pharmacotherapies for COVID-19 were extracted and queried from the first quarter of 2015 through the first quarter of 2020. We included the study period from 2015 and forward because the goal of the study was to investigate the risks of cardiac AEs associated with the possible pharmacotherapies for COVID-19. Therefore, although the medications may not be used for COVID-19 before the end of 2019, the potential risks may still be possible for other indications and are worthy of evaluation. In addition, the FAERS data were limited since the COVID-19 pandemic, therefore, we included data from 2015 and forwards to evaluate the safety of the therapies. These drugs were commonly used in clinical settings or under investigation to treat patients with COVID-19 [16].
The FAERS is a post-marketing surveillance system that collects spontaneous AEs reported directly from consumers, healthcare professionals, pharmaceutical companies, or others [17]. The database contains nearly 20 million reports from 1969 to March 2020 [17]. The database contains detailed information on patient demographics, indications, medication use, outcomes, and sources of reports. All AEs were coded using Preferred Terms (PTs) in the Medical Dictionary for Regulatory Activities terminology [18]. The Medical Dictionary for Regulatory Activities hierarchy consists of five levels, from specific to broad categories. These coded terms are arranged in a hierarchy of five categories. The “System Organ Classes”, grouped by disease etiology, manifestation site, or purpose, are the high-level group terms. The PTs, describing the disease symptoms or diagnosis, an indication, laboratory results, and procedures, are the low-level group terms and were used in the FAERS database [18].
Identification of Exposures
We searched the FAERS database to identify reports involving drug generic names, including chloroquine, hydroxychloroquine, lopinavir, ritonavir, ribavirin, umifenovir, tocilizumab, sarilumab, darunavir, favipiravir, azithromycin, moxifloxacin, ceftriaxone, piperacetazine, tazobactam, ampicillin, sulbactam, and tobramycin. A clinical pharmacist also reviewed the medications identified by the search queries. Oseltamivir was not included in the analysis because it was an investigational drug and not permitted for use outside of clinical trials. Drugs coded as suspect or concomitant use were also examined. For AEs reported in the first quarter of 2020, we further limited to those reports with coronavirus infection, to identify individuals with COVID-19.
Identification of Cardiac Disorder
To search for cardiac-related terms, we used the following PTs, including myocardial infarction, tachycardia, bradycardia, palpitations, cardiac failure, cardiac arrest, coronary artery disease, atrial fibrillation, and arrhythmia [19]. To understand the risks of overall cardiac AEs, we also searched the PTs listed under the System Organ Class of cardiac disorders in the Medical Dictionary for Regulatory Activities [18].
Identification of Coronavirus Infection
To identify patients with COVID-19, we searched reports involving “coronavirus infection” or “coronavirus test positive”, in the first quarter of 2020. To test this data mining strategy, we also compared the number of individuals with coronavirus infection from 2015 Q1 through 2019 Q4. The number of individuals was fewer than 40. In the first quarter of 2020, there were 311 individuals with coronavirus infection. Given the substantial increase in the number of infections, most of them should have COVID-19.
Data Analyses
To evaluate the risk of drug-associated AEs, we calculated the reporting odds ratio (ROR) [20], the data mining algorithm commonly used in a pharmacovigilance assessment. The RORs were calculated in the contingency 2 × 2 table, as described elsewhere [20]. We calculated the ROR for each drug of interest. If the lower bound of the 95% confidence interval (CI) of a ROR is greater than the threshold of 1.0, then the signal of an AE is considered as significant, or the detected AE is associated with a statistically significantly higher number of reports following the use of the drug of interest, compared with those reports following the use of all other drugs [20].
Results
Individuals Without Coronavirus Infection
In the FAERS database from 2015 Q1 to 2020 Q1, a total of 6.12 million reports were identified. The number of individuals reporting the use of each drug was 347,034 for chloroquine/hydroxychloroquine, 7506 for lopinavir/ritonavir, 38,810 for ribavirin, 5615 for darunavir, 38,049 for tocilizumab/sarilumab, 10 for umifenovir, 11 for favipiravir, 26,093 for azithromycin, 8838 for moxifloxacin, 12,595 for ceftriaxone, 1478 for piperacetazine/tazobactam, 351 for ampicillin/sulbactam, and 11,456 for tobramycin (Fig. 1a).Fig. 1 Frequency of cardiac disorders in the FDA Adverse Event Reporting System 2015 Q1 to 2020 Q1. a Demonstrates the proportion of cardiac disorders among individuals without coronavirus indications. b Demonstrates the proportion of cardiac disorders among individuals with coronavirus indications. AEs adverse events, CQ chloroquine, HCQ hydroxychloroquine, Sulbacta sulbactam, Tazo tazobactam
Of 6.12 million reports, 288,232 reports of cardiac AEs were indented. Table 1 compared basic characteristics of FAERS reports. The total number of cardiac AEs were 24,618 (Fig. 1a, 7.09%) for chloroquine/hydroxychloroquine, 501 (6.67%) for lopinavir/ritonavir, 1311 (3.38%) for ribavirin, 279 (4.97%) for darunavir, 1683 (4.42%) for tocilizumab/sarilumab, 2 (20%) for umifenovir, 2 (18.18%) for favipiravir, 1582 (6.06%) for azithromycin, 839 (9.49%) for moxifloxacin, 1045 (8.30%) for ceftriaxone, 131 (8.86%) for piperacetazine/tazobactam, 21 (5.98%) for ampicillin/sulbactam, and 239 (2.09%) for tobramycin, respectively.Table 1 Patient characteristics in the FDA Adverse Event Reporting System (FAERS) database 2015 Q1 to 2020 Q1
Characteristics Without coronavirus infection With coronavirus infectiona
No cardiac disorders
n (%) Cardiac disorders
n (%) P value No cardiac disorders
n (%) Cardiac disorders
n (%) P value
Age, years < 0.0001 < 0.0001
0–17 7371 (2.56) 17,990 (2.94) 11 (3.86) 10 (38.46)
18–44 35,932 (12.47) 691,341 (11.31) 38 (13.33) 3 (11.54)
45–64 64,994 (22.55) 1,170,182 (19.14) 56 (19.65) 3 (11.54)
65–75 42,702 (14.82) 649,677 (10.62) 31 (10.88) 2 (7.69)
75 and over 40,274 (13.97) 540,490 (8.84) 13 (4.56) 4 (15.38)
Unknown 96,959 (33.64) 2,883,488 (47.15) 136 (47.72) 4 (15.38)
Sex < 0.0001 0.120
Female 142,923 (49.59) 3,308,570 (54.1) 116 (40.70) 16 (61.54)
Male 116,680 (40.48) 2,026,205 (33.13) 133 (46.67) 8 (30.77)
Unknown 28,629 (9.93) 780,393 (12.76) 36 (12.63) 2 (7.69)
Year <0.0001
2015 49,631 (17.22) 1,038,146 (16.98)
2016 48,839 (16.94) 1,055,895 (17.27)
2017 51,771 (17.96) 1,090,998 (17.84)
2018 60,304 (20.92) 1,290,049 (21.1)
2019 61,198 (21.23) 1,285,828 (21.03)
2020 16,489 (5.72) 354,252 (5.79) 285 (100) 26 (100)
Country < 0.0001 0.0357
USA 145,599 (50.51) 4,461,211 (72.95) 136 (47.72) 18 (69.23)
Non-USA 142,633 (49.49) 1,653,957 (27.05) 149 (52.28) 8 (30.77)
Reporter’s type of occupation < 0.0001 0.0584
Consumer 112,593 (39.06) 3,034,172 (49.62) 113 (39.65) 4 (15.38)
Lawyer 5266 (1.83) 81,556 (1.33) 0 (0.00) 0 (0.00)
Physician 71,291 (24.73) 1,260,021 (20.6) 94 (32.98) 10 (38.46)
Other health professional 71,276 (24.73) 1,121,967 (18.35) 50 (17.54) 7 (26.92)
Pharmacist 19,830 (6.88) 453,270 (7.41) 15 (5.26) 4 (15.38)
Unknown 7976 (2.77) 164,182 (2.68) 0 (0.00) 1 (3.85)
aReports identified with “Coronavirus infection” in the FAERS from 1 January to 31 March, 2020
For chloroquine/hydroxychloroquine, the most frequently reported cardiac AaEs were palpitations (Fig. 2a, n = 3079), cardiac failure (n = 3129), myocardial infarction [MI] (n = 2964), tachycardia (n = 2859), and atrial fibrillation [AF] (n = 2441). The RORs (95% CI) associated with chloroquine/hydroxychloroquine were statistically significant, including 1.68 (1.66–1.70) for overall cardiac disorders, 1.35 (1.28–1.42) for cardiac arrest, 1.45 (1.40–1.50) for MI, 1.73 (1.66–1.80) for tachycardia, 1.77 (1.67–1.87) for arrhythmia, 1.79 (1.70–1.88) for bradycardia, 1.80 (1.73–1.86) for cardiac failure, and 2.28 (2.05–2.53) for CAD. When chloroquine/hydroxychloroquine concomitantly with azithromycin, the RORs were still significant (Fig. 2b). This finding was also consistent with previous findings that azithromycin may be associated with increased cardiac risks [25, 26, 28]. Taken together, close monitoring for QTc prolongation is necessary for patients who are female, older, have a history of HF, or use chloroquine/hydroxychloroquine with azithromycin.Fig. 2 Reporting odds ratio (ROR) of cardiac adverse events among individuals without coronavirus infection. The ROR and the 95% confidence interval (CI) of each cardiac adverse event following the use of a chloroquine/hydroxychloroquine (CQ/HCQ), b CQ/HCQ plus azithromycin, c lopinavir/ritonavir, d ribavirin, e darunavir, f tocilizumab/sarilumab, g azithromycin, h ceftriaxone, i moxifloxacin, j piperacetazine/tazobactam, and k ampicillin\sulbactam are provided in the adjacent tables. Note that the vertical red bar shows the line of ROR = 1. RORs (95% CI) in bold represent the significant signals of cardiac adverse events. Data source: FDA Adverse Event Reporting System 2015 Q1–2020 Q1
As shown in Fig. 2c, the most frequently reported cardiac AEs for lopinavir/ritonavir were cardiac failure (n = 82), MI (n = 77), palpitations (n = 56), tachycardia (n = 44), and AF (n = 44). The significant ROR signals were 1.52 (1.39–1.66) for overall cardiac disorders, 1.70 (1.36–2.13) for MI, 2.23 (1.63–3.06) for arrhythmia, 2.19 (1.63–2.95) for bradycardia, 2.09 (1.68–2.60) for cardiac failure, and 1.57 (1.17–2.11) for AF. The signal for palpitations was detected for ribavirin (Fig. 2d, ROR = 1.18, 95% CI 1.04–1.35). For darunavir (Fig. 2e), the ROR signals for MI and CAD were 2.95 (2.42–3.60) and 4.72 (2.79–7.98), respectively. For tocilizumab/sarilumab (Fig. 2f), the ROR signal for MI was 1.45 (1.30–1.62). For umifenovir and favipiravir, the number of events was too small to calculate RORs. For azithromycin only, the most frequently reported cardiac AEs were tachycardia (Fig. 2g, n = 212), palpitations (n = 197), AF (n = 172), and cardiac failure (n = 163). The RORs (95% CI) was 1.37 (1.30–1.44) for overall cardiac disorders, 1.51 (1.26–1.80) for cardiac arrest, 1.64 (1.44–1.88) for tachycardia, 1.45 (1.26–1.67) for palpitations, 1.26 (1.02–1.55) for arrhythmia, 1.51 (1.23–1.86) for bradycardia, 1.19 (1.02–1.39) for cardiac failure, and 1.77 (1.52–2.06) for CAD, respectively. For ceftriaxone (Fig. 2h), the significant ROR signals were 1.92 (1.80–2.05) for overall cardiac disorders, 4.50 (3.88–5.23) for cardiac arrests, 3.43 (2.99–3.93) for tachycardia, 1.39 (1.03–1.90) for arrhythmia, 2.65 (2.15–3.27) for bradycardia, 1.67 (1.38–2.02) for cardiac failure, and 1.77 (1.42–2.19) for AF, respectively. For moxifloxacin (Fig. 2i), the RORs (95% CI) were 2.23 (2.08–2.39) for overall cardiac disorders, 1.88 (1.43–2.47) for cardiac arrest, 2.32 (1.91–2.82) for tachycardia, 3.32 (2.61–4.22) for arrhythmia, 1.52 (1.10–2.11) for bradycardia, 1.86 (1.51–2.30) for cardiac failure, 1.51 (1.15–2.00) for AF, and 2.56 (1.45–4.52) for CAD. For piperacetazine/tazobactam (Fig. 2j), the significant ROR signals were 2.06 (1.72–2.47) for overall cardiac disorders, 3.70 (2.29–5.96) for cardiac arrest, 5.15 (3.71–7.13) for tachycardia, 1.77 (0.84–3.72) for bradycardia, 3.26 (2.20–4.84) for AF, and 4.39 (2.93–6.58) for CAD. The signal for cardiac failure was detected for ampicillin/sulbactam (Fig. 2k, ROR = 2.74, 95% CI 1.13–6.62).
Individuals with Coronavirus Infection
During the first quarter of 2020, a total of 311 individuals with coronavirus infection were identified. The number of patients reporting the use of the following drugs were 16 for chloroquine/hydroxychloroquine (Fig. 1b), 43 for lopinavir/ritonavir, 7 for ribavirin, 1 for darunavir, 1 for tocilizumab/sarilumab, 7 for umifenovir, 4 for azithromycin, 3 for moxifloxacin, 8 for ceftriaxone, and 2 for tobramycin, respectively. Among them, six drugs were reported with cardiac AEs, including chloroquine/hydroxychloroquine (n = 5, 31.25%), lopinavir/ritonavir (n = 1, 2.33%), ribavirin (n = 1, 14.29%), umifenovir (n = 1, 14.29%), azithromycin (n = 2, 50.00%), and ceftriaxone (n = 1, 12.50%).
Of 311 individuals with coronavirus infections, 26 patients reported cardiac AEs. As shown in Table 1, ten or 38.5% of individuals were dominantly aged under 17 years (p < 0.001). For chloroquine/hydroxychloroquine, as shown in Fig. 3a, the most frequently reported cardiac AEs included cardiac arrest (n = 1), tachycardia (n = 2), and QT prolongation (n = 2). When chloroquine/hydroxychloroquine was combined with azithromycin, cardiac arrest and QT prolongation were reported (Fig. 3b). Two cases of QT prolongation were reported for individuals using chloroquine/hydroxychloroquine.Fig. 3 Reporting odds ratio (ROR) of cardiac adverse events among individuals with coronavirus infection. Individuals with Preferred Terms of “Coronavirus infection”. The ROR and the 95% confidence interval (CI) of each cardiac adverse event following the use of a chloroquine/hydroxychloroquine (CQ/HCQ), b CQ/HCQ plus azithromycin, c lopinavir/ritonavir, d ribavirin, e umifenovir, f azithromycin, and g ceftriaxone are provided in the adjacent tables. Note that the vertical red bar shows the line of ROR = 1. RORs (95% CI) in bold represent the significant signals of cardiac adverse events. Data source: FDA Adverse Event Reporting System 2020 Q1
Cardiac arrest (n = 1) and tachycardia (n = 1) were reported for azithromycin with strong signals (Fig. 3f). For ceftriaxone, the two cases of cardiac AEs were tachycardia and cardiac arrest (Fig. 3g). The signals of cardiac AEs were not strong for lopinavir/ritonavir (n = 1), ribavirin (n = 1), and umifenovir (n = 1).
Discussion
This study found that the existing potential pharmacotherapies are associated with increased risks of overall cardiac disorders. We also found that nearly half of the individuals with coronavirus infections reported cardiac disorders following pharmacotherapies. In particular, chloroquine/hydroxychloroquine was reported to develop serious cardiac AEs, including tachycardia, cardiac arrest, and QT prolonged in the overall sample. In addition, individuals with coronavirus infections had further elevated risks of cardiac disorders compared with the overall sample. We also observed variations in the cardiac safety profiles of the pharmacotherapies available for patients with COVID-19. Therefore, in clinical practice, clinicians should be aware of the elevated cardiac AEs in patients with COVID-19 and weigh up both the benefits and harms of the therapies. Continued pharmacovigilance is needed on cardiac disorders of other possible pharmacotherapies for COVID-19 to improve patient health outcomes.
The increased cardiac risks reported in patients with COVID-19 using chloroquine/hydroxychloroquine and azithromycin can be explained by drug-induced QTc prolongation, a measure of delayed ventricular repolarization [21]. It can be fatal enough to result in sudden death. Excessive QTc prolongation with a corrected interval >500 ms can predispose the myocardium to the development of early arrhythmia, which in turn can trigger re-entrant tachycardia as the deadly Tdp. As a surrogate marker for developing Tdp, QTc prolongation has been an established side effect of class I and III anti-arrhythmic medications. This analysis revealed that azithromycin and hydroxychloroquine were associated with QT prolongations and cardiac arrest, consistent with a recent multi-national cohort study, in which chloroquine/hydroxychloroquine with or without azithromycin increased the risks of arrhythmias and in-hospital mortality.
Hydroxychloroquine specifically was consistent with increased risks of arrhythmia-related events such as palpitations, tachycardia, and a further complication of AF. For antiretrovirals used for COVID-19, most cardiac AEs are statistically significant in the group of lopinavir/ritonavir, especially for high-risk individuals with pre-existing cardiac injury or comorbidities such as HF and prior MI, resulting in its early stop in 13.8% of patients because of unfavorable reactions. In comparison with lopinavir/ritonavir, other antiretrovirals are not as prominent while it is important to weigh the risk-benefit ratio when selecting the best therapy. For instance, darunavir should be avoided in individuals with a history of CAD or prior MI as it significantly increases the risks of cardiac deterioration. Selected antibacterial agents for the treatment of COVID-19 have not shown promising outcomes but significantly increased risks of developing unwanted cardiac AEs. These findings strongly suggest caution in the use of certain medications with respect to cardiac adverse risks, particularly those patients at a high risk of cardiac disorders, either for COVID-19 treatment or pre-exposure prophylaxis.
Frequently used azithromycin and moxifloxacin have consistently shown increased risks of cardiovascular damage and mortality, especially among elderly individuals with pneumonia [23]. While beta-lactams such as ceftriaxone and zosyn cause more harms than benefits in patients who are more likely to experience tachycardia, and have symptoms of AF, HF, and cardiac arrest [24]. The risk of developing TdP is not solely based upon one medication but a cumulative effect of multiple risk factors such as female sex, increasing age, genetic disposition, and the use of multiple medications that can prolong QTc intervals, affect the metabolism of another QTc-prolonging drug, or cause renal/hepatic dysfunction [25, 26]. Hence, it is important to evaluate the patient demographic and clinical profile before administering possible pharmacotherapies for COVID-19 to minimize cardiac disorders.
In addition to drug-induced cardiac AEs, SARS-CoV-2 itself may cause heart inflammation, and is notorious in worsening pre-existing cardiovascular conditions in patients with myocarditis, HF, and arrhythmia [11]. Different etiologies of acute cardiac injury resulting from COVID-19 may include right-sided HF secondary to hypoxia-mediated pulmonary hypertension, worsening of coronary perfusion due to reduced oxygen-blood saturation, and most severely, a hyperacute systematic inflammatory response syndrome like sepsis, especially seen in older patients with multiple underlying chronic diseases admitted to the intensive care units. Moreover, a problem concerning potassium levels has arisen in patients with COVID-19 as a result of the interaction of SARS-CoV2 with the renal artery stenosis system [27]. Hypokalemia is known to increase the susceptibility of patients to arrhythmia and heart rhythm irregularities. Here, we found that chloroquine/hydroxychloroquine was associated with higher risks of cardiac arrhythmias. Therefore, it is recommended for the management of arrhythmia to optimize electrolyte concentrations through appropriate supplementation and fluids, avoiding high-risk medications, and closely monitoring the electrocardiograms of patients taking QTc-prolonging agents.
This study has some strengths worth mentioning. The FAERS database includes a large amount of cardiac AEs of possible pharmacotherapies for COVID-19 reported worldwide. This enables researchers to examine cardiac AEs and compare to those in patients with COVID-19. This study further provides early signals for health professionals regarding adverse cardiovascular reactions during the selection of specific medications to be utilized or placed in future guidelines while ensuring maximal efficacy and patient safety. Onsite clinical judgment and incorporation of individualized patient factors are also important for optimizing treatment outcomes for patients with COVID-19.
This study possesses some limitations that should be considered. First, most case reports submitted were based upon personal observations and did not have a commonly agreed pathological pattern and treatment preference, leading to inconsistent data quality and potentially incomplete reports with missing information. Second, the reporting to the FAERS database is voluntary and can be easily biased. Depending on the variable criteria used for the selection of events, some cases may not be interpreted as incidence and can be omitted. Third, the sample size of patients with COVID-19 was relatively limited owing to the unavailability of the latest data in the FAERS database. Fourth, we could not exclude the possibility of unmeasured confounding factors, such as disease severity and coexisting conditions and complications, which may over- or under-estimate the association with potential pharmacotherapies and the risk of cardiac AEs. Hence, further studies are needed to make a causal link between drug exposure and cardiac AEs. Last, we cannot exclude the possibility that some patients with coronavirus infection actually had other conditions, such as influenza, rather than COVID-19. By comparing the number of individuals in the previous quarters, more than 90% of individuals identified in the 2020 Q1 are expected to have COVID-19.
Conclusions
The current pharmacotherapies for COVID-19, particularly chloroquine/hydroxychloroquine and azithromycin, are associated with increased risks of cardiac AEs. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. The choice of pharmacotherapy should be based on demographic and clinical profiles. Cardiac monitoring should be employed for patients with COVID-19, especially those at high risk.
Appendix
See Tables Table 2 List of preferred terms
Preferred terms
Acute coronary syndrome
Aortic valve disease
Asystole
Atrial fibrillation
Atrial flutter
Atrioventricular block complete
Atrioventricular block first degree
Cardiac arrest
Chest pain—cardiac
Conduction disorder
Constrictive pericarditis
Heart failure
Left ventricular systolic dysfunction
Mitral valve disease
Mobitz (type) II atrioventricular block
Mobitz type I
Myocardial infarction
Myocarditis
Palpitations
Paroxysmal atrial tachycardia
Pericardial effusion
Pericardial tamponade
Pericarditis
Pulmonary valve disease
Restrictive cardiomyopathy
Right ventricular dysfunction
Sick sinus syndrome
Sinus bradycardia
Sinus tachycardia
Supraventricular tachycardia
Tricuspid valve disease
Ventricular arrhythmia
Ventricular fibrillation
Ventricular tachycardia
Wolff-Parkinson-White syndrome
2 and Table 3 Number of individuals with coronavirus infection in the FDA Adverse Event Reporting System database, 2015 Q1–2020 Q1
Quarter Number of individuals with coronavirus infection
2020Q4 311
2019Q4 32
2019Q3 36
2019Q2 37
2019Q1 43
2018Q4 38
2018Q3 40
2018Q2 40
2018Q1 39
2017Q4 12
2017Q3 9
2017Q2 21
2017Q1 23
2016Q4 14
2016Q3 10
2016Q2 9
2016Q1 7
2015Q4 2
2015Q3 0
2015Q2 6
2015Q1 6
3.
Declarations
Funding
This research did not receive any funding.
Conflicts of Interest/Competing interest
Jing Yuan, Minghui Li, Xiaoqiang Xiang, Tai-Ying Lee, Gang Lv, Yiqun Yu, Bing Han, and Z. Kevin Lu have no conflicts of interest that are directly relevant to the content of this article.
Ethics approval
This research does not involve human subjects. It is not required to obtain institutional review board approval.
Consent to participate
Not applicable.
Consent for Publication
Not applicable.
Availability of data and material
Data are available upon reasonable request.
Code availability
SAS codes are available upon reasonable request.
Authors’ contributions
Concept and design: JY, ML, XX, ZKL. Acquisition, analysis, or interpretation of data: JY, ZKL, GL, XX, ML. Drafting of the manuscript: JY, ZKL, GL, ML. Critical revision of the manuscript for important intellectual content: JY, ZKL, GL, ML, YY, BH, XX. Statistical analysis: JY, ML. Administrative, technical, or material support: ZKL, XX, BH. Supervision: ZKL, XX, BH.
Jing Yuan, Minghui Li, Yiqun Yu, Bing Han have contributed equally to the article. | Not recovered | ReactionOutcome | CC BY-NC | 33569736 | 18,935,191 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acne cystic'. | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | METHYLPREDNISOLONE, PRAZIQUANTEL | DrugsGivenReaction | CC BY | 33571228 | 19,154,807 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anxiety'. | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | METHYLPREDNISOLONE, PRAZIQUANTEL | DrugsGivenReaction | CC BY | 33571228 | 19,154,807 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood glucose increased'. | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | METHYLPREDNISOLONE, PRAZIQUANTEL | DrugsGivenReaction | CC BY | 33571228 | 19,154,807 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cushingoid'. | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | METHYLPREDNISOLONE, PRAZIQUANTEL | DrugsGivenReaction | CC BY | 33571228 | 19,154,807 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Folliculitis'. | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | METHYLPREDNISOLONE, PRAZIQUANTEL | DrugsGivenReaction | CC BY | 33571228 | 19,154,807 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Insomnia'. | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | METHYLPREDNISOLONE, PRAZIQUANTEL | DrugsGivenReaction | CC BY | 33571228 | 19,154,807 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Transaminases increased'. | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | METHYLPREDNISOLONE, PRAZIQUANTEL | DrugsGivenReaction | CC BY | 33571228 | 19,154,807 | 2021-02 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33571228 | 19,154,807 | 2021-02 |
What was the dosage of drug 'PRAZIQUANTEL'? | Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: A tertiary referral centre experience.
Neuroschistosomiasis is a severe complication of schistosomiasis, triggered by the local immune reaction to egg deposition, with spinal cord involvement the most well recognised form. Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae. The rarity of this condition in returning travellers to high income countries can result in delayed diagnosis and treatment. We aimed to evaluate the diagnosis and management of neuroschistosomiasis in a UK national referral centre.
A retrospective review of confirmed clinical cases of spinal schistosomiasis referred to the Hospital for Tropical Diseases, UK, between January 2016 and January 2020 was undertaken. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data collected.
Four cases of neuroschistosomiasis were identified. The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. All patients presented with features of transverse myelitis including back pain, leg weakness, paraesthesia and urinary dysfunction. The mean time from presentation to health services to definitive treatment was 42.5 days (range 16-74 days). Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiological features on MRI spine included enhancement focused predominantly in the lower thoracic spinal cord in three cases and the conus in one patient. All patients received a minimum of three days of oral praziquantel and high dose steroids. At three-month follow-up, one patient had complete resolution of symptoms and three had residual deficit; one patient was left with urinary and faecal incontinence, another had urinary retention, and the final patient has persistent leg pains and constipation.
We observed a marked delay in diagnosis of neuroschistosomiasis in a non-endemic country. We advocate undertaking a thorough travel history, early use of imaging and CSF schistosomal serology to ensure early diagnosis of neuroschistosomiasis in patients presenting with consistent symptoms. If schistosomal diagnostics are not immediately available, presumptive treatment under the guidance of a tropical medicine specialist should be considered to minimize the risk of residual disability. We advocate for consensus guidelines to be produced and reporting to be performed in a uniform way for patients with spinal schistosomiasis.
Introduction
200 million people worldwide are currently estimated to be infected with schistosomiasis [1]; 120 million of these have symptomatic schistosomiasis and 20 million develop severe disease [2,3]. Schistosomiasis is a parasitic infection acquired through contact with contaminated fresh water. Adult schistosomes are blood dwelling trematode helminths which excrete eggs via the urine (S. haematobium) and faeces (S. mansoni, S. japonicum). Eggs that are not excreted can become trapped in human tissues causing a peri-ovular granulomatous inflammatory reaction [1], the main mechanism of disease in schistosomiasis. The largest burden of infection lies within sub-Saharan Africa although there is a significant burden of disease in other regions of Africa, the Middle East, Asia, South America [4], and more recently, cases from a focus in southern Europe [5]. In a review of UK travellers presenting with acute schistosomiasis [6], Lake Malawi was found to be the commonest site of exposure (53% of patients). As global travel increases, an awareness of the complications of this condition is vital.
Neuroschistosomiasis is a rare and severe complication of schistosomiasis triggered by the immune reaction to egg deposition in the central nervous system (CNS). It is almost entirely caused by S. mansoni, S. haematobium or S. japonicum. S. mansoni and S. haematobium usually affect the spinal cord [7,8,9,10,11] whereas S. japonicum usually causes intracranial disease [12]. Neuroschistosomiasis is estimated to affect between 1% and 4% of people with systemic schistosomal infections [4]. This is thought to be secondary to two possible mechanisms: 1) the adult Schistosoma worms lay eggs in the hepatic portal system that then travel through the valveless paravertebral veins of Batson (Batson’s plexus) to reach the lower spinal cord and 2) adult worms migrate to the CNS and produce eggs in-situ in the local venules [4]. Worldwide, 90% of cases of neuroschistosomiasis are estimated to occur in sub-Saharan Africa [8] although an increasing number of cases outside of endemic areas are being noted due to global travel.
The diagnosis of neuroschistosomiasis can be difficult. Along with a history consistent with the risk of exposure, observation of schistosomal ova in urine, stool or rectal biopsy, or positive serum schistosomal serology can support a diagnosis [1]. However, the absence of eggs in these samples does not exclude neuroschistosomiasis. Serology is valuable in making the diagnosis but it must be interpreted in the context of a travel history and any previous treatment. Cerebrospinal fluid (CSF) tends to indicate an inflammatory phenotype with elevated protein and white cell count, often with a lymphocyte predominance; eosinophils are estimated to be detectable in 50% of patients’ CSF [1]. Neuroschistosomiasis leads to characteristic changes on imaging which can be crucial in diagnosis. MRI findings typically include: enlargement of spinal cord (especially the lower cord and conus medullaris); thickening of spinal nerve roots (especially cauda equina); intermedullary T2 hyperintense and T1 hypointense signal reflecting oedema; and on post gadolinium T1 weighted images a heterogeneous multinodular pattern of contrast enhancement, thought to be related to ova induced granulomas within the spinal cord [1,4]. Spinal cord schistosomiasis is traditionally divided into three clinical forms: medullary (spinal cord predominant), myeloradicular (spinal cord and nerve root predominance), and a conus-cauda equina syndrome. However, patients may often present with either a combination of the above or evolve between these divisions during their disease progression. Spinal schistosomiasis typically presents as a lower cord syndrome of acute/subacute nature with typical symptoms of lower limb or back pain, leg weakness and sensory disturbance, and bladder, sphincter and erectile dysfunction [1,4]. A definitive diagnosis can only be made with histopathological sampling of CNS tissue though this is rarely done due to the risks involved [1].
The accepted criteria for confirmation of spinal cord schistosomiasis are as follows [1]:
Evidence of lower thoracic or upper lumbar neurological lesions clinically and on imaging
Evidence of infection with schistosomiasis through parasite isolation in tissue or serological techniques
Exclusion of other causes of myelitis.
Early treatment with praziquantel and high dose steroids leads to a reduction of neurological sequelae [9, 11–13]. There are no consensus guidelines or randomized controlled trials for the treatment of neuroschistosomiasis. Regimens combine anti-parasitics, corticosteroids and surgery in selected cases. Praziquantel is the anti-parasitic agent of choice for schistosomiasis with a reported cure rate of 70–90% [12]. Dosing regimens vary from 40–60 mg/kg/day given in divided doses, and treatment duration varies widely from 1–14 days in neuroschistosomiasis. Duration of steroid weaning is highly variable in reported cases [12]. Surgery is typically reserved for people with neuroschistosomiasis who have severe neurological symptoms and evidence of CSF flow obstruction [4].
We note that in non-endemic regions, neuroschistosomiasis is rare [1,4,8] and there is evidence that diagnosis can be delayed due to lack of clinical awareness of this condition. We present a series of patients with spinal cord schistosomiasis presenting to a national referral centre in the United Kingdom. We aim to provide an update on this condition to improve recognition and clinical management of patients with neuroschistosomiasis, with a focus on spinal schistosomiasis, the most common CNS complication.
Methods
Ethics statement
Ethical approval for this study was deemed not required according to University College London Hospitals policy. Signed patient consent forms were obtained from individual patients included within the case series.
Study design
We performed a retrospective review of confirmed clinical cases of neuroschistosomiasis referred to a national referral centre for parasitic infections involving the central nervous system.
Study setting
The Hospital of Tropical Diseases (HTD) works in partnership with the National Hospital for Neurology and Neurosurgery (NHNN) in providing a national referral centre for neuroschistosomiasis and other tropical neurological disorders including neurocysticercosis and hydatid disease. All cases were discussed at the regular Neuroparasitology Multidisciplinary Team Meeting (MDT). The Neuroparasitology MDT is based at the HTD, London. It receives referral cases nationally from the UK, often following discussion with specialist teams locally. The MDT includes neurology, neuroradiology and parasitology specialists with expertise in parasitic infections. Diagnosis is made based on clinical history, radiology and available parasitological results. Serum and CSF antibody detection ELISAs are performed in-house, in the national Parasitology Referral Laboratory, accredited by the national United Kingdom Accreditation Service.
Data collection
Cases of neuroschistosomiasis discussed in the HDT Neuroparasitology MDT between January 2016 and January 2020 were reviewed. Electronic referral records were interrogated and patient demographic, clinical, laboratory, and radiological data included. Routine clinical information was collated and analysed, and pathology data was analysed for confirmatory testing.
Results
Case 1
A 50 year old male Nigerian clerical worker presented to UK health services in June 2016 with a short history of fever and back pain. He had returned from rural travel to Nigeria, where he had been undertaking farming work for 1 year; he reported swimming regularly in a local freshwater lake. On admission, his malaria film was positive for Plasmodium falciparum (0.1% parasitaemia) and he was treated with a 3 day course of atovaquone-proguanil combination therapy. During the first four days of his admission he continued to report back and leg pain. On more detailed questioning he revealed these symptoms had been ongoing 3 weeks prior to admission, with a 7 day history of constipation. On day 4 of admission he went into urinary retention and was unable to walk. He was noted to have a rising eosinophil count, increasing from normal on admission to 1.2x10^9/L on day 4. He underwent a lumbar spine MRI which was initially locally reported as normal but showed in retrospect high signal and swelling of the conus medullaris (Fig 1). He continued to deteriorate neurologically with flaccid paraplegia and was treated for presumed Guillain Barre Syndrome with intravenous immunoglobulin. He subsequently underwent a repeat MRI, reported as transverse myelitis of the thoracic spine from T4-T10. CSF analysis showed a CSF glucose within normal range at 4.2mg/dl, elevated CSF protein at 1.87g/L and a white cell count (WCC) of 12 leucocytes/mm3 (100% monocytes). The case was discussed with the UK Imported Fever Service who directed further investigation of the case. The discussion centred on the possibility of spinal schistosomiasis, or Strongyloides infection exacerbated by HTLV-1. HTLV-1 and strongyloides investigations were subsequently negative. The patient was discussed in the HTD Neuroparasitology MDT where the initial unenhanced MRI was felt to demonstrate a subtle conus lesion. The repeat whole spine MRI had nodular enhancement typical of spinal schistosomiasis. Urgent schistosomiasis serology was arranged by the HTD parasitology team and returned strongly positive on serum (ELISA optical density (OD) 1.132, cut off 0.26) and CSF (ELISA OD 1.139, cut off 0.26). Terminal urine was negative for ova. Treatment was commenced 16 days after presentation to UK medical services. The exact time from exposure to freshwater to symptom onset was unclear, as the patient was likely to have been exposed regularly during his year in Nigeria when swimming in a local lake. He completed a 5 day course of praziquantel under dexamethasone cover, which was tapered over the course of one year. He also received empirical treatment with ivermectin (15mg per day for 2 days) to cover the possibility of coincidental occult Strongyloides infection which might fulminate on steroid therapy.
10.1371/journal.pntd.0009161.g001Fig 1 Initial MRI of patient 1 (locally reported as normal): showing subtle T2 hyperintense signal change (arrow) and mild swelling of conus medullaris.
Subsequent to this treatment, the patient received neurorehabilitation and his mobility improved and the patient was able to walk unaided at 2 months. The patient was given a second course of praziquantel in November 2017 as a precaution to ensure eradication of schistosomiasis, due to concerns regarding ongoing spasticity and bladder dysfunction. There was no history of re-exposure. Repeat schistosomal serology was negative the following year in October 2018 (OD 0.212, cut off 0.26). Despite this, the patient had persistent complications of neuroschistosomiasis including a broad-based gait, and ongoing urinary dysfunction which required botox detrusor injections and urinary sheath use at 3 year follow up. In addition, he reported ongoing lumbar back and leg pain which was managed with pregabalin and specialist pain team input. During the prolonged steroid treatment, the patient developed steroid induced insomnia, weight gain, and a heel ulcer thought to be related to steroid therapy.
Case 2
A 21 year old female student presented to UK medical services on 1st June 2018. She presented with several months of fatigue, followed by an acute 3 day history of lower back pain and progressive leg weakness. On presentation, the patient had difficulty with micturition and defecation, and was unable to walk. She was initially diagnosed and treated for neuromyelitis optica with high dose steroids and plasma exchange. She was discharged to a rehabilitation unit and required walking aids to mobilise at this stage. At a subsequent clinical encounter the patient volunteered a travel history, recalling swimming in the Ugandan Nile in June 2017 and in Thailand in July 2017, prompting consideration of a tropical infection causing her symptoms. At this point, her case was discussed with the HTD Neuroparasitology MDT where a diagnosis of spinal schistosomiasis was felt likely, and appropriate investigations coordinated. Schistosomal serology returned positive on serum (OD 0.48, cut off 0.26) and CSF (OD 0.543, cut off 0.26). CSF microscopy revealed an elevated WCC of 297 leukocytes/mm3 which were predominantly lymphocytes (87%). The patient’s CSF protein was normal at 0.4g/L and CSF glucose 3.9 (no paired serum sample available). MRI spine demonstrated extensive T2 hyperintense signal change throughout the spinal cord which was most prominent in the lower thoracic cord and conus medullaris. Contrast enhanced imaging of the spine demonstrated two areas of pathological enhancement (D7 to D8 and at D11 to D12), (Fig 2) A diagnosis of neuroschistosomiasis was made and she was treated initially with 1 day (40mg/kg/day) in August 2018 followed by a 3 day course (40mg/kg/day) in September 2018 alongside a 6 month course of weaning steroids. She received a repeat course of praziquantel (20mg/kg TDS for 3 days) to cover the possibility of S. japonicum infection in October 2018. Following anti-schistosomal treatment her symptoms completely resolved and she was discharged from follow up. Time from exposure to freshwater in a schistosomiasis endemic region to presentation with symptoms was 11 months. Length of time from initial presentation to commencing appropriate anti-parasitic treatment was 74 days. Follow up MRI in January 2019 showed oedema within the spinal cord was much improved with no enhancement. No treatment related adverse events were described. She remains symptom free at the time of reporting.
10.1371/journal.pntd.0009161.g002Fig 2 Sagittal (A and B, patient 2) and axial (C and D, patient 2) gadolinium-enhanced images of spine demonstrating pathological contrast enhancement at D7+D8 and D11+D12 levels (arrows).
Fig 3A and 3B detail further imaging findings for case 1 and 2 respectively.
10.1371/journal.pntd.0009161.g003Fig 3 Sagittal T2 weighted MRIs in patients 1 (A), 2 (B), 3 (C) and 4 (D) showing intramedullary hyper intense signal, affecting the lower thoracic cord/conus medullaris in all patients with variable extension into mid thoracic cord.
Case 3
A 31 year old male presented to UK medical services on 7th November 2018 with two weeks of lower limb pain, paraesthesia, and dysuria. His dysuria was initially treated as a urinary tract infection but failed to improve. Following worsening of his symptoms a lumbar puncture and MRI were performed. CSF microscopy showed elevated WCC of 297 (261 lymphocytes, 36 polymorphs); with elevated eosinophil count, a moderately raised protein level of 0.96g/dl and glucose within the normal range. He reported travel to Malawi in October 2017 during which he recalled swimming and undertaking water sports in Lake Malawi. MRI spine demonstrated high signal in the conus and signs of severe oedema up to the level of the thoracic spine (Fig 3C). There was contrast enhancement revealing multifocal cord lesions. He was initially treated with 3 days of intravenous methylprednisolone and plasma exchange for an inflammatory transverse myelitis at his local hospital. Routine bloods were normal and peripheral eosinophil counts were not raised during admission, ranging between 0.0–0.4x10^9/L. On 13th December 2018 he was discussed in the Neuroparasitology MDT which recommended treatment for neuroschistosomiasis based on imaging findings and epidemiological risk. He received praziquantel (60mg/kg/day for 3 days). He was subsequently found to have positive serum schistosomal serology (serum ELISA positive at 1.5, cut off 1.2; IgG confirmed on Western blot, external laboratory result); in-house CSF schistosomal serology was positive (OD 0.677, cut off 0.26). Length of time from exposure to freshwater in an endemic region to symptom onset was 12 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 31 days. He had a recurrence of worsening neurological symptoms following the first attempt to wean his steroids, but they were successfully tapered and stopped in July 2019. Steroid related side-effects were described including elevated blood glucose, transaminitis, Cushingoid facies, cystic acne, folliculitis, insomnia and anxiety. His dermatological side-effects warranted referral to tertiary care for dermatology input. At 18 month follow-up he had ongoing complications of neuroschistosomiasis including dysesthesias in his lower limbs and constipation requiring laxatives.
Case 4
A 25 year old male pilot presented to UK medical services on 3rd of August 2019 with symptoms of pain and paraesthesia of both legs, and difficulty passing urine. He was found to be in urinary retention with a residual volume of 1 litre and was catheterised. He reported travel to Uganda in March 2017 on a military expedition during which he canoed from Lake Victoria along the White Nile and was in contact with river water. No advice on schistosomiasis prevention was given before the trip and no screening for schistosomiasis was undertaken after the trip. During his admission he was found to have a varying peripheral blood eosinophil count (range 0.0 to 0.6x10^9/L). MRI spine performed on 9th August 2019 showed high abnormal T2/STIR signal in the spinal cord from T7-T11 (Fig 3D). He was initially diagnosed and treated as a case of inflammatory transverse myelitis, receiving 5 days of intravenous methylprednisolone in August 2019. CSF analysis demonstrated an elevated protein of 0.7g/L and WCC of 132 (81% lymphocytes). CSF schistosomal ELISA was positive (OD 1.7, cut off 0.26). CSF glucose was not available at time of writing. Serum schistosomal serology performed at another laboratory was positive (ELISA positive at 8.8, cut off 1.2; IgG confirmed on Western blot). After discussion with the parasitology team at the HTD, he commenced a 3 day course of praziquantel (60mg/kg/day) in September 2019 alongside a 3 day course of 60mg prednisolone followed by a steroid wean over 66 days. The diagnosis was confirmed in the Neuroparasitology MDT. At 8 months’ follow up he requires ongoing intermittent self-catheterisation for improving but ongoing urinary retention. He retains reduced left ankle dorsiflexion (MRC grade 4+/5) and bilaterally absent ankle jerks. He requires the occasional use of a stick to aid walking. He has improved but ongoing subjectively altered sensation of bowel movements. The length of time from exposure to freshwater in a schistosomal endemic region and symptom onset was 29 months. Length of time from initial UK presentation to commencing appropriate anti-parasitic treatment was 44 days. No specific adverse effects from medication were reported for this patient.
Summary of case series
Four cases of neuroschistosomiasis were referred to the Neuroparasitology MDT over a four year period (Table 1 and Fig 4). The median age at diagnosis was 28 (range 21 to 50) with three male patients. All patients had epidemiological risk factors for schistosomiasis based on travel history and freshwater exposure; two in Uganda (River Nile), one in Malawi and one in Nigeria. Mean time between travel from endemic regions and presentation was 12.7 months (range 0–29 months) (Fig 4). All patients presented with back pain, leg weakness, paraesthesia and urinary dysfunction. Two patients also presented with abnormal defecation. Of those, one had constipation and one had faecal incontinence. Mean time from first presentation to UK health services to commencement of praziquantel was 42.15 days (range 16–74 days) (Fig 4). Peripheral blood eosinophilia was detected in three out of four patients, however detection of schistosomal ova in stool or urine was reported in no patients; rectal snips were not performed. CSF lymphocytosis was present in all four patients. Diagnosis was confirmed with CSF serology for schistosomiasis in all cases. Radiology features included typical enhancement of the lower thoracic spine in three cases and enhancement of the conus in one patient. We note that in one case (patient 1) MRI findings were only noted to be typical for schistosomiasis on review by a neuroradiologist with expertise in parasitic neurological infection. All patients received a minimum of 3 days praziquantel and high dose steroids. Clinical features resolved fully in only one out of four patients.
10.1371/journal.pntd.0009161.g004Fig 4 Diagram showing timing of exposure, symptom development, healthcare seeking, treatment and outcomes of neuroschistosomiasis.
10.1371/journal.pntd.0009161.t001Table 1 Clinical features of Neuroschistosomiasis cases.
Patient Age Sex Country of exposure Time since travel (months) Presentation to anti parasitic treatment (days) Blood eosinophilia CSF WCC count (differential) Serum schistosomiasis serology CSF schistosomiasis ELISA Anti-parasitic therapy (length) Duration steroid wean Outcome/ongoing morbidly
1 50 M Nigeria 0 16 Yes 14 (100% monocytes) Positive Positive Praziquantel (5 days) One year Urinary dysfunction, broad based gait, back and leg pain, steroid induced insomnia, weight gain and heel ulcer.
2 31 M Malawi 11 36 No 37 (100% monocytes) Positive Positive Praziquantel (3 days) 8 months Constipation; leg pain; reduced sensation; steroids—cushingoid facies, cystic acne; recurrence on weaning steroids initially
3 21 F Uganda 11 74 Yes 261 lymphocytosis, 36 polymorphs Positive Positive Praziquantel (3 days) 6 months Full recovery
4 25 M Uganda 29 44 Yes 132 (81% lymphocytes) Positive Positive Praziquantel (3 days) 66 days Urinary dysfunction requiring ongoing intermittent self-catheterisation;
Discussion
Spinal cord involvement is a rare but severe complication of schistosomiasis. We report four cases of spinal schistosomiasis diagnosed in the UK. All four cases had relevant travel histories and presented with spinal cord syndromes. This series provides the most detailed description of a series of spinal schistosomiasis diagnosed in the UK, and highlights the delayed time from presentation to medical services to commencement of effective treatment, an important prognostic factor for long term morbidity.
The major clinical features found in our cases were found to be lower limb weakness, altered sensation, sphincter dysfunction (most commonly urinary retention), and back and leg pain. Lambertucci et al [13], based in a schistosomal endemic area, have previously described twenty-three patients with neuroschistosomiasis of whom 70% were unable to walk unaided at presentation, in keeping with the severity described in our cohort. In our series only one patient made a complete neurological recovery, with the remaining three patients demonstrating some improvement following anti-parasitic and steroid treatment. Once again, this is similar to previously reported outcomes; Lambertucci et al reported a 21.7% (5/23) rate of full neurological recovery in their cohort [13], highlighting the severity of neuroschistosomiasis.
Since the diagnosis of neuroschistosomiasis was not initially considered, the first patient was treated as a case of Guillain Barre Syndrome until the exposure history and MRI scans were reviewed. The other three patients were diagnosed as cases of inflammatory myelitis and treated with high dose steroids and in one case intravenous immunoglobulin. Despite incorrect diagnoses in these cases, fortunately steroids are part of management for spinal schistosomiasis. However it is clear that misdiagnosis can result in the administration of unnecessary treatments and particularly late prescription of anti-parasitic agents alongside steroids, which is likely to be suboptimal.
Significant delay was observed in diagnosis and treatment of neuroschistosomiasis in our patients. There is concern that this is likely to lead to poorer outcomes. Often specialist guidance from the Neuroparasitology MDT at the Hospital for Tropical Diseases was sought after relevant exposure history was elicited, or volunteered by patients. In our patient with the shortest time of presentation-to-treatment (16 days), travel history was elicited early by the attending neurologist, who was then able to seek advice from specialist infectious diseases services. Furthermore, the maximum time from travel to an endemic region and presentation (29 months), illustrates the potential pitfalls in taking only a recent travel history. Therefore, we advocate the importance of a full travel history, including freshwater exposure, in all patients presenting with spinal cord syndromes.
Serum and CSF schistosomal serology was of particular use for diagnosis. Both testing modalities were positive in all our cases. We found peripheral eosinophilia to be present in three out of four patients prior to treatment. All our patients had a reactive CSF but the presence or absence of a CSF eosinophilia was only reported in one patient. Unfortunately, in cases confirmed by histopathology following biopsy of spinal lesions, testing of blood and CSF for anti-schistosomal antibodies is infrequently reported [13], leading to an as yet poorly defined specificity and sensitivity of immunoassays in confirmed spinal schistosomiasis. Our report adds value to the available literature by suggesting that in cases of spinal schistosomiasis, high quality CSF serology assays should be positive. Lambertucci et al [13] reported 90% of patients to have elevated CSF protein levels, and elevated eosinophilis in 40% of cases sampled in an endemic area. They also found eggs in stool, urine or positive peripheral blood serology were non-specific and not sufficient for diagnosis of neuroschistosomiasis. However, that would not be the case in returning travellers normally resident in locations where schistosomiasis is not transmitted.
Detection of schistosomal ova in stool, urine or rectal biopsies is not an essential requirement for diagnosis, not least because eggs from ectopic worm pairs in Batson’s plexus are unable to reach the intestine or urinary tract. There is heterogeneity within the literature with regard to what constitutes a confirmed diagnosis of neuroschistosomiasis.
We recommend that all patients with a consistent travel history for schistosomal exposure and neurological symptoms have schistosomal serology from serum and CSF sent urgently to avoid a delay in diagnosis. The reference laboratory should be telephoned in advance to ensure that samples are prioritised for testing. Additionally, a raised peripheral eosinophilia in the context of neurological symptoms should prompt clinical suspicion of a parasitic infection involving the CNS.
Our patients were diagnosed in a non-endemic setting where clinical exposure to neuroschistosomiasis is rare. We found discussion in the specialist Neuroparasitology MDT provided or confirmed a diagnosis in all four patients, prompted testing in three of four cases, and the MDT team directed management in all four patients. In the case of patient 3, his treatment was in fact directed prior to serology results on the basis of clinical history, epidemiology and typical MRI findings. The typical imaging findings of spinal schistosomiasis are demonstrated well by our four cases; T2 hyperintense signal change in the lower thoracic cord and conus medullaris, heterogeneous nodular enhancement; and oedema and swelling of the cord. These imaging findings are often misdiagnosed as tumours and inflammatory transverse myelitis [7]. The differential diagnosis for such findings also includes spinal cord oedema secondary to a dural arteriovenous fistula.
Subtle changes recognised in a specialist MDT with the presence of an appropriate epidemiology history can expedite diagnosis; this is most clearly demonstrated in the case of patient 1, with an initial MRI spine reported locally as normal but with typical features of spinal schistosomiasis identified in the Neuroparasitology MDT. This highlights the need for potential cases of neuroschistosomiasis to be referred early to an expert MDT in non-endemic settings where clinician exposure to such conditions locally may be sparse. Furthermore, early discussion in a specialist MDT may avoid the need for spinal biopsy in cases of diagnostic difficulty by pointing to a diagnosis of neuroschistosomiasis.
In summary, neuroschistosomiasis can cause severe and permanent disability. Prompt diagnosis and treatment relies on taking of an effective travel history and can be improved by discussion of cases with specialists in the diagnosis and management of neuroparasitic infections. | 60 MG/KG, 1X/DAY | DrugDosageText | CC BY | 33571228 | 19,154,807 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pemphigoid'. | The association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors: a ten-year prospective observational study.
BACKGROUND
Bullous pemphigoid is the most common bullous chronic autoimmune skin disease. Recent studies have suggested dipeptidyl-peptidase 4 inhibitors as possible predisposing agents of bullous pemphigoid. The objective of our study was to prospectively estimate the association between gliptins and the development of bullous pemphigoid.
METHODS
We conducted a prospective study which included all patients diagnosed with biopsy-proven bullous pemphigoid in the Dermatology Department of our hospital between April 1, 2009 and December 31,2019. The diagnosis of bullous pemphigoid was based on specific clinical, histological and immunological features.
RESULTS
Overall 113 consecutive patients (age 75 ± 13 years, 62 females) with the diagnosis of bullous pemphigoid were enrolled. Seventy-six patients (67.3%) suffered from type 2 Diabetes and 52 (46%) were treated with dipeptidyl-peptidase 4 inhibitors. The most frequent prescribed gliptin was vildagliptin, being administered to 45 cases (39.8% of total patients enrolled, 86.5% of the patients treated with gliptins). Gliptins were withdrawn immediately after the diagnosis of bullous pemphigoid, which together with steroid administration led to remission of the rash.
CONCLUSIONS
This study revealed that treatment with dipeptidyl-peptidase 4 inhibitors, especially vildagliptin, is significantly associated with an increased risk of bullous pemphigoid development.
Background
Bullous pemphigoid (BP) is the most common chronic bullous autoimmune skin disease which is characterized by the presentation of subepidermical blisters. It is considered as a disease of the elderly people and is associated with significant morbility and mortality [1]. The pathogenesis of BP is characterized by autoimmune response against hemidesmosomal protein (BP180, BP320) at the dermoepidermal junction. Although the etiology of BP is unknown an increased number of neurologic and psychiatric disorder have been described to raise the risk of BP. Furthermore, various drugs (spironolactone, furosemide, antibiotics) have been reported as possible risk factors for the development of BP. Recent studies have suggested that dipeptidyl peptidase-4 inhibitors (DPP4-is), an incretin-based drug for type 2 diabetes, as possible predisposing agents of BP [2, 3]. DPP4-is inhibit the degradation of incretins resulted in the improvement of blood glucose levels by increasing insulin secretion and decreasing of glucagon secretion. The objective of our study was to estimate the association between the use of DPP4-is and the development of BP in the setting of a tertiary university hospital and to raise awareness for everyday clinical practice, both among dermatologists as well as all physicians following patients with diabetes.
Methods
Design and study population
The study was designed as an observational prospective study. In our study included all patients who received a new diagnosis of BP and hospitalized in the Dermatology Department between April 1, 2009 and December 31, 2019.Inclusion criteria for the study were the diagnosis of new-onset BP (presentation of BP the last 4 months) and severe/extensive BP requiring hospitalization in the dermatology department. Exclusion criteria were: οther forms of pemphigoid (non-bullous), malignancy and patients under treatment with DPP4-is for more than 2 years were exclusion criteria. Diagnosis of BP was based on the following criteria: a) compatible clinical characteristics including urticarial, eczematous, excoriated and/or bullous lesions associated with variable itch b) subepidermal clefts, eosinophilic spongiosis, and/or dermal infiltration of eosinophils in specimen from the edge of the blister as assessed by histopathologic analysis c) deposition of IgG and C3 in the linear band on at dermal-epidermal junction of perilesional skin by direct IF microscopy. All patients have been inadequately treated with topical corticosteroids as a primary regimen and therefore admitted to the tertiary hospital for optimal management with systemic corticosteroids, with the addition of immunosuppressant medications, namely azathioprine, in some cases. We recorded medical data including patients’ age, sex, comorbidities, concomitant medications. This study was approved by the institutional ethical board of Attikon University hospital. A signed informed consent was obtained from all subjects prior to any procedure included in the study protocol. All methods were carried out in accordance with relevant guidelines and regulations. (Declaration of Helsinki)
Statistical analysis
The mean and standard deviation for continuous variables and the number and percentage of patients within each categorical variable were used. The association between the use of DPP4-is and the severity of BP was evaluated in univariate and multivariate logistic regression analysis. For multivariate analysis variables with p < 0.1 at univariate analysis or with clinical significance were used. A value of Bullous Pemphigoid Disease Area Index (BPDAI) greater than 56 was used as a measure of severe BP as previously published [4] (This cut off value was identical with the median value of BPDAI in our study cohort).
The Odds Ratio (OR) and the respective 95% confidence intervals (CIs) were calculated. A p value< 0.05 was considered statistically significant. Data analysis was performed using IBM SPSS V23.
Clinical outcomes
We reviewed the percentage of patients with type 2 diabetes among all patients with BP. The number of patients who were under treatment with DPP4-is and the specific type of DPP4-is prescribed (vildagliptin, sitagliptin, linagliptin, saxagliptin and alogliptin) were also examined. We also assessed other comorbidities and co treatments. The effect of different types of treatment (systemic corticosteroids, immunosuppressive agents) on BP outcome was also evaluated.
Results
Demographic characteristics
Overall, 113 consecutive patients with the diagnosis of BP were enrolled in the study. The mean (SD) age was 75(13) years, and 62 patients were female (54.9%).
The prevalence of DPP4-is and DM among the patients
Seventy-six patients (67.3%) suffered from type 2 Diabetes Mellitus. The mean (SD) age was 75(11) years, and 41 patients were female (54%). There were no differences in age and sex between diabetic and non-diabetic patients.
Fifty-two (46%) were under treatment with DPP-4is at the onset of BP. The mean (SD) age was 74 (10.17) years, and 23 patients were female (44.23%). The mean (SD) time between the initiation of DPP4-is administration and the onset of the skin lesions was 10 ± 2 months. The most frequent prescribed DPP4-i was vildagliptin, being administered to 45 cases (39.8% of total patients enrolled, 86.5% of the patients treated with DPP4-is). Three patients (2.7%) were treated with linagliptin, three (2.7%) with sitagliptin, one (0.9%) with alogliptin and one (0.9%) with saxagliptin (Table 1).
Table 1 Percentage of patients with Bullous pemphigoid and diabetes mellitus according to the type of gliptins
n % patients with BP % patients with type 2 diabetes
Patients with diabetes 76 67.3% 100%
Treatment with DPP-4is 52 46% 68%
Vildagliptin 11 9.7% 14.4%
Vildagliptin-Metformin 34 30.1% 44.73%
Linagliptin 3 2.7% 3.9%
Sitagliptin 1 0.9% 1.3%
Sitagliptin-Metformin 2 1.8% 2.6%
Alogliptin-Metformin 1 0.9% 1.3%
Saxagliptin 1 0.9% 13%
BP Bullous pemphigoid, DPP-4is Dipeptidyl-peptidase 4 inhibitors
Concomitant medications possibly associated with BP
No possible association of the patients’ concomitant medications and BP was found, except for two (1,7%) patients receiving spironolactone, three (2,6%) patients receiving levodopa and one patient receiving biperiden. However, as the patients had been for at least 3 years on these regimens, any possible causal relationship between the drugs and the BP was rejected.
The association of DPP4-is with bullous pemphigoid severity
By multivariate analysis after adjustment for age and sex, the odds ratio of DPP4 use for severe BP (BPDAI> 56) was OR: 2.97, 95% CI = 1.24–7.02, p = 0.014. Female sex was associated with BP severity with OR: 2.88, 95% CI = 1.20–6.89, p = 0.017 in multivariate analysis. By univariate analysis spironolactone, levodopa and biperiden were not associated with the development of severe BP (BPDAI> 56), (p > 0.1 for all associations).
Rash remission-treatment
DPP4-is were withdrawn immediately after the diagnosis of BP. 92 (81.4%) patients were treated with systemic corticosteroids and 14 patients (12.4%) received azathioprine as an add-on therapy to systemic corticosteroids. Prednisolone was administered in 80 (70,8%) cases and methylprednisolone was administered in 12 (10,6%) cases. Complete remission of the rash was observed in all cases. The mean (SD) time for the remission of the rash was 15 ± 5 days. The remission was sustained after the definitive withdrawal of DPP-4is and no cases of relapse were reported.
Discussion
This study suggests that treatment with DPP4-is, especially vildagliptin in this specific Greek population, are significantly associated with an increased risk of BP development. In addition, in our study we have shown that medication with DPP4-is was associated with BP severity as assessed by BPDAI score. The mechanism which is responsible for the development of BP has not yet been elucidated. It is known that DPP4 is a cell-surface glycoprotein with enzymatic activity that is expressed throughout the body including the skin. Various cell types, including keratinocytes and T cells, express DPP4, and its inhibition can increase the activity of numerous proinflammatory cytokines, leading to cutaneous eosinophil activation and blister formation [5]. Furthermore, DPP4 leads to the formation of plasmin, a major serine protease which cleaves the major BP autoantigen BP180; therefore, inhibition of DPP4 may lead to inappropriate cleavage and immunotolerance [6]. Association of BP with vildagliptin was significantly higher compared to the other DPP4-is. The reason for this is unclear, however, it has been suggested that the lower selectivity of vildagliptin for DPP4 compared to other DPP4-is leads to inhibition of DPP8 and DPP9 and a subsequent activation of the caspase-1 pathway, which plays a role in the pathogenesis of BP [7]. Furthermore, during the time that our study was conducted, vildagliptin had the highest market share among DPP4-is in Greece.
Since the introduction of DPP4-is as a standard treatment regimen for type 2 diabetes, numerous cases of patients developing BP following this treatment have been published [8, 9]. In accordance with the results of our study, vildagliptin has shown the strongest correlation in most reports [2, 10]. Skandalis et al. were the first who reported the risk of BP development in patients exposed to gliptins [11]. More recently, Kridin et al. found that DPP4-i exposure was associated with a 3-fold increased risk for BP, with the odds ratio (OR) being even higher for vildagliptin (10.7), and similar were the results in a study by Lee et al., where the OR for developing BP under DPP4-i treatment was 1.58, with the highest adjusted OR being associated with the use of vildagliptin (1.81) [2, 10]. A significant limitation of our study is that it was not possible to establish whether DPP4-is per se or their combination with metformin may contribute to the development of BP. In all patients who received the combination DPP4-i/metformin, only the DPP4-i was discontinued. It is useful to mention, however, that there is no literature data implying an association between BP and metformin treatment. Furthermore, some of our patients were on medications that have been associated with BP. In the results we examined the percentage of patients who received drugs associated with BP based on metanalysis of Sian-De Liu et al. [12]. However, as the patients had been for at least 3 years on these regimens, any possible causal relationship between the drugs and the BP was rejected.
On the other hand, the main strength of our study is that has been designed as prospective study. To our knowledge is the first prospective study revealed the association between DPP4-is and BP. Another strength of our study is that it comprises a large number of patients with clinical and immunological diagnosis of BP who were exposed to DPP4-is, which is enough to establish an association between BP and these agents, especially vildagliptin. Moreover, as dermatologists and physicians treating people with diabetes rarely work together, and such cases may skip attention, we emphasize the importance of a multidisciplinary approach of such a population for early diagnosis, and the need to raise awareness for the contribution of DPP4-is to the development of BP with increasing prevalence.
Conclusions
In conclusion, our study supports that there is a high risk of BP in patients exposed to DPP4-is. Further studies are warranted to determine the causal relationship between DPP4-is and BP development. Discontinuation of treatment with DPP-4 inhibitors was followed by remission of the rash, suggesting that such discontinuation should be immediately considered when BP is suspected. The increased exposure to these agents may be responsible for the increasing incidence of BP, especially in the elderly. The administration of DPP4-is needs to be carefully evaluated in high-risk patients.
Abbreviations
BPBullous pemphigoid
BP180Bullous pemphigoid antigen 180
BPDAIBullous Pemphigoid Disease Area Index
CIConfidence interval
DPP4Dipeptidyl peptidase 4
DPP8Dipeptidyl peptidase 8
DPP9Dipeptidyl peptidase 9
DPP4-iDipeptidyl peptidase 4 inhibitor
OROdds Ratio
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors thank all the patients who participated in the study and the staff in Attikon University Hospital.
Authors’ contributions
All authors have made a substantial contribution to the work and approved it for publication, with Associate Professor Vaia Lambadiari being the guarantor for the contents of the article. V.L., E.P., I.I., P.K., S.T., G.K., K.T., L.P. were responsible for the diagnosis and treatment of the patients along with the design of the study. A.K., E.K., F.K. were responsible for the data collection, the writing of the manuscript and the search of the bibliography. All the authors approved the final version of the manuscript.
Funding
No funding was received for this study.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by Ethics Commitee of General University Hospital Attikon. An informed consent statement was obtained from all the participants.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests. | ALOGLIPTIN | DrugsGivenReaction | CC BY | 33573656 | 19,700,916 | 2021-02-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Candida osteomyelitis'. | Successful outcome of disseminated Candida tropicalis osteomyelitis on remission induction for childhood Philadelphia chromosome-positive acute lymphoblastic leukaemia-case report.
BACKGROUND
Invasive fungal infection (IFI) is one of the most challenging complications in children undergoing acute lymphoblastic leukaemia (ALL) treatment, but acute fungal osteomyelitis (OM) is rarely encountered.
METHODS
Here, we describe a case of Candida tropicalis osteomyelitis in a 10-year-old patient with Philadelphia chromosome (Ph)-positive ALL. He was on remission induction therapy at the time of neutropenia, and an abscess developed in his right arm. The blood and bone cultures were positive for C. tropicalis. Antibiotics and antifungals were administered. Magnetic resonance imaging of the arm revealed an intraosseous abscess, suggestive of OM. Surgical irrigation and debridement of the bone were performed immediately. The patient was effectively treated with antifungal therapy and ALL treatment. He has fully recovered into complete clinical remission but with visible sequelae on magnetic resonance imaging (MRI). He took oral posaconazole for consolidation until disappearance of the lesion shadows on MRI and received subsequent cycles of chemotherapy in parallel.
CONCLUSIONS
In the successful management of Ph-positive ALL, dasatinib, a second-generation Abl-tyrosine kinase inhibitor, is crucial. The recommended treatment for Candida osteomyelitis in Ph-positive ALL patients is a fungicidal agent combined with surgery and modification chemotherapy with dasatinib. The use of combined modalities of treatment seems to be crucial in the successful management of Ph-positive ALL.
Background
Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy [1]. Children with ALL are immunocompromised patients who are at high risk of infection associated with high morbidity and mortality rates [2]. Invasive fungal infection (IFI) is one of the most challenging complications in children with ALL treatment [3], but acute fungal osteomyelitis (OM) is rarely encountered. In immunocompromised children, the most common mechanism of these complications includes fungal osteomyelitis due to continuous infiltration or haematogenous spread [4]. Candida species are weak pathogens that are common commensal organisms inhabiting the skin and mucous membranes of most individuals. However, the rate of incidence of invasive Candida infection is increasing among newborns in the ICU and in immunosuppressive therapy, the augmented use of intravenous catheters and haematological malignancy and neutropenia in children [5]. Successfully managing fungal osteomyelitis and chemotherapy for ALL is quite difficult. Here, we report a case of childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukaemia, complicated by disseminated Candida tropicalis osteomyelitis of the right humerus during remission induction that was successfully managed by timely and appropriate administration without compromising anti-leukaemia therapy.
Case presentation
A 10-year-old boy was confirmed to have Philadelphia chromosome (Ph)-positive ALL. According to the Chinese Children’s Cancer Group study ALL-2015 (CCCG-ALL-2015), he was provisionally assigned as intermediate-risk based on his presenting clinical features, aged 10 years, and immunophenotype B- cell and Philadelphia chromosome–positive ALL. According to CCCG-ALL-2015, the patient will receive MRD directed, risk-stratified treatment, modified from the St Jude Children’s Research Hospital Total XV and XVI studies and the Shanghai Children’s Medical Center ALL-2005 trial. For MRD ≥ 1% at the end of remission induction, provisional intermediate-risk patient has to be escalated to high risk. Allogeneic transplant was recommended. He received upfront window therapy with dexamethasone for 4 days followed by remission induction with prednisone acetate, vincristine, daunorubicin hydrochloride (DNR), and pegaspargase from days 5 to 28.
He began to receive dasatinib (80 mg/m2 per day) as soon as the diagnosis was made on day 5 of remission induction. On day 18 of remission induction, he was hospitalized for cough, fever, and pain, tenderness and swelling over the right elbow. Laboratory tests were notable for neutropenia and elevated inflammatory markers (Fig. 1). A computed tomography (CT) chest scan showed the patchy shadows in the anterior lobe of left upper lung and the middle lobe of right lung. The right upper limb ultrasound revealed swelling of soft tissue without previous trauma. Empiric treatment with broad-spectrum antibiotics was initiated to cover both gram-positive and gram-negative bacteria. The lesion progressed to an abscess in the upper right arm. Twenty-two hours later, blood culture showed fungus positivity and pus. Empirical amphotericin B therapy was initiated. There are two reasons we chose amphotericin B. First, Candida infection is the most common fungal infection. Second, vincristine is one of the drugs used in remission induction chemotherapy. Voriconazole may increase the toxic side effects of vincristine, so voriconazole was not our first option [6]. The blood culture results suggested C. tropicalis 2 days later. Minimal inhibitory concentrations indicated susceptibility to amphotericin B (minimal inhibitory concentration < =0.5 μg/mL), fluconazole (1) and voriconazole (0.125) and flucytosine (<=0.4). He subsequently developed pain and swelling over the right upper arm and forearm. Five days after admission, he was afebrile, but pain, oedema, and limited function of the right elbow were progressive. Repeated ultrasound revealed discrete periosteal oedema adjacent to the humerus 1 week after admission. Magnetic resonance imaging (MRI) of the right humerus showed an intraosseous abscess and probable osteomyelitis (Fig. 2). Surgical irrigation and debridement of the bone were performed immediately (Fig. 3). Culture of bone aspirates obtained during surgery showed that C. tropicalis was sensitive to amphotericin B, which is the same result as the blood culture. A small study of the bone fragments collected during surgery revealed fungal spores. All chemotherapy, except prednisone was continued, was withdrawn for 1 week. Debridement was repeated on the third postoperative day, resulting in considerable improvement of clinical and laboratory findings. His condition improved. One week later, when he was nontoxic, haemodynamically stable, with no signs of haematopoietic toxicity and inflammatory markers within the normal range, induction chemotherapy was continued with some modification with prednisolone and dasatinib, and treatment was carried out for osteomyelitis with amphotericin B, meropenem and vancomycin in parallel. Successful control of osteomyelitis was achieved by serial surgical debridement of the lesion, antibiotics, amphotericin B and HBO therapy. Treatment with amphotericin B was administered for a total of 3 weeks; during this time, he regained the ability to move his arm and transitioned to oral posaconazole for consolidation, which he is currently receiving on an ongoing basis. Vincristine (D19 and D26) and L-asparaginase (D26) were administered until the fever was controlled and the neutrophil count (ANC) exceeded 500/mm3. After completion of remission induction therapy, he achieved complete remission (CR). Then, we removed the remission induction treatment consisting of cyclophosphamide (CTX), cytarabine (Ara-c), and mercaptopurine (6-MP) from days 29 to 35. The next chemotherapy regimen was continued with dasatinib, weekly vincristine and daily mercaptopurine for 3 weeks. Subsequent cycles of chemotherapy were reinitiated as per the protocol. At follow-up 5 months later, the patient continued to feel good.
Fig. 1 The results of the laboratory test, antimicrobial treatment and chemotherapy
Fig. 2 The MRI results of the right arm at first (a). At the follow-up MRI, the previous abnormal signals narrowed significantly (b)
Fig. 3 Surgical irrigation and debridement of the bone
Discussion and conclusions
Candida are found on the skin and in the respiratory tract, vagina and stools. According to a multicentre study in Australia [7], Candida species accounted for the majority of infections associated with neutropenia in immunocompromised patients with ALL, of which Candida albicans and Candida parapsilosis were most frequently detected. According to another retrospective study, the proportion of Candida is increasing in children with ALL [8]. To our knowledge, there are few reports of C. tropicalis osteomyelitis in a child with ALL. Predisposing factors present in our case were underlying leukaemia, steroids, neutropenia, and immunosuppressive therapy, which is consistent with the literature report [9].
Proving a diagnosis is the first key step in the successful management of IFI. Isolating and identifying the causative fungus on culture is important for epidemiological and research purposes. The culture of specimens from surgery is more sufficient than blood to determine the pathogen and helps to establish the diagnosis as quickly as possible.
A combination of early diagnosis, surgical debridement and antifungal therapy seems to be crucial. The timely administration of empirical amphotericin B on suspicion of fungal infection in our case along with debridement of necrotic tissue may be responsible for a successful outcome.
In the successful management of Ph-positive ALL, in the pre-TKI era, matched donor allogeneic stem cell transplantation was beneficial [10]. Sequential addition of imatinib (a tyrosine kinase inhibitor) to the chemotherapy regimen in Ph-positive ALL dramatically improved the outcomes for children with Ph-positive ALL [11]. TKIs administered in the early phases of therapy can dramatically improve the outcome of childhood Ph-positive ALL. According to the study, there was no significant difference in 5-year disease-free survival (DFS) for patients who received imatinib alone versus patients who received imatinib followed by HSCT [12]. Dasatinib is a crucial second-generation Abl–tyrosine kinase inhibitor. According to our randomized clinical trial, dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Ph-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day [13]. Anti-infection combined with surgical incision and drainage and dasatinib administration together led to the successful treatment of osteomyelitis while maintaining a remission state of Ph-positive ALL.
The importance of judicious concomitant administration of antifungal and anti-leukaemia treatment during induction therapy in ALL is highlighted. Moreover, we emphasize that the most efficient diagnostic and treatment strategy for patients with fungal osteomyelitis with ALL is the combination of medical and surgical management. When there is significant marrow toxicity and infection in a patient with Ph-positive ALL, concurrent myelosuppressive agents such as DNR, Ara-C, CTX, MTX, and 6-MP should be stopped instead of dasatinib. It can be an effective treatment option for patients who need both infection control and ALL treatment.
Abbreviations
ALLAcute lymphoblastic leukaemia
Ara-cCytarabine
CCCG-ALL-2015Chinese Children’s Cancer Group study ALL-2015
CTComputed tomography
CRComplete remission
CTXCyclophosphamide
DNRDaunorubicin hydrochloride
IFIInvasive fungal infection
OMOsteomyelitis
PhPhiladelphia chromosome
ANCNeutrophil granulocyte
MRIMagnetic resonance imaging
6-MPMercaptopurine
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Sanming Project of Medicine in Shenzhen (SZSM201512033).
Authors’ contributions
XLC designed the data analysis and wrote the manuscript; Qingling Long and Guichi Zhou provided imaging assistance; Sixi Liu and Feiqiu Wen contributed to critical revision. All of the authors have read and approved the manuscript.
Funding
Not applicable.
Availability of data and materials
The microarray data will be available in the NCBI database.
Ethics approval and consent to participate
This study was approved by the ethics committee of Shenzhen Children’s Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent for publication
Written consent to publish this information was obtained from the parents of the study participants.
Competing interests
The authors declare that they have no competing interests. | DASATINIB, DAUNORUBICIN, DEXAMETHASONE, PEGASPARGASE, PREDNISONE, VINCRISTINE | DrugsGivenReaction | CC BY | 33573668 | 19,023,891 | 2021-02-11 |
What was the dosage of drug 'DASATINIB'? | Successful outcome of disseminated Candida tropicalis osteomyelitis on remission induction for childhood Philadelphia chromosome-positive acute lymphoblastic leukaemia-case report.
BACKGROUND
Invasive fungal infection (IFI) is one of the most challenging complications in children undergoing acute lymphoblastic leukaemia (ALL) treatment, but acute fungal osteomyelitis (OM) is rarely encountered.
METHODS
Here, we describe a case of Candida tropicalis osteomyelitis in a 10-year-old patient with Philadelphia chromosome (Ph)-positive ALL. He was on remission induction therapy at the time of neutropenia, and an abscess developed in his right arm. The blood and bone cultures were positive for C. tropicalis. Antibiotics and antifungals were administered. Magnetic resonance imaging of the arm revealed an intraosseous abscess, suggestive of OM. Surgical irrigation and debridement of the bone were performed immediately. The patient was effectively treated with antifungal therapy and ALL treatment. He has fully recovered into complete clinical remission but with visible sequelae on magnetic resonance imaging (MRI). He took oral posaconazole for consolidation until disappearance of the lesion shadows on MRI and received subsequent cycles of chemotherapy in parallel.
CONCLUSIONS
In the successful management of Ph-positive ALL, dasatinib, a second-generation Abl-tyrosine kinase inhibitor, is crucial. The recommended treatment for Candida osteomyelitis in Ph-positive ALL patients is a fungicidal agent combined with surgery and modification chemotherapy with dasatinib. The use of combined modalities of treatment seems to be crucial in the successful management of Ph-positive ALL.
Background
Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy [1]. Children with ALL are immunocompromised patients who are at high risk of infection associated with high morbidity and mortality rates [2]. Invasive fungal infection (IFI) is one of the most challenging complications in children with ALL treatment [3], but acute fungal osteomyelitis (OM) is rarely encountered. In immunocompromised children, the most common mechanism of these complications includes fungal osteomyelitis due to continuous infiltration or haematogenous spread [4]. Candida species are weak pathogens that are common commensal organisms inhabiting the skin and mucous membranes of most individuals. However, the rate of incidence of invasive Candida infection is increasing among newborns in the ICU and in immunosuppressive therapy, the augmented use of intravenous catheters and haematological malignancy and neutropenia in children [5]. Successfully managing fungal osteomyelitis and chemotherapy for ALL is quite difficult. Here, we report a case of childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukaemia, complicated by disseminated Candida tropicalis osteomyelitis of the right humerus during remission induction that was successfully managed by timely and appropriate administration without compromising anti-leukaemia therapy.
Case presentation
A 10-year-old boy was confirmed to have Philadelphia chromosome (Ph)-positive ALL. According to the Chinese Children’s Cancer Group study ALL-2015 (CCCG-ALL-2015), he was provisionally assigned as intermediate-risk based on his presenting clinical features, aged 10 years, and immunophenotype B- cell and Philadelphia chromosome–positive ALL. According to CCCG-ALL-2015, the patient will receive MRD directed, risk-stratified treatment, modified from the St Jude Children’s Research Hospital Total XV and XVI studies and the Shanghai Children’s Medical Center ALL-2005 trial. For MRD ≥ 1% at the end of remission induction, provisional intermediate-risk patient has to be escalated to high risk. Allogeneic transplant was recommended. He received upfront window therapy with dexamethasone for 4 days followed by remission induction with prednisone acetate, vincristine, daunorubicin hydrochloride (DNR), and pegaspargase from days 5 to 28.
He began to receive dasatinib (80 mg/m2 per day) as soon as the diagnosis was made on day 5 of remission induction. On day 18 of remission induction, he was hospitalized for cough, fever, and pain, tenderness and swelling over the right elbow. Laboratory tests were notable for neutropenia and elevated inflammatory markers (Fig. 1). A computed tomography (CT) chest scan showed the patchy shadows in the anterior lobe of left upper lung and the middle lobe of right lung. The right upper limb ultrasound revealed swelling of soft tissue without previous trauma. Empiric treatment with broad-spectrum antibiotics was initiated to cover both gram-positive and gram-negative bacteria. The lesion progressed to an abscess in the upper right arm. Twenty-two hours later, blood culture showed fungus positivity and pus. Empirical amphotericin B therapy was initiated. There are two reasons we chose amphotericin B. First, Candida infection is the most common fungal infection. Second, vincristine is one of the drugs used in remission induction chemotherapy. Voriconazole may increase the toxic side effects of vincristine, so voriconazole was not our first option [6]. The blood culture results suggested C. tropicalis 2 days later. Minimal inhibitory concentrations indicated susceptibility to amphotericin B (minimal inhibitory concentration < =0.5 μg/mL), fluconazole (1) and voriconazole (0.125) and flucytosine (<=0.4). He subsequently developed pain and swelling over the right upper arm and forearm. Five days after admission, he was afebrile, but pain, oedema, and limited function of the right elbow were progressive. Repeated ultrasound revealed discrete periosteal oedema adjacent to the humerus 1 week after admission. Magnetic resonance imaging (MRI) of the right humerus showed an intraosseous abscess and probable osteomyelitis (Fig. 2). Surgical irrigation and debridement of the bone were performed immediately (Fig. 3). Culture of bone aspirates obtained during surgery showed that C. tropicalis was sensitive to amphotericin B, which is the same result as the blood culture. A small study of the bone fragments collected during surgery revealed fungal spores. All chemotherapy, except prednisone was continued, was withdrawn for 1 week. Debridement was repeated on the third postoperative day, resulting in considerable improvement of clinical and laboratory findings. His condition improved. One week later, when he was nontoxic, haemodynamically stable, with no signs of haematopoietic toxicity and inflammatory markers within the normal range, induction chemotherapy was continued with some modification with prednisolone and dasatinib, and treatment was carried out for osteomyelitis with amphotericin B, meropenem and vancomycin in parallel. Successful control of osteomyelitis was achieved by serial surgical debridement of the lesion, antibiotics, amphotericin B and HBO therapy. Treatment with amphotericin B was administered for a total of 3 weeks; during this time, he regained the ability to move his arm and transitioned to oral posaconazole for consolidation, which he is currently receiving on an ongoing basis. Vincristine (D19 and D26) and L-asparaginase (D26) were administered until the fever was controlled and the neutrophil count (ANC) exceeded 500/mm3. After completion of remission induction therapy, he achieved complete remission (CR). Then, we removed the remission induction treatment consisting of cyclophosphamide (CTX), cytarabine (Ara-c), and mercaptopurine (6-MP) from days 29 to 35. The next chemotherapy regimen was continued with dasatinib, weekly vincristine and daily mercaptopurine for 3 weeks. Subsequent cycles of chemotherapy were reinitiated as per the protocol. At follow-up 5 months later, the patient continued to feel good.
Fig. 1 The results of the laboratory test, antimicrobial treatment and chemotherapy
Fig. 2 The MRI results of the right arm at first (a). At the follow-up MRI, the previous abnormal signals narrowed significantly (b)
Fig. 3 Surgical irrigation and debridement of the bone
Discussion and conclusions
Candida are found on the skin and in the respiratory tract, vagina and stools. According to a multicentre study in Australia [7], Candida species accounted for the majority of infections associated with neutropenia in immunocompromised patients with ALL, of which Candida albicans and Candida parapsilosis were most frequently detected. According to another retrospective study, the proportion of Candida is increasing in children with ALL [8]. To our knowledge, there are few reports of C. tropicalis osteomyelitis in a child with ALL. Predisposing factors present in our case were underlying leukaemia, steroids, neutropenia, and immunosuppressive therapy, which is consistent with the literature report [9].
Proving a diagnosis is the first key step in the successful management of IFI. Isolating and identifying the causative fungus on culture is important for epidemiological and research purposes. The culture of specimens from surgery is more sufficient than blood to determine the pathogen and helps to establish the diagnosis as quickly as possible.
A combination of early diagnosis, surgical debridement and antifungal therapy seems to be crucial. The timely administration of empirical amphotericin B on suspicion of fungal infection in our case along with debridement of necrotic tissue may be responsible for a successful outcome.
In the successful management of Ph-positive ALL, in the pre-TKI era, matched donor allogeneic stem cell transplantation was beneficial [10]. Sequential addition of imatinib (a tyrosine kinase inhibitor) to the chemotherapy regimen in Ph-positive ALL dramatically improved the outcomes for children with Ph-positive ALL [11]. TKIs administered in the early phases of therapy can dramatically improve the outcome of childhood Ph-positive ALL. According to the study, there was no significant difference in 5-year disease-free survival (DFS) for patients who received imatinib alone versus patients who received imatinib followed by HSCT [12]. Dasatinib is a crucial second-generation Abl–tyrosine kinase inhibitor. According to our randomized clinical trial, dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Ph-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day [13]. Anti-infection combined with surgical incision and drainage and dasatinib administration together led to the successful treatment of osteomyelitis while maintaining a remission state of Ph-positive ALL.
The importance of judicious concomitant administration of antifungal and anti-leukaemia treatment during induction therapy in ALL is highlighted. Moreover, we emphasize that the most efficient diagnostic and treatment strategy for patients with fungal osteomyelitis with ALL is the combination of medical and surgical management. When there is significant marrow toxicity and infection in a patient with Ph-positive ALL, concurrent myelosuppressive agents such as DNR, Ara-C, CTX, MTX, and 6-MP should be stopped instead of dasatinib. It can be an effective treatment option for patients who need both infection control and ALL treatment.
Abbreviations
ALLAcute lymphoblastic leukaemia
Ara-cCytarabine
CCCG-ALL-2015Chinese Children’s Cancer Group study ALL-2015
CTComputed tomography
CRComplete remission
CTXCyclophosphamide
DNRDaunorubicin hydrochloride
IFIInvasive fungal infection
OMOsteomyelitis
PhPhiladelphia chromosome
ANCNeutrophil granulocyte
MRIMagnetic resonance imaging
6-MPMercaptopurine
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Sanming Project of Medicine in Shenzhen (SZSM201512033).
Authors’ contributions
XLC designed the data analysis and wrote the manuscript; Qingling Long and Guichi Zhou provided imaging assistance; Sixi Liu and Feiqiu Wen contributed to critical revision. All of the authors have read and approved the manuscript.
Funding
Not applicable.
Availability of data and materials
The microarray data will be available in the NCBI database.
Ethics approval and consent to participate
This study was approved by the ethics committee of Shenzhen Children’s Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent for publication
Written consent to publish this information was obtained from the parents of the study participants.
Competing interests
The authors declare that they have no competing interests. | 80 MILLIGRAM/SQ. METER (PER DAY) | DrugDosageText | CC BY | 33573668 | 19,023,891 | 2021-02-11 |
What was the dosage of drug 'PEGASPARGASE'? | Successful outcome of disseminated Candida tropicalis osteomyelitis on remission induction for childhood Philadelphia chromosome-positive acute lymphoblastic leukaemia-case report.
BACKGROUND
Invasive fungal infection (IFI) is one of the most challenging complications in children undergoing acute lymphoblastic leukaemia (ALL) treatment, but acute fungal osteomyelitis (OM) is rarely encountered.
METHODS
Here, we describe a case of Candida tropicalis osteomyelitis in a 10-year-old patient with Philadelphia chromosome (Ph)-positive ALL. He was on remission induction therapy at the time of neutropenia, and an abscess developed in his right arm. The blood and bone cultures were positive for C. tropicalis. Antibiotics and antifungals were administered. Magnetic resonance imaging of the arm revealed an intraosseous abscess, suggestive of OM. Surgical irrigation and debridement of the bone were performed immediately. The patient was effectively treated with antifungal therapy and ALL treatment. He has fully recovered into complete clinical remission but with visible sequelae on magnetic resonance imaging (MRI). He took oral posaconazole for consolidation until disappearance of the lesion shadows on MRI and received subsequent cycles of chemotherapy in parallel.
CONCLUSIONS
In the successful management of Ph-positive ALL, dasatinib, a second-generation Abl-tyrosine kinase inhibitor, is crucial. The recommended treatment for Candida osteomyelitis in Ph-positive ALL patients is a fungicidal agent combined with surgery and modification chemotherapy with dasatinib. The use of combined modalities of treatment seems to be crucial in the successful management of Ph-positive ALL.
Background
Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy [1]. Children with ALL are immunocompromised patients who are at high risk of infection associated with high morbidity and mortality rates [2]. Invasive fungal infection (IFI) is one of the most challenging complications in children with ALL treatment [3], but acute fungal osteomyelitis (OM) is rarely encountered. In immunocompromised children, the most common mechanism of these complications includes fungal osteomyelitis due to continuous infiltration or haematogenous spread [4]. Candida species are weak pathogens that are common commensal organisms inhabiting the skin and mucous membranes of most individuals. However, the rate of incidence of invasive Candida infection is increasing among newborns in the ICU and in immunosuppressive therapy, the augmented use of intravenous catheters and haematological malignancy and neutropenia in children [5]. Successfully managing fungal osteomyelitis and chemotherapy for ALL is quite difficult. Here, we report a case of childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukaemia, complicated by disseminated Candida tropicalis osteomyelitis of the right humerus during remission induction that was successfully managed by timely and appropriate administration without compromising anti-leukaemia therapy.
Case presentation
A 10-year-old boy was confirmed to have Philadelphia chromosome (Ph)-positive ALL. According to the Chinese Children’s Cancer Group study ALL-2015 (CCCG-ALL-2015), he was provisionally assigned as intermediate-risk based on his presenting clinical features, aged 10 years, and immunophenotype B- cell and Philadelphia chromosome–positive ALL. According to CCCG-ALL-2015, the patient will receive MRD directed, risk-stratified treatment, modified from the St Jude Children’s Research Hospital Total XV and XVI studies and the Shanghai Children’s Medical Center ALL-2005 trial. For MRD ≥ 1% at the end of remission induction, provisional intermediate-risk patient has to be escalated to high risk. Allogeneic transplant was recommended. He received upfront window therapy with dexamethasone for 4 days followed by remission induction with prednisone acetate, vincristine, daunorubicin hydrochloride (DNR), and pegaspargase from days 5 to 28.
He began to receive dasatinib (80 mg/m2 per day) as soon as the diagnosis was made on day 5 of remission induction. On day 18 of remission induction, he was hospitalized for cough, fever, and pain, tenderness and swelling over the right elbow. Laboratory tests were notable for neutropenia and elevated inflammatory markers (Fig. 1). A computed tomography (CT) chest scan showed the patchy shadows in the anterior lobe of left upper lung and the middle lobe of right lung. The right upper limb ultrasound revealed swelling of soft tissue without previous trauma. Empiric treatment with broad-spectrum antibiotics was initiated to cover both gram-positive and gram-negative bacteria. The lesion progressed to an abscess in the upper right arm. Twenty-two hours later, blood culture showed fungus positivity and pus. Empirical amphotericin B therapy was initiated. There are two reasons we chose amphotericin B. First, Candida infection is the most common fungal infection. Second, vincristine is one of the drugs used in remission induction chemotherapy. Voriconazole may increase the toxic side effects of vincristine, so voriconazole was not our first option [6]. The blood culture results suggested C. tropicalis 2 days later. Minimal inhibitory concentrations indicated susceptibility to amphotericin B (minimal inhibitory concentration < =0.5 μg/mL), fluconazole (1) and voriconazole (0.125) and flucytosine (<=0.4). He subsequently developed pain and swelling over the right upper arm and forearm. Five days after admission, he was afebrile, but pain, oedema, and limited function of the right elbow were progressive. Repeated ultrasound revealed discrete periosteal oedema adjacent to the humerus 1 week after admission. Magnetic resonance imaging (MRI) of the right humerus showed an intraosseous abscess and probable osteomyelitis (Fig. 2). Surgical irrigation and debridement of the bone were performed immediately (Fig. 3). Culture of bone aspirates obtained during surgery showed that C. tropicalis was sensitive to amphotericin B, which is the same result as the blood culture. A small study of the bone fragments collected during surgery revealed fungal spores. All chemotherapy, except prednisone was continued, was withdrawn for 1 week. Debridement was repeated on the third postoperative day, resulting in considerable improvement of clinical and laboratory findings. His condition improved. One week later, when he was nontoxic, haemodynamically stable, with no signs of haematopoietic toxicity and inflammatory markers within the normal range, induction chemotherapy was continued with some modification with prednisolone and dasatinib, and treatment was carried out for osteomyelitis with amphotericin B, meropenem and vancomycin in parallel. Successful control of osteomyelitis was achieved by serial surgical debridement of the lesion, antibiotics, amphotericin B and HBO therapy. Treatment with amphotericin B was administered for a total of 3 weeks; during this time, he regained the ability to move his arm and transitioned to oral posaconazole for consolidation, which he is currently receiving on an ongoing basis. Vincristine (D19 and D26) and L-asparaginase (D26) were administered until the fever was controlled and the neutrophil count (ANC) exceeded 500/mm3. After completion of remission induction therapy, he achieved complete remission (CR). Then, we removed the remission induction treatment consisting of cyclophosphamide (CTX), cytarabine (Ara-c), and mercaptopurine (6-MP) from days 29 to 35. The next chemotherapy regimen was continued with dasatinib, weekly vincristine and daily mercaptopurine for 3 weeks. Subsequent cycles of chemotherapy were reinitiated as per the protocol. At follow-up 5 months later, the patient continued to feel good.
Fig. 1 The results of the laboratory test, antimicrobial treatment and chemotherapy
Fig. 2 The MRI results of the right arm at first (a). At the follow-up MRI, the previous abnormal signals narrowed significantly (b)
Fig. 3 Surgical irrigation and debridement of the bone
Discussion and conclusions
Candida are found on the skin and in the respiratory tract, vagina and stools. According to a multicentre study in Australia [7], Candida species accounted for the majority of infections associated with neutropenia in immunocompromised patients with ALL, of which Candida albicans and Candida parapsilosis were most frequently detected. According to another retrospective study, the proportion of Candida is increasing in children with ALL [8]. To our knowledge, there are few reports of C. tropicalis osteomyelitis in a child with ALL. Predisposing factors present in our case were underlying leukaemia, steroids, neutropenia, and immunosuppressive therapy, which is consistent with the literature report [9].
Proving a diagnosis is the first key step in the successful management of IFI. Isolating and identifying the causative fungus on culture is important for epidemiological and research purposes. The culture of specimens from surgery is more sufficient than blood to determine the pathogen and helps to establish the diagnosis as quickly as possible.
A combination of early diagnosis, surgical debridement and antifungal therapy seems to be crucial. The timely administration of empirical amphotericin B on suspicion of fungal infection in our case along with debridement of necrotic tissue may be responsible for a successful outcome.
In the successful management of Ph-positive ALL, in the pre-TKI era, matched donor allogeneic stem cell transplantation was beneficial [10]. Sequential addition of imatinib (a tyrosine kinase inhibitor) to the chemotherapy regimen in Ph-positive ALL dramatically improved the outcomes for children with Ph-positive ALL [11]. TKIs administered in the early phases of therapy can dramatically improve the outcome of childhood Ph-positive ALL. According to the study, there was no significant difference in 5-year disease-free survival (DFS) for patients who received imatinib alone versus patients who received imatinib followed by HSCT [12]. Dasatinib is a crucial second-generation Abl–tyrosine kinase inhibitor. According to our randomized clinical trial, dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Ph-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day [13]. Anti-infection combined with surgical incision and drainage and dasatinib administration together led to the successful treatment of osteomyelitis while maintaining a remission state of Ph-positive ALL.
The importance of judicious concomitant administration of antifungal and anti-leukaemia treatment during induction therapy in ALL is highlighted. Moreover, we emphasize that the most efficient diagnostic and treatment strategy for patients with fungal osteomyelitis with ALL is the combination of medical and surgical management. When there is significant marrow toxicity and infection in a patient with Ph-positive ALL, concurrent myelosuppressive agents such as DNR, Ara-C, CTX, MTX, and 6-MP should be stopped instead of dasatinib. It can be an effective treatment option for patients who need both infection control and ALL treatment.
Abbreviations
ALLAcute lymphoblastic leukaemia
Ara-cCytarabine
CCCG-ALL-2015Chinese Children’s Cancer Group study ALL-2015
CTComputed tomography
CRComplete remission
CTXCyclophosphamide
DNRDaunorubicin hydrochloride
IFIInvasive fungal infection
OMOsteomyelitis
PhPhiladelphia chromosome
ANCNeutrophil granulocyte
MRIMagnetic resonance imaging
6-MPMercaptopurine
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Sanming Project of Medicine in Shenzhen (SZSM201512033).
Authors’ contributions
XLC designed the data analysis and wrote the manuscript; Qingling Long and Guichi Zhou provided imaging assistance; Sixi Liu and Feiqiu Wen contributed to critical revision. All of the authors have read and approved the manuscript.
Funding
Not applicable.
Availability of data and materials
The microarray data will be available in the NCBI database.
Ethics approval and consent to participate
This study was approved by the ethics committee of Shenzhen Children’s Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent for publication
Written consent to publish this information was obtained from the parents of the study participants.
Competing interests
The authors declare that they have no competing interests. | 80 MILLIGRAM/SQ. METER (PER DAY) | DrugDosageText | CC BY | 33573668 | 19,023,891 | 2021-02-11 |
What was the outcome of reaction 'Candida osteomyelitis'? | Successful outcome of disseminated Candida tropicalis osteomyelitis on remission induction for childhood Philadelphia chromosome-positive acute lymphoblastic leukaemia-case report.
BACKGROUND
Invasive fungal infection (IFI) is one of the most challenging complications in children undergoing acute lymphoblastic leukaemia (ALL) treatment, but acute fungal osteomyelitis (OM) is rarely encountered.
METHODS
Here, we describe a case of Candida tropicalis osteomyelitis in a 10-year-old patient with Philadelphia chromosome (Ph)-positive ALL. He was on remission induction therapy at the time of neutropenia, and an abscess developed in his right arm. The blood and bone cultures were positive for C. tropicalis. Antibiotics and antifungals were administered. Magnetic resonance imaging of the arm revealed an intraosseous abscess, suggestive of OM. Surgical irrigation and debridement of the bone were performed immediately. The patient was effectively treated with antifungal therapy and ALL treatment. He has fully recovered into complete clinical remission but with visible sequelae on magnetic resonance imaging (MRI). He took oral posaconazole for consolidation until disappearance of the lesion shadows on MRI and received subsequent cycles of chemotherapy in parallel.
CONCLUSIONS
In the successful management of Ph-positive ALL, dasatinib, a second-generation Abl-tyrosine kinase inhibitor, is crucial. The recommended treatment for Candida osteomyelitis in Ph-positive ALL patients is a fungicidal agent combined with surgery and modification chemotherapy with dasatinib. The use of combined modalities of treatment seems to be crucial in the successful management of Ph-positive ALL.
Background
Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy [1]. Children with ALL are immunocompromised patients who are at high risk of infection associated with high morbidity and mortality rates [2]. Invasive fungal infection (IFI) is one of the most challenging complications in children with ALL treatment [3], but acute fungal osteomyelitis (OM) is rarely encountered. In immunocompromised children, the most common mechanism of these complications includes fungal osteomyelitis due to continuous infiltration or haematogenous spread [4]. Candida species are weak pathogens that are common commensal organisms inhabiting the skin and mucous membranes of most individuals. However, the rate of incidence of invasive Candida infection is increasing among newborns in the ICU and in immunosuppressive therapy, the augmented use of intravenous catheters and haematological malignancy and neutropenia in children [5]. Successfully managing fungal osteomyelitis and chemotherapy for ALL is quite difficult. Here, we report a case of childhood Philadelphia chromosome (Ph)-positive acute lymphoblastic leukaemia, complicated by disseminated Candida tropicalis osteomyelitis of the right humerus during remission induction that was successfully managed by timely and appropriate administration without compromising anti-leukaemia therapy.
Case presentation
A 10-year-old boy was confirmed to have Philadelphia chromosome (Ph)-positive ALL. According to the Chinese Children’s Cancer Group study ALL-2015 (CCCG-ALL-2015), he was provisionally assigned as intermediate-risk based on his presenting clinical features, aged 10 years, and immunophenotype B- cell and Philadelphia chromosome–positive ALL. According to CCCG-ALL-2015, the patient will receive MRD directed, risk-stratified treatment, modified from the St Jude Children’s Research Hospital Total XV and XVI studies and the Shanghai Children’s Medical Center ALL-2005 trial. For MRD ≥ 1% at the end of remission induction, provisional intermediate-risk patient has to be escalated to high risk. Allogeneic transplant was recommended. He received upfront window therapy with dexamethasone for 4 days followed by remission induction with prednisone acetate, vincristine, daunorubicin hydrochloride (DNR), and pegaspargase from days 5 to 28.
He began to receive dasatinib (80 mg/m2 per day) as soon as the diagnosis was made on day 5 of remission induction. On day 18 of remission induction, he was hospitalized for cough, fever, and pain, tenderness and swelling over the right elbow. Laboratory tests were notable for neutropenia and elevated inflammatory markers (Fig. 1). A computed tomography (CT) chest scan showed the patchy shadows in the anterior lobe of left upper lung and the middle lobe of right lung. The right upper limb ultrasound revealed swelling of soft tissue without previous trauma. Empiric treatment with broad-spectrum antibiotics was initiated to cover both gram-positive and gram-negative bacteria. The lesion progressed to an abscess in the upper right arm. Twenty-two hours later, blood culture showed fungus positivity and pus. Empirical amphotericin B therapy was initiated. There are two reasons we chose amphotericin B. First, Candida infection is the most common fungal infection. Second, vincristine is one of the drugs used in remission induction chemotherapy. Voriconazole may increase the toxic side effects of vincristine, so voriconazole was not our first option [6]. The blood culture results suggested C. tropicalis 2 days later. Minimal inhibitory concentrations indicated susceptibility to amphotericin B (minimal inhibitory concentration < =0.5 μg/mL), fluconazole (1) and voriconazole (0.125) and flucytosine (<=0.4). He subsequently developed pain and swelling over the right upper arm and forearm. Five days after admission, he was afebrile, but pain, oedema, and limited function of the right elbow were progressive. Repeated ultrasound revealed discrete periosteal oedema adjacent to the humerus 1 week after admission. Magnetic resonance imaging (MRI) of the right humerus showed an intraosseous abscess and probable osteomyelitis (Fig. 2). Surgical irrigation and debridement of the bone were performed immediately (Fig. 3). Culture of bone aspirates obtained during surgery showed that C. tropicalis was sensitive to amphotericin B, which is the same result as the blood culture. A small study of the bone fragments collected during surgery revealed fungal spores. All chemotherapy, except prednisone was continued, was withdrawn for 1 week. Debridement was repeated on the third postoperative day, resulting in considerable improvement of clinical and laboratory findings. His condition improved. One week later, when he was nontoxic, haemodynamically stable, with no signs of haematopoietic toxicity and inflammatory markers within the normal range, induction chemotherapy was continued with some modification with prednisolone and dasatinib, and treatment was carried out for osteomyelitis with amphotericin B, meropenem and vancomycin in parallel. Successful control of osteomyelitis was achieved by serial surgical debridement of the lesion, antibiotics, amphotericin B and HBO therapy. Treatment with amphotericin B was administered for a total of 3 weeks; during this time, he regained the ability to move his arm and transitioned to oral posaconazole for consolidation, which he is currently receiving on an ongoing basis. Vincristine (D19 and D26) and L-asparaginase (D26) were administered until the fever was controlled and the neutrophil count (ANC) exceeded 500/mm3. After completion of remission induction therapy, he achieved complete remission (CR). Then, we removed the remission induction treatment consisting of cyclophosphamide (CTX), cytarabine (Ara-c), and mercaptopurine (6-MP) from days 29 to 35. The next chemotherapy regimen was continued with dasatinib, weekly vincristine and daily mercaptopurine for 3 weeks. Subsequent cycles of chemotherapy were reinitiated as per the protocol. At follow-up 5 months later, the patient continued to feel good.
Fig. 1 The results of the laboratory test, antimicrobial treatment and chemotherapy
Fig. 2 The MRI results of the right arm at first (a). At the follow-up MRI, the previous abnormal signals narrowed significantly (b)
Fig. 3 Surgical irrigation and debridement of the bone
Discussion and conclusions
Candida are found on the skin and in the respiratory tract, vagina and stools. According to a multicentre study in Australia [7], Candida species accounted for the majority of infections associated with neutropenia in immunocompromised patients with ALL, of which Candida albicans and Candida parapsilosis were most frequently detected. According to another retrospective study, the proportion of Candida is increasing in children with ALL [8]. To our knowledge, there are few reports of C. tropicalis osteomyelitis in a child with ALL. Predisposing factors present in our case were underlying leukaemia, steroids, neutropenia, and immunosuppressive therapy, which is consistent with the literature report [9].
Proving a diagnosis is the first key step in the successful management of IFI. Isolating and identifying the causative fungus on culture is important for epidemiological and research purposes. The culture of specimens from surgery is more sufficient than blood to determine the pathogen and helps to establish the diagnosis as quickly as possible.
A combination of early diagnosis, surgical debridement and antifungal therapy seems to be crucial. The timely administration of empirical amphotericin B on suspicion of fungal infection in our case along with debridement of necrotic tissue may be responsible for a successful outcome.
In the successful management of Ph-positive ALL, in the pre-TKI era, matched donor allogeneic stem cell transplantation was beneficial [10]. Sequential addition of imatinib (a tyrosine kinase inhibitor) to the chemotherapy regimen in Ph-positive ALL dramatically improved the outcomes for children with Ph-positive ALL [11]. TKIs administered in the early phases of therapy can dramatically improve the outcome of childhood Ph-positive ALL. According to the study, there was no significant difference in 5-year disease-free survival (DFS) for patients who received imatinib alone versus patients who received imatinib followed by HSCT [12]. Dasatinib is a crucial second-generation Abl–tyrosine kinase inhibitor. According to our randomized clinical trial, dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Ph-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day [13]. Anti-infection combined with surgical incision and drainage and dasatinib administration together led to the successful treatment of osteomyelitis while maintaining a remission state of Ph-positive ALL.
The importance of judicious concomitant administration of antifungal and anti-leukaemia treatment during induction therapy in ALL is highlighted. Moreover, we emphasize that the most efficient diagnostic and treatment strategy for patients with fungal osteomyelitis with ALL is the combination of medical and surgical management. When there is significant marrow toxicity and infection in a patient with Ph-positive ALL, concurrent myelosuppressive agents such as DNR, Ara-C, CTX, MTX, and 6-MP should be stopped instead of dasatinib. It can be an effective treatment option for patients who need both infection control and ALL treatment.
Abbreviations
ALLAcute lymphoblastic leukaemia
Ara-cCytarabine
CCCG-ALL-2015Chinese Children’s Cancer Group study ALL-2015
CTComputed tomography
CRComplete remission
CTXCyclophosphamide
DNRDaunorubicin hydrochloride
IFIInvasive fungal infection
OMOsteomyelitis
PhPhiladelphia chromosome
ANCNeutrophil granulocyte
MRIMagnetic resonance imaging
6-MPMercaptopurine
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Sanming Project of Medicine in Shenzhen (SZSM201512033).
Authors’ contributions
XLC designed the data analysis and wrote the manuscript; Qingling Long and Guichi Zhou provided imaging assistance; Sixi Liu and Feiqiu Wen contributed to critical revision. All of the authors have read and approved the manuscript.
Funding
Not applicable.
Availability of data and materials
The microarray data will be available in the NCBI database.
Ethics approval and consent to participate
This study was approved by the ethics committee of Shenzhen Children’s Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent for publication
Written consent to publish this information was obtained from the parents of the study participants.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33573668 | 19,023,891 | 2021-02-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | CARBOPLATIN, CETUXIMAB, FLUOROURACIL | DrugsGivenReaction | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | CARBOPLATIN, CETUXIMAB, FLUOROURACIL | DrugsGivenReaction | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrolyte imbalance'. | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | CARBOPLATIN, CETUXIMAB, FLUOROURACIL | DrugsGivenReaction | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy toxic'. | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | CARBOPLATIN, CETUXIMAB, FLUOROURACIL | DrugsGivenReaction | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
What was the dosage of drug 'CARBOPLATIN'? | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | DAY 1 | DrugDosageText | CC BY-NC-ND | 33574215 | 19,430,981 | 2021-02-12 |
What was the outcome of reaction 'Anaemia'? | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | Fatal | ReactionOutcome | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
What was the outcome of reaction 'Disease progression'? | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | Fatal | ReactionOutcome | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
What was the outcome of reaction 'Electrolyte imbalance'? | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | Fatal | ReactionOutcome | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
What was the outcome of reaction 'Nephropathy toxic'? | Myocardial Metastasis of Tongue Cancer: A Rare Localization.
BACKGROUND Cardiac metastases of head and neck tumors are extremely rare, and antemortem diagnosis is even rarer. In most cases, patients show symptoms or electrocardiographic abnormalities and expected survival is considerably low. CASE REPORT A 72-year-old man was admitted to our cardiology ward with suspected endocarditis 2 months after a right hemiglossectomy for a squamous cell carcinoma. He was asymptomatic and showed no electrocardiogram abnormalities. Echocardiography showed an iso-ipoechogenic round-shaped formation at the right ventricle apex that was suspected to be a metastasis owing to 2 cardiac magnetic resonance imaging examinations showing a significant increase in its volume over 14 days. The patient was evaluated by a multidisciplinary team and referred for first-line chemotherapy with carboplatin, 5-fluoruracil, and cetuximab. He died after almost 4 months of follow-up. CONCLUSIONS This case presents a very rare diagnosis as well as some unique features, including the intramyocardial localization, the absence of symptoms, and electrocardiogram abnormalities. Our report shows the relevance of imaging techniques in defining even the most unusual clinical findings, and it emphasizes the significance of early recognition of cardiac masses in order to identify the appropriate medical or surgical therapy for patients.
Background
Cardiac tumors represent a rare, yet challenging diagnosis and can be differentiated into primary tumors (rates between 0.001% and 0.3%) and secondary tumors (ranging from 2.3% and 18.3%) [1]. In theory, the heart can be metastasized by any malignant neoplasm, but antemortem diagnosis is very rare because clinical manifestations are subtle or even absent, especially at an early stage [1,2]. At more advanced stages, however, metastatic tumors gradually lead to heart failure, conduction disturbances, or valvular disease resembling mitral stenosis, anginal pain, or Stokes-Adams syndrome [3]. Cardiac metastasis is more frequently detected accidentally, usually at surgery or autopsy (in 2.3–7.1% of cases) [4].
In order of frequency, tumors metastasize to the pericardium, endocardium and valves, and the myocardium. The mechanisms of metastasis to the heart remain uncertain, but explanatory hypotheses include hematogenous spread via the coronary arteries, retrograde lymphatic extension, and intracavitary diffusion either by the inferior vena cava or by pulmonary veins [2,3]. Lymphatic spread tends to give rise to pericardial metastases, as seen in lung and breast cancer, owing to their topography; whereas, hematogenous spread leads to myocardial metastases [5]. The most common primary tumors that produce cardiac metastasis are melanoma, carcinoma of the bronchus, breast carcinoma, and lymphoma. Due to their propensity for generalized hematogenous spread, malignant melanomas frequently metastasize to the heart in this manner; whereas, esophageal and breast cancers metastasize to the heart predominantly by lymphatics [5].
Case Report
A 72-year-old man received a diagnosis of tongue carcinoma in December 2018. He subsequently underwent a right subtotal hemiglossectomy with right lateral neck dissection and a reconstruction with a fasciocutaneous flap from the left thigh. Histological examination revealed poorly differentiated (G3) ulcerated squamocellular carcinoma infiltrating the muscular tissue and various metastatic lymph nodes (pT3, N2b, M0). About a month after surgery the patient was admitted to the Emergency Department for a surgical wound infection and dismissed with an oral antimicrobial therapy.
In January 2019, computed tomography-positron emission tomography (CT-PET) was performed and showed hypermetabolic activity in the patient’s tonsils and laterocervical lymph nodes. A hypermetabolic signal (standardized uptake value, maximum 15.1) was also shown in the heart at the ostium of the mitral valve and near the apex of the right ventricle (Figure 1). These images were thought to be suggestive of a septic thrombus. The patient was admitted to our cardiology ward with suspected endocarditis.
The patient presented no symptoms and, in particular, he did not report chest discomfort, palpitations, dyspnea, or syncope. Physical evaluation was normal, and an electrocardiogram (ECG) showed no significant abnormalities. The patient’s C-reactive protein and erythrocyte sedimentation rate were slightly increased. With few clinical data to confirm or exclude the suspected diagnosis of endocarditis, a better characterization of the hypermetabolic signal areas shown by CT-PET was essential.
A transthoracic echocardiography (TTE) (Figure 2A, 2B, Video 1) was done, and it showed an iso-ipoechogenic round-shaped formation at the right ventricle apex, with no signs of vascularization. The patient next underwent a cardiac magnetic resonance imaging (MRI) scan (Figure 3A, 3B, Video 2) for better tissue characterization. A round-shaped mass with a diameter of 17 mm, hardly distinguishable from the right ventricular wall, was found. The mass showed a hyperintense signal in T2-weighted images and in T1-weighted scans with late gadolinium enhancement and a hypointense signal in T1 scans with early gadolinium enhancement. These findings were suggestive of cardiac metastasis.
The patient was re-evaluated by a multidisciplinary team of oncologists, radiologists, and maxillofacial surgeons. A second TTE (Figure 4, Video 3) and a follow-up MRI scan (Figure 5A, 5B, Video 4) were done 14 days later and showed significant augmentation in the sizes of the right ventricular lesion (34×25×34 mm) and infiltration of the right ventricular free wall and the pericardial adipose tissue. This formation also showed, in the patient’s intracavitary portion, a nodular extension wedged between the right ventricular trabeculae with synchronous movement in cine sequences.
Because of the lesion localization, it was impossible to obtain a sample for histological examination. During the first weeks of his hospital stay, the patient had also developed a subcutaneous lesion that appeared as a protuberance in the right frontal area that rapidly increased in volume. This lesion was not evident on admission, nor was it reported on the initial CT-PET. It was also investigated with an MRI scan of the head and neck district, and findings suggested that it was a metastasis. An incisional biopsy of the lesion was then performed, and the results were compatible with the localization of a squamocellular carcinoma.
From February to April 2019, the patient received 2 cycles of first-line chemotherapy according to the scheme carboplatin area under the curve (AUC) of 5 on day 1, 5-fluoruracil 800 mg/m2/d from day 1 to day 5 every 21 days, along with the anti-epidermal growth factor receptor drug cetuximab, at a loading dose of 400 mg/m2 for the first cycle and then at the standard dose of 250 mg/m2 weekly [6]. Treatment toxicity was assessed every 3 weeks, according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE version 4.03, 2010).
Moderate renal toxicity with moderate anemia, associated with electrolyte imbalances, was recorded. The ECG started to show some changes, including repolarization abnormalities in the anterior leads that were not present in the first ECG. Moreover, a central venous catheter infection (that required removal of the catheter) was reported. Objective response was clinically evaluated before every cycle and by imaging after the 2 cycles. The patient was restaged by radiological imaging with a contrast-enhanced CT scan. The patient’s objective response rate was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [7]. The patient experienced progression of disease due to the appearance of a new cardiac metastasis. Because of disease progression, chemotherapy was definitively suspended, and the patient received supportive care during the rapid decline of his physical condition. The patient died in April 2019.
Discussion
Head and neck tumors represent an extremely rare source of cardiac metastasis, with fewer than 15 cases described in the medical literature [2,5,8] (Table 1). Differential diagnosis has to include a number of clinical conditions. In our case, the main imaging finding at admission was a hypermetabolic mass described in the apex of the right ventricle and at the ostium of the mitral valve. The suspected diagnosis on admission was endocarditis. This hypothesis was subsequentially excluded based on clinical findings. The patient did not show any clinical characteristics of endocarditis. His levels of C-reactive protein and other inflammatory markers were just slightly altered, and his blood cultures were repeatedly negative. In addition, the TTE images were also highly atypical for endocarditis, with a round-shaped mass detected near the apex of the right ventricle. Other possible causes of cardiac hypermetabolic signals are primary tumors of the heart, but they are 40 times as rare as secondary tumors (with a reported prevalence in autopsy series of 0.001–0.3%). Furthermore, the most common tumor in this group is the myxoma, which generally shows very low or absent 2-[18F]fluoro-2-deoxy-d-glucose (FDG) up-take [19]. Blood thrombi can occasionally present as circular masses, but they tend to show no FDG uptake [20].
The main clinical findings that supported the diagnosis of a myocardial metastasis, even in the absence of a direct histological confirmation, were the tissue characterization and demonstration of tissue infiltration based on MRI and the significative volumetric increase of the mass in a limited time frame. The diagnosis was also reinforced by the detection of a sub-cutaneous metastasis that suggested widespread disease.
We believe that our case presents a series of particularities that stand out even in the frame of a very rare diagnosis. In our literature search we observed that symptoms or electrocardiographic abnormalities were reported in most cases. In contrast, our patient remained completely asymptomatic for months and did not show any significant abnormality in his initial ECG. We also believe that our case can be considered unusual for the intramyocardial localization because most reported patients showed pericardial or intracavitary metastasis. Life expectancy is considered to be of few weeks in most patients, while our patient had a survival of about 4 months.
Conclusions
The paucity of antemortem diagnosis of cardiac metastasis emphasizes the importance of early recognition of cardiac masses in order to determine appropriate medical or surgical therapy for patients. Our case highlights the significance of echocardiography and MRI in the antemortem detection of a single metastasis, even in the most unusual localizations.
Figure 1. Computed tomography-positron emission tomography scan. A hypermetabolic signal is visible near the apex of the right ventricle (arrow), showing a high standardized uptake value (maximum 15.1).
Figure 2. First transthoracic echocardiography. Two different (a and b) zoomed subcostal views of an intramyocardial mass (arrow) with a maximum diameter of approximately 1.6 cm.
Figure 3. First magnetic resonance imaging scan. (A) Four-chamber steady-state free precession and (B) short-axis T2 short tau inversion recovery, showing a 17-mm round-shaped mass (arrow) that is hardly distinguishable from the right ventricular wall.
Figure 4. Control transthoracic echocardiography. After 14 days, the mass (arrow) showed a significant increase in linear dimensions with a maximum diameter of approximately 3 cm.
Figure 5. Control magnetic resonance imaging. Four-chamber (A) and short-axis (B) views confirming the lesion’s (arrow) volumetric increase and showing infiltration of right ventricular free wall and pericardial adipose tissue.
Video 1. First transthoracic echocardiography: subcostal view showing the intramyocardial mass near the right ventricle apex.
Video 2. First magnetic resonance imaging scan: cine steady-state free precession sequences showing the intramyocardial mass and its movement, synchronous with the right ventricular wall.
Video 3. Control transthoracic echocardiography: subcostal view showing a significative dimensional increase of right ventricular mass.
Video 4. Control magnetic resonance imaging scan: cine steady-state free precession sequences, 4 chamber views confirming a significant augmentation in the sizes of the right ventricular lesion.
Table 1. Summary of published cases.
Study Year of publication Primary site Location of metastases Symptoms ECG anomalies Treatment Follow-up period
Werbel et al [9] 1985 Tongue Pericardium, right atrium Cardiac murmur, chest pain ST depression, T waves inversion Radiotherapy 7 wk
Rivkin et al [10] 1999 Tongue Right ventricle Chest pain ST elevation, Q waves, AF Chemotherapy “Several months”
Schwender et al [11] 2002 Buccal mucosa Pericardium Weakness, respiratory distress AF None N/A
Hans et al [12] 2009 Tongue Right ventricle Dyspnea, lower extremity edema, hemoptysis Right bundle branch block None N/A
Onwuchekwa et al [13] 2012 Tongue Right ventricle, interventricular septum Syncope, dyspnea None None N/A
Onwuchekwa et al [13] 2012 Tongue Left ventricle Palpitations, dyspnea ST elevation, AF Radiotherapy 2 mo
Nagata et al [8] 2012 Tongue Pericardium, left lower pulmonary vein Fever None Surgery 3 wk
Nagata et al [8] 2012 Soft palatal mucosa Right atrium, right ventricle, pericardium None Q waves None 3 wk
Browning et al [14] 2015 Tongue Right ventricle N/A N/A None N/A
Malekzadeh et al [15] 2017 Tongue Right ventricle Acute chest pain ST elevation Chemotherapy 2 mo
Kumar et al [16] 2019 Tongue Interventricular septum Syncope Complete heart block Pacemaker implant 1 wk
Shafiq et al [17] 2019 Tongue Left ventricle None ST elevation Chemotherapy Months
Tandon et al [18] 2019 Tongue Left and right ventricle Acute chest pain ST elevation None N/A
Present case 2020 Tongue Right ventricle None None Chemotherapy 4 mo
AF – atrial fibrillation; ECG – electrocardiogram; N/A – not applicable. | Fatal | ReactionOutcome | CC BY-NC-ND | 33574215 | 19,414,907 | 2021-02-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial.
Vaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.
Introduction
Vaginal and vulvar cancers are rare malignancies that have similar estimated incidence (0.7 and 2.6 diagnoses per 100,000 women per year, respectively) and mortality (0.2 and 0.6 deaths per 100,000 women per year, respectively) rates in the United States1. Due to the difficulty of performing large prospective randomized trials in these rare tumor populations, systemic chemotherapeutic regimens have generally been extrapolated from experience in the management of cervical cancer as these malignancies share similar epidemiologic risk factors, are predominantly of squamous cell carcinoma (SCC) histologic subtype, and are strongly associated with human papilloma virus (HPV) infection2–4. However, vaginal and vulvar cancers can be challenging to treat when disease is not amenable to radiation or surgical resection5,6. Treatment response rates to systemic chemotherapeutic regimens are variable in the recurrent setting for vaginal and vulvar SCC; there is currently no consensus on effective regimens5–8. Additionally, given the propensity of vaginal and vulvar SCC to develop at older stages of life, treatment options may be further limited by associated toxicity and morbidity3,4.
There has been a growing interest for immunotherapy in the field of oncology. Immune checkpoint inhibitors have demonstrated impressive, durable responses even among patients who have undergone multiple lines of prior systemic therapy. Specifically, use of immunotherapy in HPV-related cancers is of particular interest given that carcinogenesis is associated with the inability of the immune system to clear the virus9,10. An anti-PD-1 monoclonal antibody, pembrolizumab blocks the PD-1/PD-L1 pathway (an escape mechanism that malignant cells use to evade immune surveillance) thereby augmenting T-cell mediated anti-tumor activity.
Pembrolizumab has demonstrated impressive clinical response in microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumors, which led to the US Food and Drug Administration (FDA) approval for use in MSI-H/dMMR solid tumors11,12. In gynecologic cancers, single-agent pembrolizumab has FDA approval for MSI-H endometrial cancer (response rates 53–57.1%) or PD-L1 positive (Combined Positive Score ≥ 1%) cervical cancer (response rates 12.2–17%) who have progressed on prior systemic therapy11–14. As the first drug to receive FDA approval for a tissue agnostic indication, pembrolizumab may be of clinical benefit in other solid tumors and possibly among those with HPV-associated gynecologic cancers such as vaginal or vulvar SCC. Given the rarity of vaginal or vulvar SCC, few studies have examined the use of immune checkpoint inhibitors in these tumor types.
Thus as part of a clinical phase II basket trial for patients with advanced rare malignancies, we report three cases of SCC (two vaginal and one vulvar) who were treated with single-agent pembrolizumab.
Cases
Clinical trial design
We present three patients with recurrent, metastatic vaginal (patient 1 and 2) or vulvar (patient 3) SCC who were enrolled into cohort 10 (“other rare tumor histologies” category) of an open-label, phase II basket clinical trial (ClinicalTrials.gov: NCT02721732) at the University of Texas MD Anderson Cancer Center (enrolment period August 15, 2016–July 27, 2018). In brief, the trial sought to examine the clinical efficacy and safety of single-agent pembrolizumab (200 mg IV every 3 weeks) in 10 prespecified cohorts of advanced, rare tumors regardless of PD-L1 status. Trial design and overall trial results are described elsewhere15. All trial patients had PD-L1 and tumor infiltrating lymphocyte (TIL) characterization of tumor tissue that was correlated with treatment response, as described previously15. PD-L1 characterization was reported as Combined Positive Score (CPS) which is defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100. CPS ≥ 1% denoted PD-L1 positive expression16. Treatment response was evaluated using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) guidelines on serial radiologic imaging at baseline, every 9 weeks until the first 6 months followed by every 12 weeks at the discretion of the investigator. Safety and tolerability were assessed by characterization and grading of adverse events via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. All patients provided informed consent prior to enrolment. Furthermore, the protocol was approved by the FDA and the Institutional Review Board at The University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
Vaginal SCC cases
Baseline clinical and tumor characteristics as well as prior treatment histories are demonstrated in Tables 1 and 2, respectively. The two patients (patient 1 and 2) were 72 and 63 years old (respectively) women with recurrent vaginal cancer and had grade 2 SCC histologies with infra- and supra-diaphragmatic metastatic disease. Both patients had multiple lines of prior systemic therapy (four and six, respectively) and prior radiation therapy before trial enrolment. Among prior systemic therapies received, the treatment with the longest duration of disease control after first disease recurrence for patient 1 was carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab (7 months total). For patient 2, the systemic treatment with the longest duration of disease control following first recurrence was selinexor/eribulin (6 months).Table 1 Baseline clinical and tumor characteristics.
Pt Age Cancer Grade ECOG PS Years since initial diagnosis FIGO 2009a Sites of metastasis prior to treatmentb PD-L1 CPS TIL infiltration
1 72 Vaginal 2 1 3 IVB AA, AN, AT, N 5 2
2 63 Vaginal 2 1 3 IVB AA, B, H, L, 2 2
3 88 Vulvar 1 1 20 I AR, V 5 2
CPS = Combined Positive Score, defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100; CPS ≥ 1% denoted PD-L1 positive expression ECOG PS = Eastern Cooperative Oncology Group Performance Status. N/A = Not applicable. Pt = patient. TIL infiltration = intensity of tumor-infiltrating lymphocytes within tumor nests on a scale of 0 to 3; 0 = absence of TIL, 1 = few amounts of TIL, 2 = moderate amounts of TIL, 3 = high amount of TIL. SCC = squamous cell carcinoma.
aInternational Federation of Gynecology and Obstetrics (FIGO) 2009 staging at diagnosis.
bSites of metastatic disease prior to treatment: AA = adenopathy of the abdomen, AN = adenopathy of the neck, AT = adenopathy of the thorax, AR = anorectum, B = bone, H = hepatic metastases, L = lung metastases, N = neck, V = vagina.
Table 2 Prior treatments before pembrolizumab treatment.
Pt Prior radiation treatments Number of prior surgeries Number of prior systemic therapies Prior systemic therapiesa
1 1. External beam radiation therapy and brachytherapy
2. Chemoradiationb
0 4 1. Carboplatin/paclitaxel
2. Cisplatinb
3. Carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumabc
4. Topotecan/bevacizumab
2 1. Palliative radiation to the groin and neck 0 6 1. Carboplatin/paclitaxel
2. Cisplatin/topotecan
3. Cetuximab/prexasertib
4. Sapanisertib/afibercept
5. Bimiralisib
6. Selinexor/eribulinc
3 1. External beam radiation therapy 11 1 1. Carboplatinc
Pt: patient.
aLines of systemic therapy are ordered chronologically.
bRadiation was given concurrently with weekly cisplatin.
cLongest duration of disease control on a systemic therapeutic regimen following recurrence.
Figures 1 and 2 demonstrate the best percentage change in tumor target lesions compared to baseline and the dynamic changes in tumor measurements compared to baseline, respectively. With single-agent pembrolizumab, patient 1 had a 68% decrease in the size of the target lesions following three cycles and this continued with increasing cycles of treatment (74% decrease after cycle 6 and 81% decrease after cycle 9). Despite both progressive reduction of the size of the target lesions and clinical benefit, patient 1 had developed new nodal lesions and progression of non-measurable lesions after cycle 6 and this was confirmed on subsequent imaging studies. Per trial protocol, the patient was permitted to continue pembrolizumab following confirmation of disease progression until repeat radiologic imaging 4 weeks after the confirmatory scan as long as she was clinically stable. Repeat radiologic imaging demonstrated disease progression and thus a total of 10 cycles was administered prior to treatment discontinuation. Patient 1’s best objective response was classified as stable disease using irRECIST criteria. For patient 2, there was no objective response. There was a 71% increase in the patient’s tumor measurements according to irRECIST criteria following three cycles of pembrolizumab and treatment was discontinued. Her best objective response was classified as progressive disease (Figs. 1 and 2).Figure 1 Radiologic response to pembrolizumab in patients with vaginal or vulvar cancer. Waterfall plot illustrating the best objective response to pembrolizumab in three evaluable patients using irRECIST criteria. Each bar represents a patient and shows the maximum percentage change from baseline in the sum of the longest diameters of all target lesions and any new lesions while on pembrolizumab. The area above the upper red dotted line represents progressive disease (≥ 20% increase in the sum of the diameters of the target lesions compared with the baseline). The area between both upper and lower red dotted lines represents stable disease. The area below the lower red dotted line represents treatment response (≥ 30% increase in the sum of the diameters of the target lesions compared with the baseline). P1–3: Patient 1–3. *Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria and would be classified as having stable disease as the best objective response.
Figure 2 Tumor response by irRECIST across time. This spider plot demonstrates the tumor measurements from baseline using irRECIST criteria during the course of treatment with pembrolizumab in the three patients. Patient 1 and 2 had progression of disease prior to stopping treatment while patient 3 stopped treatment due to treatment-related toxicity. Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria. Despite a significant reduction in the size of the target lesions on her initial scan at cycle 3 with partial response, her follow-up scans at cycle 6 and cycle 9 demonstrated the appearance of new lesions and progression of non-measurable lesions; the best objective response is stable disease. Patient 3 had an unconfirmed partial response due to treatment discontinuation (after cycle 5) following initial evaluation of partial response; the best objective response is stable disease.
Overall, the treatment was tolerable for both patients with grade 2 fatigue as the only treatment-related adverse event (TRAE) for patient 2 and this was observed after cycle 3. Patient 1 did not have any TRAEs.
For tumor characterization, PD-L1 expression was positive in both patients with a CPS score of 5 and 2, respectively. Both patients’ tumors had moderate amounts of TIL (score 2 on a scale of 0 to 3).
Vulvar SCC case
Patient 3 was an 88-year-old woman with a grade 1 SCC and long-standing disease with the bulk of the suspected disease recurrence involving the vagina followed by the ano-rectal region (Table 1). This patient with vulvar cancer had multiple surgical interventions (eight cytoreductive and three ablative procedures), radiation therapy, and most recently had disease progression on single-agent carboplatin prior to study enrolment (Table 2). Although her disease localization made a pelvic exenteration a possible treatment option, there was consensus between the patient, her medical provider, and a multidisciplinary tumor board that the procedure could result in excessive surgical morbidity (given her age). Thus, the patient opted for clinical trial enrolment and was ultimately included into the vaginal cancer expansion cohort of the phase II trial with pembrolizumab for several reasons. First, there was no available cohort of vulvar SCC on trial given the rarity of the tumor. Second, as HPV-related malignancies, systemic treatment of vaginal and vulvar cancers are very similar with strategies extrapolated from cervical cancer studies. Finally, it was difficult to determine with absolute certainty that her disease would be related to recurrent vulvar cancer rather than de novo vaginal cancer given her vaginal biopsies also demonstrated SCC. Due to the bulk of her disease was in the vagina, the patient was treated in the vaginal cancer expansion cohort of trial.
On pembrolizumab, there was a 27% reduction in the target lesions following three cycles and a 30% reduction following another two cycles (Figs. 1 and 2). Due to a grade 3 TRAE, treatment was discontinued after cycle 5 before a confirmatory scan for partial response could be performed. Thus, her best objective response was stable disease by irRECIST criteria. Patient 3 reported a grade 1 maculopapular rash following cycle 1 and grade 2 pruritus after cycle 4. Grade 3 mucositis led to treatment discontinuation. All the aforementioned TRAEs were immune-related. For tumor characterization, patient 3 had positive PD-L1 expression (CPS score of 5) and moderate amounts of TIL (score 2 on a scale of 0 to 3).
Disclaimer
The views expressed in this manuscript are the authors’ own views and are not the official position of the institution or supporting funding sources.
Ethics approval and consent to participate
The protocol was approved by the US Food and Drug Administration (FDA) and the Institutional Review Board at the University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment.
Consent for publication
All the study participants provided written informed consent prior clinical trial enrollment.
Discussion
In this case series, we present two patients (patient 1 and 2) with recurrent vaginal SCC and one patient (patient 3) with recurrent vulvar SCC who received single-agent pembrolizumab as part of a phase II basket trial. Although there were no confirmed objective responses that were observed, patient 1 had a significant reduction in size of the tumor measurements on radiologic imaging (61% decrease) following cycle 3 of pembrolizumab. However, this objective response was not confirmed on repeat imaging after cycle 6. In her case, subsequent imaging showed new metastatic lesions with progression of non-target lesions despite persistent reduction in the measured target lesion sizes (74% followed by 81% decrease). Patient 3 had a 30% reduction in target lesions after five cycles of pembrolizumab but discontinued study treatment due to a grade 3 TRAE (oral mucositis) before repeat imaging could confirm a partial response. Thus, it is possible that the treatment could have resulted in further tumor reduction. In contrast, patient 2 had no tumor reduction and had significant disease progression after 3 cycles of pembrolizumab.
Multiple factors may explain differences in clinical benefit to pembrolizumab for these patients. The first attributable factor may be the difference PD-L1 expression in the tumor microenvironment as evidenced by the PD-L1 CPS scores of 5, 2, and 5 for patients 1–3, respectively. PD-L1 status has been described as a predictive biomarker of response to PD-1 inhibitor monotherapy and increasing PD-L1 expression has been associated with improved response16–19. Thus, the higher expression of PD-L1 in patient 1 and 3 (CPS score 5) may explain a better response compared to patient 2 (CPS score 2) despite similar amounts of TIL (another predictive biomarker for response)17–19. Immunosuppressive factors in the tumor microenvironment may also modulate response to PD-1 inhibitors despite PD-L1 expression (CPS ≥ 1%) and TIL infiltration, leading to poor response in patient 2. Unfortunately, evaluation of possible contributory immunosuppressive factors was not part of the trial design. Furthermore, pembrolizumab is observed to respond more favorably in tumors with high tumor mutational burden or microsatellite instability-high status. For trial participation, patients were not required to have testing for these aforementioned molecular features and it is possible that their tumors could have had low mutational burden or been microsatellite stable.
Although there was not a confirmed partial response for patient 3, there was a trend for tumor reduction. This tumor reduction may have persisted if treatment was not discontinued due to a grade 3 toxicity (oral mucositis). This association between immune-related adverse events and relatively improved treatment response is suggestive of an active immune system and this observation has been similarly reported in multiple studies20–22.
Due to tumor rarity and lack of strong trial data, management of recurrent/metastatic vaginal and vulvar SCCs has largely been extrapolated from treatment strategies in cervical cancer. These strategies have typically consisted of platinum-based systemic combinations when chemoradiation or surgery is not possible5,6. These systemic combinations have not been consistently efficacious in these patient populations. In vaginal cancer, efficacy of systemic treatment has been largely anecdotal but one study has demonstrated an ORR of 6.25% for single agent cisplatin in 16 patients5,7. For vulvar cancer, studies evaluating systemic chemotherapy regimens have had small sample sizes with variable response rates (0–40%)6,23. Currently there are no standardized systemic regimens for vaginal and vulvar cancers5,6,23. Thus, other alternative treatment therapies have been investigated, with immunotherapy gaining interest. In this present study, two of the three patients with vaginal or vulvar SCC were observed to derive clinical benefit (stable disease as per irRECIST criteria). Two other studies have demonstrated some clinical benefit for these tumor types. In a phase I/II trial (CheckMate 358), nivolumab (PD-1 inhibitor) monotherapy efficacy was evaluated in a small cohort of recurrent/metastatic vaginal or vulvar SCC24. Although a small sample size (two vaginal and three vulvar cancers), the investigators observed a 20% objective response rate (one partial response in a vulvar cancer patient) with 40% of patients with 6 months of disease control24. In another case report of vulvar SCC, the patient with a PD-L1 positive tumor was observed to have a complete response to pembrolizumab25. In CheckMate 358 and the aforementioned case report, PD-1 inhibitor therapy was well-tolerated with no significant TRAEs24,25.
Strengths of our case series include the evaluation of the use of pembrolizumab in a rare cohort of vaginal and vulvar SCC with correlation to translational PD-L1 and TIL data. It represents the first reported use of pembrolizumab for vaginal SCC. Furthermore, tumor responses were objectively measured using irRECIST criteria. As mentioned earlier, tumor mutational burden characterization and microsatellite-instability status testing was not a requirement for patients who were included in this phase II clinical trial and this represents a study limitation.
In conclusion, single-agent pembrolizumab was shown, in this study, to be generally safe to utilize for vaginal and vulvar SCC and has demonstrated some clinical benefit. However, given the small size of this cohort of patients, future studies should examine the role of pembrolizumab in the treatment of vaginal and vulvar SCC. Predictive biomarkers (possibly established in other SCC cohorts such as cervical, anal, or head and neck cancers) should be investigated to identify patients who would derive the greatest clinical benefit.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
J.A.H. and A.N. made significant contributions in conceptualization, project administration, data analysis/interpretation, and drafting, reviewing and editing the majority of the original and final manuscript. A.A.J., P.T.S., N.D.F., J.G., S.A.P.P., F.J., and B.S. made significant contributions in project administration, data analysis/interpretation, and revising and reviewing the original and final manuscript.
Funding
This work was supported by Merck and the NIH/NCI under award numbers P30CA016672 (supporting the MD Anderson Clinical Trials Office) and T32 CA101642 JH (T32 training grant). Furthermore, this work was also supported by the Dr. Henry R. Shibata Fellowship Award/Cedars Cancer Foundation (JH).
Data availability
Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request and approval from study sponsor according to available guidelines at time of request.
Competing interests
Jeffrey How reports grants from NIH (T32 CA101642) and the Cedars Cancer Foundation during the conduct of the study. Amir Jazaeri reports personal fees from Gerson and Lehrman Group, Guidepoint, Iovance Advisory Board Meeting, Nuprobe, Simcere, and Pact Pharma outside the submitted work. He reports grants from AstraZenea, BMS, Iovance, Aravive, Pfizer, Immatics USA, and Eli Lilly outside the submitted work. He reports conference traveling fees from AstraZeneca outside the submitted work. Pamela Soliman reports research grant funding from Novartis and Incyte for outside the submitted work. Nicole Fleming reports personal fees from Tesaro, BMS, and Pfizer Advisory Boards outside the submitted work. Sarina A. Piha-Paul receives research/grant funding from outside the submitted work and include AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Chugai Pharmaceutical Co, Curis, Daichi Sanko, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp, Incyte Corp, Jacobio Pharmaceuticals Co, Medimmune LLC, Medivation, Merck Sharp and Dohme Corp, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Inc, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, and NCI/NIH; P30CA016672—Core Grant (CCSG Shared Resources) outside submitted work. Filip Janku reports grants from Novartis, Gentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, Bristol-Myers Squibb, and IFM Therapeutics. He reports personal fees from Synlogic, Guardant Health, Ideaya, PureTech Health, Trovagene, Immunomet, Jazz Pharmaceuticals, and Sotio, outside the submitted work. Aung Naing reports grants from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology. He is on the advisory board for CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, and STCube Pharmaceuticals. He has received travel and accommodation expenses from ARMO BioSciences. Aung Naing’s spouse receives research funding from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta. She is also on the advisory board for Takeda, CSL, Behring, Horizon, and Pharming. Jing Gong and Bettzy Stephen have nothing to disclose. | CARBOPLATIN | DrugsGivenReaction | CC BY | 33574401 | 18,973,640 | 2021-02-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial.
Vaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.
Introduction
Vaginal and vulvar cancers are rare malignancies that have similar estimated incidence (0.7 and 2.6 diagnoses per 100,000 women per year, respectively) and mortality (0.2 and 0.6 deaths per 100,000 women per year, respectively) rates in the United States1. Due to the difficulty of performing large prospective randomized trials in these rare tumor populations, systemic chemotherapeutic regimens have generally been extrapolated from experience in the management of cervical cancer as these malignancies share similar epidemiologic risk factors, are predominantly of squamous cell carcinoma (SCC) histologic subtype, and are strongly associated with human papilloma virus (HPV) infection2–4. However, vaginal and vulvar cancers can be challenging to treat when disease is not amenable to radiation or surgical resection5,6. Treatment response rates to systemic chemotherapeutic regimens are variable in the recurrent setting for vaginal and vulvar SCC; there is currently no consensus on effective regimens5–8. Additionally, given the propensity of vaginal and vulvar SCC to develop at older stages of life, treatment options may be further limited by associated toxicity and morbidity3,4.
There has been a growing interest for immunotherapy in the field of oncology. Immune checkpoint inhibitors have demonstrated impressive, durable responses even among patients who have undergone multiple lines of prior systemic therapy. Specifically, use of immunotherapy in HPV-related cancers is of particular interest given that carcinogenesis is associated with the inability of the immune system to clear the virus9,10. An anti-PD-1 monoclonal antibody, pembrolizumab blocks the PD-1/PD-L1 pathway (an escape mechanism that malignant cells use to evade immune surveillance) thereby augmenting T-cell mediated anti-tumor activity.
Pembrolizumab has demonstrated impressive clinical response in microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumors, which led to the US Food and Drug Administration (FDA) approval for use in MSI-H/dMMR solid tumors11,12. In gynecologic cancers, single-agent pembrolizumab has FDA approval for MSI-H endometrial cancer (response rates 53–57.1%) or PD-L1 positive (Combined Positive Score ≥ 1%) cervical cancer (response rates 12.2–17%) who have progressed on prior systemic therapy11–14. As the first drug to receive FDA approval for a tissue agnostic indication, pembrolizumab may be of clinical benefit in other solid tumors and possibly among those with HPV-associated gynecologic cancers such as vaginal or vulvar SCC. Given the rarity of vaginal or vulvar SCC, few studies have examined the use of immune checkpoint inhibitors in these tumor types.
Thus as part of a clinical phase II basket trial for patients with advanced rare malignancies, we report three cases of SCC (two vaginal and one vulvar) who were treated with single-agent pembrolizumab.
Cases
Clinical trial design
We present three patients with recurrent, metastatic vaginal (patient 1 and 2) or vulvar (patient 3) SCC who were enrolled into cohort 10 (“other rare tumor histologies” category) of an open-label, phase II basket clinical trial (ClinicalTrials.gov: NCT02721732) at the University of Texas MD Anderson Cancer Center (enrolment period August 15, 2016–July 27, 2018). In brief, the trial sought to examine the clinical efficacy and safety of single-agent pembrolizumab (200 mg IV every 3 weeks) in 10 prespecified cohorts of advanced, rare tumors regardless of PD-L1 status. Trial design and overall trial results are described elsewhere15. All trial patients had PD-L1 and tumor infiltrating lymphocyte (TIL) characterization of tumor tissue that was correlated with treatment response, as described previously15. PD-L1 characterization was reported as Combined Positive Score (CPS) which is defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100. CPS ≥ 1% denoted PD-L1 positive expression16. Treatment response was evaluated using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) guidelines on serial radiologic imaging at baseline, every 9 weeks until the first 6 months followed by every 12 weeks at the discretion of the investigator. Safety and tolerability were assessed by characterization and grading of adverse events via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. All patients provided informed consent prior to enrolment. Furthermore, the protocol was approved by the FDA and the Institutional Review Board at The University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
Vaginal SCC cases
Baseline clinical and tumor characteristics as well as prior treatment histories are demonstrated in Tables 1 and 2, respectively. The two patients (patient 1 and 2) were 72 and 63 years old (respectively) women with recurrent vaginal cancer and had grade 2 SCC histologies with infra- and supra-diaphragmatic metastatic disease. Both patients had multiple lines of prior systemic therapy (four and six, respectively) and prior radiation therapy before trial enrolment. Among prior systemic therapies received, the treatment with the longest duration of disease control after first disease recurrence for patient 1 was carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab (7 months total). For patient 2, the systemic treatment with the longest duration of disease control following first recurrence was selinexor/eribulin (6 months).Table 1 Baseline clinical and tumor characteristics.
Pt Age Cancer Grade ECOG PS Years since initial diagnosis FIGO 2009a Sites of metastasis prior to treatmentb PD-L1 CPS TIL infiltration
1 72 Vaginal 2 1 3 IVB AA, AN, AT, N 5 2
2 63 Vaginal 2 1 3 IVB AA, B, H, L, 2 2
3 88 Vulvar 1 1 20 I AR, V 5 2
CPS = Combined Positive Score, defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100; CPS ≥ 1% denoted PD-L1 positive expression ECOG PS = Eastern Cooperative Oncology Group Performance Status. N/A = Not applicable. Pt = patient. TIL infiltration = intensity of tumor-infiltrating lymphocytes within tumor nests on a scale of 0 to 3; 0 = absence of TIL, 1 = few amounts of TIL, 2 = moderate amounts of TIL, 3 = high amount of TIL. SCC = squamous cell carcinoma.
aInternational Federation of Gynecology and Obstetrics (FIGO) 2009 staging at diagnosis.
bSites of metastatic disease prior to treatment: AA = adenopathy of the abdomen, AN = adenopathy of the neck, AT = adenopathy of the thorax, AR = anorectum, B = bone, H = hepatic metastases, L = lung metastases, N = neck, V = vagina.
Table 2 Prior treatments before pembrolizumab treatment.
Pt Prior radiation treatments Number of prior surgeries Number of prior systemic therapies Prior systemic therapiesa
1 1. External beam radiation therapy and brachytherapy
2. Chemoradiationb
0 4 1. Carboplatin/paclitaxel
2. Cisplatinb
3. Carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumabc
4. Topotecan/bevacizumab
2 1. Palliative radiation to the groin and neck 0 6 1. Carboplatin/paclitaxel
2. Cisplatin/topotecan
3. Cetuximab/prexasertib
4. Sapanisertib/afibercept
5. Bimiralisib
6. Selinexor/eribulinc
3 1. External beam radiation therapy 11 1 1. Carboplatinc
Pt: patient.
aLines of systemic therapy are ordered chronologically.
bRadiation was given concurrently with weekly cisplatin.
cLongest duration of disease control on a systemic therapeutic regimen following recurrence.
Figures 1 and 2 demonstrate the best percentage change in tumor target lesions compared to baseline and the dynamic changes in tumor measurements compared to baseline, respectively. With single-agent pembrolizumab, patient 1 had a 68% decrease in the size of the target lesions following three cycles and this continued with increasing cycles of treatment (74% decrease after cycle 6 and 81% decrease after cycle 9). Despite both progressive reduction of the size of the target lesions and clinical benefit, patient 1 had developed new nodal lesions and progression of non-measurable lesions after cycle 6 and this was confirmed on subsequent imaging studies. Per trial protocol, the patient was permitted to continue pembrolizumab following confirmation of disease progression until repeat radiologic imaging 4 weeks after the confirmatory scan as long as she was clinically stable. Repeat radiologic imaging demonstrated disease progression and thus a total of 10 cycles was administered prior to treatment discontinuation. Patient 1’s best objective response was classified as stable disease using irRECIST criteria. For patient 2, there was no objective response. There was a 71% increase in the patient’s tumor measurements according to irRECIST criteria following three cycles of pembrolizumab and treatment was discontinued. Her best objective response was classified as progressive disease (Figs. 1 and 2).Figure 1 Radiologic response to pembrolizumab in patients with vaginal or vulvar cancer. Waterfall plot illustrating the best objective response to pembrolizumab in three evaluable patients using irRECIST criteria. Each bar represents a patient and shows the maximum percentage change from baseline in the sum of the longest diameters of all target lesions and any new lesions while on pembrolizumab. The area above the upper red dotted line represents progressive disease (≥ 20% increase in the sum of the diameters of the target lesions compared with the baseline). The area between both upper and lower red dotted lines represents stable disease. The area below the lower red dotted line represents treatment response (≥ 30% increase in the sum of the diameters of the target lesions compared with the baseline). P1–3: Patient 1–3. *Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria and would be classified as having stable disease as the best objective response.
Figure 2 Tumor response by irRECIST across time. This spider plot demonstrates the tumor measurements from baseline using irRECIST criteria during the course of treatment with pembrolizumab in the three patients. Patient 1 and 2 had progression of disease prior to stopping treatment while patient 3 stopped treatment due to treatment-related toxicity. Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria. Despite a significant reduction in the size of the target lesions on her initial scan at cycle 3 with partial response, her follow-up scans at cycle 6 and cycle 9 demonstrated the appearance of new lesions and progression of non-measurable lesions; the best objective response is stable disease. Patient 3 had an unconfirmed partial response due to treatment discontinuation (after cycle 5) following initial evaluation of partial response; the best objective response is stable disease.
Overall, the treatment was tolerable for both patients with grade 2 fatigue as the only treatment-related adverse event (TRAE) for patient 2 and this was observed after cycle 3. Patient 1 did not have any TRAEs.
For tumor characterization, PD-L1 expression was positive in both patients with a CPS score of 5 and 2, respectively. Both patients’ tumors had moderate amounts of TIL (score 2 on a scale of 0 to 3).
Vulvar SCC case
Patient 3 was an 88-year-old woman with a grade 1 SCC and long-standing disease with the bulk of the suspected disease recurrence involving the vagina followed by the ano-rectal region (Table 1). This patient with vulvar cancer had multiple surgical interventions (eight cytoreductive and three ablative procedures), radiation therapy, and most recently had disease progression on single-agent carboplatin prior to study enrolment (Table 2). Although her disease localization made a pelvic exenteration a possible treatment option, there was consensus between the patient, her medical provider, and a multidisciplinary tumor board that the procedure could result in excessive surgical morbidity (given her age). Thus, the patient opted for clinical trial enrolment and was ultimately included into the vaginal cancer expansion cohort of the phase II trial with pembrolizumab for several reasons. First, there was no available cohort of vulvar SCC on trial given the rarity of the tumor. Second, as HPV-related malignancies, systemic treatment of vaginal and vulvar cancers are very similar with strategies extrapolated from cervical cancer studies. Finally, it was difficult to determine with absolute certainty that her disease would be related to recurrent vulvar cancer rather than de novo vaginal cancer given her vaginal biopsies also demonstrated SCC. Due to the bulk of her disease was in the vagina, the patient was treated in the vaginal cancer expansion cohort of trial.
On pembrolizumab, there was a 27% reduction in the target lesions following three cycles and a 30% reduction following another two cycles (Figs. 1 and 2). Due to a grade 3 TRAE, treatment was discontinued after cycle 5 before a confirmatory scan for partial response could be performed. Thus, her best objective response was stable disease by irRECIST criteria. Patient 3 reported a grade 1 maculopapular rash following cycle 1 and grade 2 pruritus after cycle 4. Grade 3 mucositis led to treatment discontinuation. All the aforementioned TRAEs were immune-related. For tumor characterization, patient 3 had positive PD-L1 expression (CPS score of 5) and moderate amounts of TIL (score 2 on a scale of 0 to 3).
Disclaimer
The views expressed in this manuscript are the authors’ own views and are not the official position of the institution or supporting funding sources.
Ethics approval and consent to participate
The protocol was approved by the US Food and Drug Administration (FDA) and the Institutional Review Board at the University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment.
Consent for publication
All the study participants provided written informed consent prior clinical trial enrollment.
Discussion
In this case series, we present two patients (patient 1 and 2) with recurrent vaginal SCC and one patient (patient 3) with recurrent vulvar SCC who received single-agent pembrolizumab as part of a phase II basket trial. Although there were no confirmed objective responses that were observed, patient 1 had a significant reduction in size of the tumor measurements on radiologic imaging (61% decrease) following cycle 3 of pembrolizumab. However, this objective response was not confirmed on repeat imaging after cycle 6. In her case, subsequent imaging showed new metastatic lesions with progression of non-target lesions despite persistent reduction in the measured target lesion sizes (74% followed by 81% decrease). Patient 3 had a 30% reduction in target lesions after five cycles of pembrolizumab but discontinued study treatment due to a grade 3 TRAE (oral mucositis) before repeat imaging could confirm a partial response. Thus, it is possible that the treatment could have resulted in further tumor reduction. In contrast, patient 2 had no tumor reduction and had significant disease progression after 3 cycles of pembrolizumab.
Multiple factors may explain differences in clinical benefit to pembrolizumab for these patients. The first attributable factor may be the difference PD-L1 expression in the tumor microenvironment as evidenced by the PD-L1 CPS scores of 5, 2, and 5 for patients 1–3, respectively. PD-L1 status has been described as a predictive biomarker of response to PD-1 inhibitor monotherapy and increasing PD-L1 expression has been associated with improved response16–19. Thus, the higher expression of PD-L1 in patient 1 and 3 (CPS score 5) may explain a better response compared to patient 2 (CPS score 2) despite similar amounts of TIL (another predictive biomarker for response)17–19. Immunosuppressive factors in the tumor microenvironment may also modulate response to PD-1 inhibitors despite PD-L1 expression (CPS ≥ 1%) and TIL infiltration, leading to poor response in patient 2. Unfortunately, evaluation of possible contributory immunosuppressive factors was not part of the trial design. Furthermore, pembrolizumab is observed to respond more favorably in tumors with high tumor mutational burden or microsatellite instability-high status. For trial participation, patients were not required to have testing for these aforementioned molecular features and it is possible that their tumors could have had low mutational burden or been microsatellite stable.
Although there was not a confirmed partial response for patient 3, there was a trend for tumor reduction. This tumor reduction may have persisted if treatment was not discontinued due to a grade 3 toxicity (oral mucositis). This association between immune-related adverse events and relatively improved treatment response is suggestive of an active immune system and this observation has been similarly reported in multiple studies20–22.
Due to tumor rarity and lack of strong trial data, management of recurrent/metastatic vaginal and vulvar SCCs has largely been extrapolated from treatment strategies in cervical cancer. These strategies have typically consisted of platinum-based systemic combinations when chemoradiation or surgery is not possible5,6. These systemic combinations have not been consistently efficacious in these patient populations. In vaginal cancer, efficacy of systemic treatment has been largely anecdotal but one study has demonstrated an ORR of 6.25% for single agent cisplatin in 16 patients5,7. For vulvar cancer, studies evaluating systemic chemotherapy regimens have had small sample sizes with variable response rates (0–40%)6,23. Currently there are no standardized systemic regimens for vaginal and vulvar cancers5,6,23. Thus, other alternative treatment therapies have been investigated, with immunotherapy gaining interest. In this present study, two of the three patients with vaginal or vulvar SCC were observed to derive clinical benefit (stable disease as per irRECIST criteria). Two other studies have demonstrated some clinical benefit for these tumor types. In a phase I/II trial (CheckMate 358), nivolumab (PD-1 inhibitor) monotherapy efficacy was evaluated in a small cohort of recurrent/metastatic vaginal or vulvar SCC24. Although a small sample size (two vaginal and three vulvar cancers), the investigators observed a 20% objective response rate (one partial response in a vulvar cancer patient) with 40% of patients with 6 months of disease control24. In another case report of vulvar SCC, the patient with a PD-L1 positive tumor was observed to have a complete response to pembrolizumab25. In CheckMate 358 and the aforementioned case report, PD-1 inhibitor therapy was well-tolerated with no significant TRAEs24,25.
Strengths of our case series include the evaluation of the use of pembrolizumab in a rare cohort of vaginal and vulvar SCC with correlation to translational PD-L1 and TIL data. It represents the first reported use of pembrolizumab for vaginal SCC. Furthermore, tumor responses were objectively measured using irRECIST criteria. As mentioned earlier, tumor mutational burden characterization and microsatellite-instability status testing was not a requirement for patients who were included in this phase II clinical trial and this represents a study limitation.
In conclusion, single-agent pembrolizumab was shown, in this study, to be generally safe to utilize for vaginal and vulvar SCC and has demonstrated some clinical benefit. However, given the small size of this cohort of patients, future studies should examine the role of pembrolizumab in the treatment of vaginal and vulvar SCC. Predictive biomarkers (possibly established in other SCC cohorts such as cervical, anal, or head and neck cancers) should be investigated to identify patients who would derive the greatest clinical benefit.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
J.A.H. and A.N. made significant contributions in conceptualization, project administration, data analysis/interpretation, and drafting, reviewing and editing the majority of the original and final manuscript. A.A.J., P.T.S., N.D.F., J.G., S.A.P.P., F.J., and B.S. made significant contributions in project administration, data analysis/interpretation, and revising and reviewing the original and final manuscript.
Funding
This work was supported by Merck and the NIH/NCI under award numbers P30CA016672 (supporting the MD Anderson Clinical Trials Office) and T32 CA101642 JH (T32 training grant). Furthermore, this work was also supported by the Dr. Henry R. Shibata Fellowship Award/Cedars Cancer Foundation (JH).
Data availability
Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request and approval from study sponsor according to available guidelines at time of request.
Competing interests
Jeffrey How reports grants from NIH (T32 CA101642) and the Cedars Cancer Foundation during the conduct of the study. Amir Jazaeri reports personal fees from Gerson and Lehrman Group, Guidepoint, Iovance Advisory Board Meeting, Nuprobe, Simcere, and Pact Pharma outside the submitted work. He reports grants from AstraZenea, BMS, Iovance, Aravive, Pfizer, Immatics USA, and Eli Lilly outside the submitted work. He reports conference traveling fees from AstraZeneca outside the submitted work. Pamela Soliman reports research grant funding from Novartis and Incyte for outside the submitted work. Nicole Fleming reports personal fees from Tesaro, BMS, and Pfizer Advisory Boards outside the submitted work. Sarina A. Piha-Paul receives research/grant funding from outside the submitted work and include AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Chugai Pharmaceutical Co, Curis, Daichi Sanko, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp, Incyte Corp, Jacobio Pharmaceuticals Co, Medimmune LLC, Medivation, Merck Sharp and Dohme Corp, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Inc, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, and NCI/NIH; P30CA016672—Core Grant (CCSG Shared Resources) outside submitted work. Filip Janku reports grants from Novartis, Gentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, Bristol-Myers Squibb, and IFM Therapeutics. He reports personal fees from Synlogic, Guardant Health, Ideaya, PureTech Health, Trovagene, Immunomet, Jazz Pharmaceuticals, and Sotio, outside the submitted work. Aung Naing reports grants from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology. He is on the advisory board for CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, and STCube Pharmaceuticals. He has received travel and accommodation expenses from ARMO BioSciences. Aung Naing’s spouse receives research funding from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta. She is also on the advisory board for Takeda, CSL, Behring, Horizon, and Pharming. Jing Gong and Bettzy Stephen have nothing to disclose. | CARBOPLATIN | DrugsGivenReaction | CC BY | 33574401 | 18,973,640 | 2021-02-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Squamous cell carcinoma of the vulva'. | Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial.
Vaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.
Introduction
Vaginal and vulvar cancers are rare malignancies that have similar estimated incidence (0.7 and 2.6 diagnoses per 100,000 women per year, respectively) and mortality (0.2 and 0.6 deaths per 100,000 women per year, respectively) rates in the United States1. Due to the difficulty of performing large prospective randomized trials in these rare tumor populations, systemic chemotherapeutic regimens have generally been extrapolated from experience in the management of cervical cancer as these malignancies share similar epidemiologic risk factors, are predominantly of squamous cell carcinoma (SCC) histologic subtype, and are strongly associated with human papilloma virus (HPV) infection2–4. However, vaginal and vulvar cancers can be challenging to treat when disease is not amenable to radiation or surgical resection5,6. Treatment response rates to systemic chemotherapeutic regimens are variable in the recurrent setting for vaginal and vulvar SCC; there is currently no consensus on effective regimens5–8. Additionally, given the propensity of vaginal and vulvar SCC to develop at older stages of life, treatment options may be further limited by associated toxicity and morbidity3,4.
There has been a growing interest for immunotherapy in the field of oncology. Immune checkpoint inhibitors have demonstrated impressive, durable responses even among patients who have undergone multiple lines of prior systemic therapy. Specifically, use of immunotherapy in HPV-related cancers is of particular interest given that carcinogenesis is associated with the inability of the immune system to clear the virus9,10. An anti-PD-1 monoclonal antibody, pembrolizumab blocks the PD-1/PD-L1 pathway (an escape mechanism that malignant cells use to evade immune surveillance) thereby augmenting T-cell mediated anti-tumor activity.
Pembrolizumab has demonstrated impressive clinical response in microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumors, which led to the US Food and Drug Administration (FDA) approval for use in MSI-H/dMMR solid tumors11,12. In gynecologic cancers, single-agent pembrolizumab has FDA approval for MSI-H endometrial cancer (response rates 53–57.1%) or PD-L1 positive (Combined Positive Score ≥ 1%) cervical cancer (response rates 12.2–17%) who have progressed on prior systemic therapy11–14. As the first drug to receive FDA approval for a tissue agnostic indication, pembrolizumab may be of clinical benefit in other solid tumors and possibly among those with HPV-associated gynecologic cancers such as vaginal or vulvar SCC. Given the rarity of vaginal or vulvar SCC, few studies have examined the use of immune checkpoint inhibitors in these tumor types.
Thus as part of a clinical phase II basket trial for patients with advanced rare malignancies, we report three cases of SCC (two vaginal and one vulvar) who were treated with single-agent pembrolizumab.
Cases
Clinical trial design
We present three patients with recurrent, metastatic vaginal (patient 1 and 2) or vulvar (patient 3) SCC who were enrolled into cohort 10 (“other rare tumor histologies” category) of an open-label, phase II basket clinical trial (ClinicalTrials.gov: NCT02721732) at the University of Texas MD Anderson Cancer Center (enrolment period August 15, 2016–July 27, 2018). In brief, the trial sought to examine the clinical efficacy and safety of single-agent pembrolizumab (200 mg IV every 3 weeks) in 10 prespecified cohorts of advanced, rare tumors regardless of PD-L1 status. Trial design and overall trial results are described elsewhere15. All trial patients had PD-L1 and tumor infiltrating lymphocyte (TIL) characterization of tumor tissue that was correlated with treatment response, as described previously15. PD-L1 characterization was reported as Combined Positive Score (CPS) which is defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100. CPS ≥ 1% denoted PD-L1 positive expression16. Treatment response was evaluated using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) guidelines on serial radiologic imaging at baseline, every 9 weeks until the first 6 months followed by every 12 weeks at the discretion of the investigator. Safety and tolerability were assessed by characterization and grading of adverse events via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. All patients provided informed consent prior to enrolment. Furthermore, the protocol was approved by the FDA and the Institutional Review Board at The University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
Vaginal SCC cases
Baseline clinical and tumor characteristics as well as prior treatment histories are demonstrated in Tables 1 and 2, respectively. The two patients (patient 1 and 2) were 72 and 63 years old (respectively) women with recurrent vaginal cancer and had grade 2 SCC histologies with infra- and supra-diaphragmatic metastatic disease. Both patients had multiple lines of prior systemic therapy (four and six, respectively) and prior radiation therapy before trial enrolment. Among prior systemic therapies received, the treatment with the longest duration of disease control after first disease recurrence for patient 1 was carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab (7 months total). For patient 2, the systemic treatment with the longest duration of disease control following first recurrence was selinexor/eribulin (6 months).Table 1 Baseline clinical and tumor characteristics.
Pt Age Cancer Grade ECOG PS Years since initial diagnosis FIGO 2009a Sites of metastasis prior to treatmentb PD-L1 CPS TIL infiltration
1 72 Vaginal 2 1 3 IVB AA, AN, AT, N 5 2
2 63 Vaginal 2 1 3 IVB AA, B, H, L, 2 2
3 88 Vulvar 1 1 20 I AR, V 5 2
CPS = Combined Positive Score, defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100; CPS ≥ 1% denoted PD-L1 positive expression ECOG PS = Eastern Cooperative Oncology Group Performance Status. N/A = Not applicable. Pt = patient. TIL infiltration = intensity of tumor-infiltrating lymphocytes within tumor nests on a scale of 0 to 3; 0 = absence of TIL, 1 = few amounts of TIL, 2 = moderate amounts of TIL, 3 = high amount of TIL. SCC = squamous cell carcinoma.
aInternational Federation of Gynecology and Obstetrics (FIGO) 2009 staging at diagnosis.
bSites of metastatic disease prior to treatment: AA = adenopathy of the abdomen, AN = adenopathy of the neck, AT = adenopathy of the thorax, AR = anorectum, B = bone, H = hepatic metastases, L = lung metastases, N = neck, V = vagina.
Table 2 Prior treatments before pembrolizumab treatment.
Pt Prior radiation treatments Number of prior surgeries Number of prior systemic therapies Prior systemic therapiesa
1 1. External beam radiation therapy and brachytherapy
2. Chemoradiationb
0 4 1. Carboplatin/paclitaxel
2. Cisplatinb
3. Carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumabc
4. Topotecan/bevacizumab
2 1. Palliative radiation to the groin and neck 0 6 1. Carboplatin/paclitaxel
2. Cisplatin/topotecan
3. Cetuximab/prexasertib
4. Sapanisertib/afibercept
5. Bimiralisib
6. Selinexor/eribulinc
3 1. External beam radiation therapy 11 1 1. Carboplatinc
Pt: patient.
aLines of systemic therapy are ordered chronologically.
bRadiation was given concurrently with weekly cisplatin.
cLongest duration of disease control on a systemic therapeutic regimen following recurrence.
Figures 1 and 2 demonstrate the best percentage change in tumor target lesions compared to baseline and the dynamic changes in tumor measurements compared to baseline, respectively. With single-agent pembrolizumab, patient 1 had a 68% decrease in the size of the target lesions following three cycles and this continued with increasing cycles of treatment (74% decrease after cycle 6 and 81% decrease after cycle 9). Despite both progressive reduction of the size of the target lesions and clinical benefit, patient 1 had developed new nodal lesions and progression of non-measurable lesions after cycle 6 and this was confirmed on subsequent imaging studies. Per trial protocol, the patient was permitted to continue pembrolizumab following confirmation of disease progression until repeat radiologic imaging 4 weeks after the confirmatory scan as long as she was clinically stable. Repeat radiologic imaging demonstrated disease progression and thus a total of 10 cycles was administered prior to treatment discontinuation. Patient 1’s best objective response was classified as stable disease using irRECIST criteria. For patient 2, there was no objective response. There was a 71% increase in the patient’s tumor measurements according to irRECIST criteria following three cycles of pembrolizumab and treatment was discontinued. Her best objective response was classified as progressive disease (Figs. 1 and 2).Figure 1 Radiologic response to pembrolizumab in patients with vaginal or vulvar cancer. Waterfall plot illustrating the best objective response to pembrolizumab in three evaluable patients using irRECIST criteria. Each bar represents a patient and shows the maximum percentage change from baseline in the sum of the longest diameters of all target lesions and any new lesions while on pembrolizumab. The area above the upper red dotted line represents progressive disease (≥ 20% increase in the sum of the diameters of the target lesions compared with the baseline). The area between both upper and lower red dotted lines represents stable disease. The area below the lower red dotted line represents treatment response (≥ 30% increase in the sum of the diameters of the target lesions compared with the baseline). P1–3: Patient 1–3. *Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria and would be classified as having stable disease as the best objective response.
Figure 2 Tumor response by irRECIST across time. This spider plot demonstrates the tumor measurements from baseline using irRECIST criteria during the course of treatment with pembrolizumab in the three patients. Patient 1 and 2 had progression of disease prior to stopping treatment while patient 3 stopped treatment due to treatment-related toxicity. Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria. Despite a significant reduction in the size of the target lesions on her initial scan at cycle 3 with partial response, her follow-up scans at cycle 6 and cycle 9 demonstrated the appearance of new lesions and progression of non-measurable lesions; the best objective response is stable disease. Patient 3 had an unconfirmed partial response due to treatment discontinuation (after cycle 5) following initial evaluation of partial response; the best objective response is stable disease.
Overall, the treatment was tolerable for both patients with grade 2 fatigue as the only treatment-related adverse event (TRAE) for patient 2 and this was observed after cycle 3. Patient 1 did not have any TRAEs.
For tumor characterization, PD-L1 expression was positive in both patients with a CPS score of 5 and 2, respectively. Both patients’ tumors had moderate amounts of TIL (score 2 on a scale of 0 to 3).
Vulvar SCC case
Patient 3 was an 88-year-old woman with a grade 1 SCC and long-standing disease with the bulk of the suspected disease recurrence involving the vagina followed by the ano-rectal region (Table 1). This patient with vulvar cancer had multiple surgical interventions (eight cytoreductive and three ablative procedures), radiation therapy, and most recently had disease progression on single-agent carboplatin prior to study enrolment (Table 2). Although her disease localization made a pelvic exenteration a possible treatment option, there was consensus between the patient, her medical provider, and a multidisciplinary tumor board that the procedure could result in excessive surgical morbidity (given her age). Thus, the patient opted for clinical trial enrolment and was ultimately included into the vaginal cancer expansion cohort of the phase II trial with pembrolizumab for several reasons. First, there was no available cohort of vulvar SCC on trial given the rarity of the tumor. Second, as HPV-related malignancies, systemic treatment of vaginal and vulvar cancers are very similar with strategies extrapolated from cervical cancer studies. Finally, it was difficult to determine with absolute certainty that her disease would be related to recurrent vulvar cancer rather than de novo vaginal cancer given her vaginal biopsies also demonstrated SCC. Due to the bulk of her disease was in the vagina, the patient was treated in the vaginal cancer expansion cohort of trial.
On pembrolizumab, there was a 27% reduction in the target lesions following three cycles and a 30% reduction following another two cycles (Figs. 1 and 2). Due to a grade 3 TRAE, treatment was discontinued after cycle 5 before a confirmatory scan for partial response could be performed. Thus, her best objective response was stable disease by irRECIST criteria. Patient 3 reported a grade 1 maculopapular rash following cycle 1 and grade 2 pruritus after cycle 4. Grade 3 mucositis led to treatment discontinuation. All the aforementioned TRAEs were immune-related. For tumor characterization, patient 3 had positive PD-L1 expression (CPS score of 5) and moderate amounts of TIL (score 2 on a scale of 0 to 3).
Disclaimer
The views expressed in this manuscript are the authors’ own views and are not the official position of the institution or supporting funding sources.
Ethics approval and consent to participate
The protocol was approved by the US Food and Drug Administration (FDA) and the Institutional Review Board at the University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment.
Consent for publication
All the study participants provided written informed consent prior clinical trial enrollment.
Discussion
In this case series, we present two patients (patient 1 and 2) with recurrent vaginal SCC and one patient (patient 3) with recurrent vulvar SCC who received single-agent pembrolizumab as part of a phase II basket trial. Although there were no confirmed objective responses that were observed, patient 1 had a significant reduction in size of the tumor measurements on radiologic imaging (61% decrease) following cycle 3 of pembrolizumab. However, this objective response was not confirmed on repeat imaging after cycle 6. In her case, subsequent imaging showed new metastatic lesions with progression of non-target lesions despite persistent reduction in the measured target lesion sizes (74% followed by 81% decrease). Patient 3 had a 30% reduction in target lesions after five cycles of pembrolizumab but discontinued study treatment due to a grade 3 TRAE (oral mucositis) before repeat imaging could confirm a partial response. Thus, it is possible that the treatment could have resulted in further tumor reduction. In contrast, patient 2 had no tumor reduction and had significant disease progression after 3 cycles of pembrolizumab.
Multiple factors may explain differences in clinical benefit to pembrolizumab for these patients. The first attributable factor may be the difference PD-L1 expression in the tumor microenvironment as evidenced by the PD-L1 CPS scores of 5, 2, and 5 for patients 1–3, respectively. PD-L1 status has been described as a predictive biomarker of response to PD-1 inhibitor monotherapy and increasing PD-L1 expression has been associated with improved response16–19. Thus, the higher expression of PD-L1 in patient 1 and 3 (CPS score 5) may explain a better response compared to patient 2 (CPS score 2) despite similar amounts of TIL (another predictive biomarker for response)17–19. Immunosuppressive factors in the tumor microenvironment may also modulate response to PD-1 inhibitors despite PD-L1 expression (CPS ≥ 1%) and TIL infiltration, leading to poor response in patient 2. Unfortunately, evaluation of possible contributory immunosuppressive factors was not part of the trial design. Furthermore, pembrolizumab is observed to respond more favorably in tumors with high tumor mutational burden or microsatellite instability-high status. For trial participation, patients were not required to have testing for these aforementioned molecular features and it is possible that their tumors could have had low mutational burden or been microsatellite stable.
Although there was not a confirmed partial response for patient 3, there was a trend for tumor reduction. This tumor reduction may have persisted if treatment was not discontinued due to a grade 3 toxicity (oral mucositis). This association between immune-related adverse events and relatively improved treatment response is suggestive of an active immune system and this observation has been similarly reported in multiple studies20–22.
Due to tumor rarity and lack of strong trial data, management of recurrent/metastatic vaginal and vulvar SCCs has largely been extrapolated from treatment strategies in cervical cancer. These strategies have typically consisted of platinum-based systemic combinations when chemoradiation or surgery is not possible5,6. These systemic combinations have not been consistently efficacious in these patient populations. In vaginal cancer, efficacy of systemic treatment has been largely anecdotal but one study has demonstrated an ORR of 6.25% for single agent cisplatin in 16 patients5,7. For vulvar cancer, studies evaluating systemic chemotherapy regimens have had small sample sizes with variable response rates (0–40%)6,23. Currently there are no standardized systemic regimens for vaginal and vulvar cancers5,6,23. Thus, other alternative treatment therapies have been investigated, with immunotherapy gaining interest. In this present study, two of the three patients with vaginal or vulvar SCC were observed to derive clinical benefit (stable disease as per irRECIST criteria). Two other studies have demonstrated some clinical benefit for these tumor types. In a phase I/II trial (CheckMate 358), nivolumab (PD-1 inhibitor) monotherapy efficacy was evaluated in a small cohort of recurrent/metastatic vaginal or vulvar SCC24. Although a small sample size (two vaginal and three vulvar cancers), the investigators observed a 20% objective response rate (one partial response in a vulvar cancer patient) with 40% of patients with 6 months of disease control24. In another case report of vulvar SCC, the patient with a PD-L1 positive tumor was observed to have a complete response to pembrolizumab25. In CheckMate 358 and the aforementioned case report, PD-1 inhibitor therapy was well-tolerated with no significant TRAEs24,25.
Strengths of our case series include the evaluation of the use of pembrolizumab in a rare cohort of vaginal and vulvar SCC with correlation to translational PD-L1 and TIL data. It represents the first reported use of pembrolizumab for vaginal SCC. Furthermore, tumor responses were objectively measured using irRECIST criteria. As mentioned earlier, tumor mutational burden characterization and microsatellite-instability status testing was not a requirement for patients who were included in this phase II clinical trial and this represents a study limitation.
In conclusion, single-agent pembrolizumab was shown, in this study, to be generally safe to utilize for vaginal and vulvar SCC and has demonstrated some clinical benefit. However, given the small size of this cohort of patients, future studies should examine the role of pembrolizumab in the treatment of vaginal and vulvar SCC. Predictive biomarkers (possibly established in other SCC cohorts such as cervical, anal, or head and neck cancers) should be investigated to identify patients who would derive the greatest clinical benefit.
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Author contributions
J.A.H. and A.N. made significant contributions in conceptualization, project administration, data analysis/interpretation, and drafting, reviewing and editing the majority of the original and final manuscript. A.A.J., P.T.S., N.D.F., J.G., S.A.P.P., F.J., and B.S. made significant contributions in project administration, data analysis/interpretation, and revising and reviewing the original and final manuscript.
Funding
This work was supported by Merck and the NIH/NCI under award numbers P30CA016672 (supporting the MD Anderson Clinical Trials Office) and T32 CA101642 JH (T32 training grant). Furthermore, this work was also supported by the Dr. Henry R. Shibata Fellowship Award/Cedars Cancer Foundation (JH).
Data availability
Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request and approval from study sponsor according to available guidelines at time of request.
Competing interests
Jeffrey How reports grants from NIH (T32 CA101642) and the Cedars Cancer Foundation during the conduct of the study. Amir Jazaeri reports personal fees from Gerson and Lehrman Group, Guidepoint, Iovance Advisory Board Meeting, Nuprobe, Simcere, and Pact Pharma outside the submitted work. He reports grants from AstraZenea, BMS, Iovance, Aravive, Pfizer, Immatics USA, and Eli Lilly outside the submitted work. He reports conference traveling fees from AstraZeneca outside the submitted work. Pamela Soliman reports research grant funding from Novartis and Incyte for outside the submitted work. Nicole Fleming reports personal fees from Tesaro, BMS, and Pfizer Advisory Boards outside the submitted work. Sarina A. Piha-Paul receives research/grant funding from outside the submitted work and include AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Chugai Pharmaceutical Co, Curis, Daichi Sanko, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp, Incyte Corp, Jacobio Pharmaceuticals Co, Medimmune LLC, Medivation, Merck Sharp and Dohme Corp, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Inc, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, and NCI/NIH; P30CA016672—Core Grant (CCSG Shared Resources) outside submitted work. Filip Janku reports grants from Novartis, Gentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, Bristol-Myers Squibb, and IFM Therapeutics. He reports personal fees from Synlogic, Guardant Health, Ideaya, PureTech Health, Trovagene, Immunomet, Jazz Pharmaceuticals, and Sotio, outside the submitted work. Aung Naing reports grants from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology. He is on the advisory board for CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, and STCube Pharmaceuticals. He has received travel and accommodation expenses from ARMO BioSciences. Aung Naing’s spouse receives research funding from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta. She is also on the advisory board for Takeda, CSL, Behring, Horizon, and Pharming. Jing Gong and Bettzy Stephen have nothing to disclose. | CARBOPLATIN | DrugsGivenReaction | CC BY | 33574401 | 18,973,640 | 2021-02-11 |
What was the administration route of drug 'CARBOPLATIN'? | Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial.
Vaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.
Introduction
Vaginal and vulvar cancers are rare malignancies that have similar estimated incidence (0.7 and 2.6 diagnoses per 100,000 women per year, respectively) and mortality (0.2 and 0.6 deaths per 100,000 women per year, respectively) rates in the United States1. Due to the difficulty of performing large prospective randomized trials in these rare tumor populations, systemic chemotherapeutic regimens have generally been extrapolated from experience in the management of cervical cancer as these malignancies share similar epidemiologic risk factors, are predominantly of squamous cell carcinoma (SCC) histologic subtype, and are strongly associated with human papilloma virus (HPV) infection2–4. However, vaginal and vulvar cancers can be challenging to treat when disease is not amenable to radiation or surgical resection5,6. Treatment response rates to systemic chemotherapeutic regimens are variable in the recurrent setting for vaginal and vulvar SCC; there is currently no consensus on effective regimens5–8. Additionally, given the propensity of vaginal and vulvar SCC to develop at older stages of life, treatment options may be further limited by associated toxicity and morbidity3,4.
There has been a growing interest for immunotherapy in the field of oncology. Immune checkpoint inhibitors have demonstrated impressive, durable responses even among patients who have undergone multiple lines of prior systemic therapy. Specifically, use of immunotherapy in HPV-related cancers is of particular interest given that carcinogenesis is associated with the inability of the immune system to clear the virus9,10. An anti-PD-1 monoclonal antibody, pembrolizumab blocks the PD-1/PD-L1 pathway (an escape mechanism that malignant cells use to evade immune surveillance) thereby augmenting T-cell mediated anti-tumor activity.
Pembrolizumab has demonstrated impressive clinical response in microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) tumors, which led to the US Food and Drug Administration (FDA) approval for use in MSI-H/dMMR solid tumors11,12. In gynecologic cancers, single-agent pembrolizumab has FDA approval for MSI-H endometrial cancer (response rates 53–57.1%) or PD-L1 positive (Combined Positive Score ≥ 1%) cervical cancer (response rates 12.2–17%) who have progressed on prior systemic therapy11–14. As the first drug to receive FDA approval for a tissue agnostic indication, pembrolizumab may be of clinical benefit in other solid tumors and possibly among those with HPV-associated gynecologic cancers such as vaginal or vulvar SCC. Given the rarity of vaginal or vulvar SCC, few studies have examined the use of immune checkpoint inhibitors in these tumor types.
Thus as part of a clinical phase II basket trial for patients with advanced rare malignancies, we report three cases of SCC (two vaginal and one vulvar) who were treated with single-agent pembrolizumab.
Cases
Clinical trial design
We present three patients with recurrent, metastatic vaginal (patient 1 and 2) or vulvar (patient 3) SCC who were enrolled into cohort 10 (“other rare tumor histologies” category) of an open-label, phase II basket clinical trial (ClinicalTrials.gov: NCT02721732) at the University of Texas MD Anderson Cancer Center (enrolment period August 15, 2016–July 27, 2018). In brief, the trial sought to examine the clinical efficacy and safety of single-agent pembrolizumab (200 mg IV every 3 weeks) in 10 prespecified cohorts of advanced, rare tumors regardless of PD-L1 status. Trial design and overall trial results are described elsewhere15. All trial patients had PD-L1 and tumor infiltrating lymphocyte (TIL) characterization of tumor tissue that was correlated with treatment response, as described previously15. PD-L1 characterization was reported as Combined Positive Score (CPS) which is defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100. CPS ≥ 1% denoted PD-L1 positive expression16. Treatment response was evaluated using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) guidelines on serial radiologic imaging at baseline, every 9 weeks until the first 6 months followed by every 12 weeks at the discretion of the investigator. Safety and tolerability were assessed by characterization and grading of adverse events via the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. All patients provided informed consent prior to enrolment. Furthermore, the protocol was approved by the FDA and the Institutional Review Board at The University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.
Vaginal SCC cases
Baseline clinical and tumor characteristics as well as prior treatment histories are demonstrated in Tables 1 and 2, respectively. The two patients (patient 1 and 2) were 72 and 63 years old (respectively) women with recurrent vaginal cancer and had grade 2 SCC histologies with infra- and supra-diaphragmatic metastatic disease. Both patients had multiple lines of prior systemic therapy (four and six, respectively) and prior radiation therapy before trial enrolment. Among prior systemic therapies received, the treatment with the longest duration of disease control after first disease recurrence for patient 1 was carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumab (7 months total). For patient 2, the systemic treatment with the longest duration of disease control following first recurrence was selinexor/eribulin (6 months).Table 1 Baseline clinical and tumor characteristics.
Pt Age Cancer Grade ECOG PS Years since initial diagnosis FIGO 2009a Sites of metastasis prior to treatmentb PD-L1 CPS TIL infiltration
1 72 Vaginal 2 1 3 IVB AA, AN, AT, N 5 2
2 63 Vaginal 2 1 3 IVB AA, B, H, L, 2 2
3 88 Vulvar 1 1 20 I AR, V 5 2
CPS = Combined Positive Score, defined as the number of PD-L1 staining cells divided by the total number of viable cells, multiplied by 100; CPS ≥ 1% denoted PD-L1 positive expression ECOG PS = Eastern Cooperative Oncology Group Performance Status. N/A = Not applicable. Pt = patient. TIL infiltration = intensity of tumor-infiltrating lymphocytes within tumor nests on a scale of 0 to 3; 0 = absence of TIL, 1 = few amounts of TIL, 2 = moderate amounts of TIL, 3 = high amount of TIL. SCC = squamous cell carcinoma.
aInternational Federation of Gynecology and Obstetrics (FIGO) 2009 staging at diagnosis.
bSites of metastatic disease prior to treatment: AA = adenopathy of the abdomen, AN = adenopathy of the neck, AT = adenopathy of the thorax, AR = anorectum, B = bone, H = hepatic metastases, L = lung metastases, N = neck, V = vagina.
Table 2 Prior treatments before pembrolizumab treatment.
Pt Prior radiation treatments Number of prior surgeries Number of prior systemic therapies Prior systemic therapiesa
1 1. External beam radiation therapy and brachytherapy
2. Chemoradiationb
0 4 1. Carboplatin/paclitaxel
2. Cisplatinb
3. Carboplatin/paclitaxel/bevacizumab followed by maintenance bevacizumabc
4. Topotecan/bevacizumab
2 1. Palliative radiation to the groin and neck 0 6 1. Carboplatin/paclitaxel
2. Cisplatin/topotecan
3. Cetuximab/prexasertib
4. Sapanisertib/afibercept
5. Bimiralisib
6. Selinexor/eribulinc
3 1. External beam radiation therapy 11 1 1. Carboplatinc
Pt: patient.
aLines of systemic therapy are ordered chronologically.
bRadiation was given concurrently with weekly cisplatin.
cLongest duration of disease control on a systemic therapeutic regimen following recurrence.
Figures 1 and 2 demonstrate the best percentage change in tumor target lesions compared to baseline and the dynamic changes in tumor measurements compared to baseline, respectively. With single-agent pembrolizumab, patient 1 had a 68% decrease in the size of the target lesions following three cycles and this continued with increasing cycles of treatment (74% decrease after cycle 6 and 81% decrease after cycle 9). Despite both progressive reduction of the size of the target lesions and clinical benefit, patient 1 had developed new nodal lesions and progression of non-measurable lesions after cycle 6 and this was confirmed on subsequent imaging studies. Per trial protocol, the patient was permitted to continue pembrolizumab following confirmation of disease progression until repeat radiologic imaging 4 weeks after the confirmatory scan as long as she was clinically stable. Repeat radiologic imaging demonstrated disease progression and thus a total of 10 cycles was administered prior to treatment discontinuation. Patient 1’s best objective response was classified as stable disease using irRECIST criteria. For patient 2, there was no objective response. There was a 71% increase in the patient’s tumor measurements according to irRECIST criteria following three cycles of pembrolizumab and treatment was discontinued. Her best objective response was classified as progressive disease (Figs. 1 and 2).Figure 1 Radiologic response to pembrolizumab in patients with vaginal or vulvar cancer. Waterfall plot illustrating the best objective response to pembrolizumab in three evaluable patients using irRECIST criteria. Each bar represents a patient and shows the maximum percentage change from baseline in the sum of the longest diameters of all target lesions and any new lesions while on pembrolizumab. The area above the upper red dotted line represents progressive disease (≥ 20% increase in the sum of the diameters of the target lesions compared with the baseline). The area between both upper and lower red dotted lines represents stable disease. The area below the lower red dotted line represents treatment response (≥ 30% increase in the sum of the diameters of the target lesions compared with the baseline). P1–3: Patient 1–3. *Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria and would be classified as having stable disease as the best objective response.
Figure 2 Tumor response by irRECIST across time. This spider plot demonstrates the tumor measurements from baseline using irRECIST criteria during the course of treatment with pembrolizumab in the three patients. Patient 1 and 2 had progression of disease prior to stopping treatment while patient 3 stopped treatment due to treatment-related toxicity. Patient 1 and 3 had unconfirmed partial responses as defined by irRECIST criteria. Despite a significant reduction in the size of the target lesions on her initial scan at cycle 3 with partial response, her follow-up scans at cycle 6 and cycle 9 demonstrated the appearance of new lesions and progression of non-measurable lesions; the best objective response is stable disease. Patient 3 had an unconfirmed partial response due to treatment discontinuation (after cycle 5) following initial evaluation of partial response; the best objective response is stable disease.
Overall, the treatment was tolerable for both patients with grade 2 fatigue as the only treatment-related adverse event (TRAE) for patient 2 and this was observed after cycle 3. Patient 1 did not have any TRAEs.
For tumor characterization, PD-L1 expression was positive in both patients with a CPS score of 5 and 2, respectively. Both patients’ tumors had moderate amounts of TIL (score 2 on a scale of 0 to 3).
Vulvar SCC case
Patient 3 was an 88-year-old woman with a grade 1 SCC and long-standing disease with the bulk of the suspected disease recurrence involving the vagina followed by the ano-rectal region (Table 1). This patient with vulvar cancer had multiple surgical interventions (eight cytoreductive and three ablative procedures), radiation therapy, and most recently had disease progression on single-agent carboplatin prior to study enrolment (Table 2). Although her disease localization made a pelvic exenteration a possible treatment option, there was consensus between the patient, her medical provider, and a multidisciplinary tumor board that the procedure could result in excessive surgical morbidity (given her age). Thus, the patient opted for clinical trial enrolment and was ultimately included into the vaginal cancer expansion cohort of the phase II trial with pembrolizumab for several reasons. First, there was no available cohort of vulvar SCC on trial given the rarity of the tumor. Second, as HPV-related malignancies, systemic treatment of vaginal and vulvar cancers are very similar with strategies extrapolated from cervical cancer studies. Finally, it was difficult to determine with absolute certainty that her disease would be related to recurrent vulvar cancer rather than de novo vaginal cancer given her vaginal biopsies also demonstrated SCC. Due to the bulk of her disease was in the vagina, the patient was treated in the vaginal cancer expansion cohort of trial.
On pembrolizumab, there was a 27% reduction in the target lesions following three cycles and a 30% reduction following another two cycles (Figs. 1 and 2). Due to a grade 3 TRAE, treatment was discontinued after cycle 5 before a confirmatory scan for partial response could be performed. Thus, her best objective response was stable disease by irRECIST criteria. Patient 3 reported a grade 1 maculopapular rash following cycle 1 and grade 2 pruritus after cycle 4. Grade 3 mucositis led to treatment discontinuation. All the aforementioned TRAEs were immune-related. For tumor characterization, patient 3 had positive PD-L1 expression (CPS score of 5) and moderate amounts of TIL (score 2 on a scale of 0 to 3).
Disclaimer
The views expressed in this manuscript are the authors’ own views and are not the official position of the institution or supporting funding sources.
Ethics approval and consent to participate
The protocol was approved by the US Food and Drug Administration (FDA) and the Institutional Review Board at the University of Texas MD Anderson Cancer Center. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment.
Consent for publication
All the study participants provided written informed consent prior clinical trial enrollment.
Discussion
In this case series, we present two patients (patient 1 and 2) with recurrent vaginal SCC and one patient (patient 3) with recurrent vulvar SCC who received single-agent pembrolizumab as part of a phase II basket trial. Although there were no confirmed objective responses that were observed, patient 1 had a significant reduction in size of the tumor measurements on radiologic imaging (61% decrease) following cycle 3 of pembrolizumab. However, this objective response was not confirmed on repeat imaging after cycle 6. In her case, subsequent imaging showed new metastatic lesions with progression of non-target lesions despite persistent reduction in the measured target lesion sizes (74% followed by 81% decrease). Patient 3 had a 30% reduction in target lesions after five cycles of pembrolizumab but discontinued study treatment due to a grade 3 TRAE (oral mucositis) before repeat imaging could confirm a partial response. Thus, it is possible that the treatment could have resulted in further tumor reduction. In contrast, patient 2 had no tumor reduction and had significant disease progression after 3 cycles of pembrolizumab.
Multiple factors may explain differences in clinical benefit to pembrolizumab for these patients. The first attributable factor may be the difference PD-L1 expression in the tumor microenvironment as evidenced by the PD-L1 CPS scores of 5, 2, and 5 for patients 1–3, respectively. PD-L1 status has been described as a predictive biomarker of response to PD-1 inhibitor monotherapy and increasing PD-L1 expression has been associated with improved response16–19. Thus, the higher expression of PD-L1 in patient 1 and 3 (CPS score 5) may explain a better response compared to patient 2 (CPS score 2) despite similar amounts of TIL (another predictive biomarker for response)17–19. Immunosuppressive factors in the tumor microenvironment may also modulate response to PD-1 inhibitors despite PD-L1 expression (CPS ≥ 1%) and TIL infiltration, leading to poor response in patient 2. Unfortunately, evaluation of possible contributory immunosuppressive factors was not part of the trial design. Furthermore, pembrolizumab is observed to respond more favorably in tumors with high tumor mutational burden or microsatellite instability-high status. For trial participation, patients were not required to have testing for these aforementioned molecular features and it is possible that their tumors could have had low mutational burden or been microsatellite stable.
Although there was not a confirmed partial response for patient 3, there was a trend for tumor reduction. This tumor reduction may have persisted if treatment was not discontinued due to a grade 3 toxicity (oral mucositis). This association between immune-related adverse events and relatively improved treatment response is suggestive of an active immune system and this observation has been similarly reported in multiple studies20–22.
Due to tumor rarity and lack of strong trial data, management of recurrent/metastatic vaginal and vulvar SCCs has largely been extrapolated from treatment strategies in cervical cancer. These strategies have typically consisted of platinum-based systemic combinations when chemoradiation or surgery is not possible5,6. These systemic combinations have not been consistently efficacious in these patient populations. In vaginal cancer, efficacy of systemic treatment has been largely anecdotal but one study has demonstrated an ORR of 6.25% for single agent cisplatin in 16 patients5,7. For vulvar cancer, studies evaluating systemic chemotherapy regimens have had small sample sizes with variable response rates (0–40%)6,23. Currently there are no standardized systemic regimens for vaginal and vulvar cancers5,6,23. Thus, other alternative treatment therapies have been investigated, with immunotherapy gaining interest. In this present study, two of the three patients with vaginal or vulvar SCC were observed to derive clinical benefit (stable disease as per irRECIST criteria). Two other studies have demonstrated some clinical benefit for these tumor types. In a phase I/II trial (CheckMate 358), nivolumab (PD-1 inhibitor) monotherapy efficacy was evaluated in a small cohort of recurrent/metastatic vaginal or vulvar SCC24. Although a small sample size (two vaginal and three vulvar cancers), the investigators observed a 20% objective response rate (one partial response in a vulvar cancer patient) with 40% of patients with 6 months of disease control24. In another case report of vulvar SCC, the patient with a PD-L1 positive tumor was observed to have a complete response to pembrolizumab25. In CheckMate 358 and the aforementioned case report, PD-1 inhibitor therapy was well-tolerated with no significant TRAEs24,25.
Strengths of our case series include the evaluation of the use of pembrolizumab in a rare cohort of vaginal and vulvar SCC with correlation to translational PD-L1 and TIL data. It represents the first reported use of pembrolizumab for vaginal SCC. Furthermore, tumor responses were objectively measured using irRECIST criteria. As mentioned earlier, tumor mutational burden characterization and microsatellite-instability status testing was not a requirement for patients who were included in this phase II clinical trial and this represents a study limitation.
In conclusion, single-agent pembrolizumab was shown, in this study, to be generally safe to utilize for vaginal and vulvar SCC and has demonstrated some clinical benefit. However, given the small size of this cohort of patients, future studies should examine the role of pembrolizumab in the treatment of vaginal and vulvar SCC. Predictive biomarkers (possibly established in other SCC cohorts such as cervical, anal, or head and neck cancers) should be investigated to identify patients who would derive the greatest clinical benefit.
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Author contributions
J.A.H. and A.N. made significant contributions in conceptualization, project administration, data analysis/interpretation, and drafting, reviewing and editing the majority of the original and final manuscript. A.A.J., P.T.S., N.D.F., J.G., S.A.P.P., F.J., and B.S. made significant contributions in project administration, data analysis/interpretation, and revising and reviewing the original and final manuscript.
Funding
This work was supported by Merck and the NIH/NCI under award numbers P30CA016672 (supporting the MD Anderson Clinical Trials Office) and T32 CA101642 JH (T32 training grant). Furthermore, this work was also supported by the Dr. Henry R. Shibata Fellowship Award/Cedars Cancer Foundation (JH).
Data availability
Data are available upon reasonable request. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request and approval from study sponsor according to available guidelines at time of request.
Competing interests
Jeffrey How reports grants from NIH (T32 CA101642) and the Cedars Cancer Foundation during the conduct of the study. Amir Jazaeri reports personal fees from Gerson and Lehrman Group, Guidepoint, Iovance Advisory Board Meeting, Nuprobe, Simcere, and Pact Pharma outside the submitted work. He reports grants from AstraZenea, BMS, Iovance, Aravive, Pfizer, Immatics USA, and Eli Lilly outside the submitted work. He reports conference traveling fees from AstraZeneca outside the submitted work. Pamela Soliman reports research grant funding from Novartis and Incyte for outside the submitted work. Nicole Fleming reports personal fees from Tesaro, BMS, and Pfizer Advisory Boards outside the submitted work. Sarina A. Piha-Paul receives research/grant funding from outside the submitted work and include AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Chugai Pharmaceutical Co, Curis, Daichi Sanko, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp, Incyte Corp, Jacobio Pharmaceuticals Co, Medimmune LLC, Medivation, Merck Sharp and Dohme Corp, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Inc, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, and NCI/NIH; P30CA016672—Core Grant (CCSG Shared Resources) outside submitted work. Filip Janku reports grants from Novartis, Gentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, Bristol-Myers Squibb, and IFM Therapeutics. He reports personal fees from Synlogic, Guardant Health, Ideaya, PureTech Health, Trovagene, Immunomet, Jazz Pharmaceuticals, and Sotio, outside the submitted work. Aung Naing reports grants from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology. He is on the advisory board for CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, and STCube Pharmaceuticals. He has received travel and accommodation expenses from ARMO BioSciences. Aung Naing’s spouse receives research funding from Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta. She is also on the advisory board for Takeda, CSL, Behring, Horizon, and Pharming. Jing Gong and Bettzy Stephen have nothing to disclose. | Transdermal | DrugAdministrationRoute | CC BY | 33574401 | 18,973,640 | 2021-02-11 |
What was the dosage of drug 'DEXAMETHASONE SODIUM PHOSPHATE'? | Absence of meaningful neurocognitive recovery in comatose patients with primary central nervous system lymphoma despite an effective response to chemotherapy: Case reports.
Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that occurs in patients who are elderly and immunocompromised. The most common treatment for PCNSL is high-dose methotrexate-based chemotherapy. Studies have suggested that the radiological response to high-dose methotrexate-based chemotherapy is associated with improved neurocognitive ability that remains stable upon follow-up. However, no study involving patients with an extremely poor neurological status before chemotherapy initiation has been reported, and the neurological prognosis of this group of patients remains unknown. The current case study described 3 patients with PCNSL diagnosed via biopsy who had comatose neurological states due to disease progression prior to treatment. All patients were treated with high-dose methotrexate-based chemotherapy. However, although effective radiological responses to treatment were achieved, no meaningful neurological or cognitive recovery was documented. Patients with PCNSL exhibiting a baseline comatose state have a poor neurological prognosis even with an effective tumour response to chemotherapy. Therefore, rapid detection and prompt treatment are crucial in patients with this disease.
Introduction
Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma that is usually confined to the brain, leptomeninges, spine, cerebrospinal fluid and eyes without evidence of systemic spread (1). PCNSL represents approximately 4% of all newly diagnosed central nervous system (CNS) tumours (2,3), and most seem to be of late or post-germinal centre B-cell origin (4,5). Immunodeficiency due to congenital immunodeficiency syndromes such as ataxia-telangiectasia and Wiskott-Aldrich syndrome, as well as secondary causes such as acquired immunodeficiency syndrome and iatrogenic immunosuppression for transplant procedures, has been implicated in the development of PCNSL (6).
The prognosis of PCNSL has improved substantially in recent years, particularly in immunocompetent patients (7). However, treatment of PCSNL may cause neurotoxicity and compromise health-related quality of life. Studies have suggested that patients treated with combined high-dose methotrexate chemotherapy and consolidation whole-brain radiotherapy (WBRT) in the treatment of PCNSL develop worse neurotoxicity and cognitive dysfunction than those treated with chemotherapy alone (8-12). Thus, consolidation WBRT is often withheld unless necessary, particularly in elderly patients (13). Conversely, cognition, as measured by mini-mental state examination (MMSE) scores, frequently improves following the successful treatment of PCNSL with chemotherapy with or without immunotherapy (rituximab) and remains stable on follow-up (10,14-16). However, currently, no study has described the neurological prognosis of PCNSL patients with a very poor neurocognitive function at baseline.
In this study, we reviewed the cases of 3 patients with neuroimaging- and biopsy-proven PCNSL who had baseline comatose neurological states at presentation (Table I). All 3 were treated with high-dose methotrexate-based chemotherapy only without WBRT and achieved either a partial or complete response to treatment, as assessed using International PCNSL Collaborative Group criteria (17).
Case reports
Case 1
A 73-year-old Chinese man presented with worsening lethargy and drowsiness, together with behavioural changes for 1 month. He had a medical history of hypertension, diabetes mellitus, hyperlipidaemia and ischaemic heart disease. During his initial admission, magnetic resonance imaging (MRI) of the brain revealed multiple foci of abnormal enhancement with low to heterogeneous T2 signals in a periventricular distribution, including the ependymal margins of both lateral ventricles, infundibular recess of the 3rd ventricle and pituitary stalk. These findings were highly suggestive of PCNSL. Despite these findings, the patient declined further work-up and was discharged against medical advice. He was subsequently re-admitted a month later for progressive drowsiness and fever. Neurological examination revealed a severely depressed level of consciousness with a Glasgow Coma Scale (GCS) of E3V1M1. Imaging of the brain showed interval disease progression and obstructive hydrocephalus. The patient subsequently underwent an external ventricular drain insertion, followed by stereotactic biopsy of the right caudate region two weeks later.
Histological evaluation confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal centre B-cell like (non-GCB) subtype. He was administered dexamethasone, procarbazine, vincristine and high-dose methotrexate (2.5 g/m2) (18). At the point of treatment initiation, the GCS remained poor at E2V2M1. The time from the initial presentation to time of treatment initiation was 2 months. Because chemotherapy was complicated by repeated infective episodes, including pyelonephritis, colitis and pneumonia, only 4 cycles were administered (up to week 8). Brain MRI performed at the end of treatment showed no residual tumour or interval new tumour, indicating a complete response (Fig. 1A).
Despite the complete response of the lymphoma to chemotherapy, the patient's neurocognitive status did not improve and the GCS remained poor at E2V2M1. The patient eventually died of relapsed disease 8 months later.
Case 2
A 42-year-old Bruneian man with no significant medical history initially presented with diplopia and was referred to the National Cancer Centre, Singapore, for suspected PCNSL on preliminary brain imaging. Physical examination revealed a GCS of E3V4M6, cranial nerve III, IV and VI palsy bilaterally, a fixed left pupil and extremely poor visual acuity with inability to visualize light bilaterally. Mild left hemiparesis was also evident. Brain MRI revealed homogeneously enhancing lesions in the optic chiasma, optic nerves and tract, midbrain and pons, and hypothalamus.
Stereotactic biopsy of the left suprasellar lesion confirmed DLBCL, non-GCB type. Unfortunately, the patient became progressively drowsier because of the interval enlargement of the known suprasellar mass associated with an increasing mass effect and worsening hydrocephalus. The patient subsequently underwent ventriculoperitoneal shunt insertion and tracheostomy, while his GCS continued to deteriorate to E1VTM1. He was administered high-dose methotrexate-based chemotherapy for 5 cycles based on the protocol by Shah et al (rituximab, vincristine, procarbazine and methotrexate 2.5 g/m2) (19). The time from the initial presentation to the start of treatment was 6 months. Post-treatment brain MRI showed a stable hypothalamus lesion and marked improvement in the lesions in the right temporal lobe, bilateral basal ganglia and brainstem, indicating an effective partial response to treatment (Fig. 1B).
Despite the overall response to treatment, the patient did not achieve significant improvement in cognition or physical function. His post-treatment GCS remained low at E2V1M1. Thereafter, he was managed with best supportive care alone at a hospice.
Case 3
A 68-year-old Chinese man with a significant medical history of hypertension, hyperlipidaemia and stroke presented with an unsteady gait with frequent falls, impairment of semantic memory and slow speech. His physical examination was unremarkable, and he had no gross neurological deficits. His GCS was E4V4M6. Brain MRI showed lobulated semi-confluent enhancing lesions at the bilateral periventricular regions involving the corpus callosum and corona radiata.
Stereotactic biopsy of the left frontal periventricular region revealed DLBCL, GCB type. Post operatively, he was administered levetiracetam and dexamethasone because he had mild fasciculations of his right thigh and twitching of his left biceps suggestive of a provoked seizure. He was intubated when his GCS subsequently deteriorated to E1V1M1, following which a tracheostomy was performed. Subsequently, he was administered high-dose methotrexate-based chemotherapy for 5 cycles including rituximab, vincristine and methotrexate (2.5 g/m2) but not procarbazine. Post-treatment brain MRI revealed complete resolution of the lesions along the periventricular region and corpus callosum, indicating a complete response to treatment (Fig. 1C).
Similar to cases 1 and 2, despite an effective tumour response to chemotherapy, he remained in a comatose state with a GCS of 3 and died 8 months later.
Discussion
We described the cases of 3 patients with extremely poor neurological statuses before treatment initiation. All 3 patients did not achieve meaningful neurological recovery despite an effective tumour response to chemotherapy, as evidenced by the low post-treatment GCS of 5, 4 and 3 for cases 1, 2 and 3, respectively. These findings contrast those of earlier studies that reported an improvement in cognitive function following the successful treatment of PCNSL (10,14-16). Although these cohorts generally comprise patients with grossly intact neurological and cognitive function (median MMSE range, 22-23), our study is novel because the 3 patients had extremely poor neurocognitive function at baseline with a GCS score of 5 or below before treatment initiation.
The GCS decreased in all 3 patients in the short time frame between the initial presentation and start of treatment, ranging from 12 days to 6 months. In case 1, treatment was delayed because the patient had initially requested for discharge against medical advice, whereas the delay in case 2 was due to the patient being referred from an overseas hospital. In case 3, treatment was promptly commenced. Thus, PCNSL is an aggressive disease with an unpredictable clinical course. A sharp decrease in the GCS representing disease progression of PCNSL may indicate a poor neurological prognosis even if the tumour responds well to chemotherapy. In such a scenario, best supportive care focusing on the quality of life may be considered and weighed carefully against aggressive chemotherapy with curative intent.
Although cases 1 and 3 involved elderly Chinese patients older than 65 years, case 2 involved a young Bruneian man aged only 42 years at diagnosis. Despite the differences in both age and race, all 3 patients had similarly poor neurological outcomes at the end of chemotherapy treatment. This supports the hypothesis that a poor neurocognitive status before treatment is a poor prognostic indicator for the post-treatment neurological outcome across various demographical factors such and age and race.
In conclusion, the neurocognitive status of PCNSL patients can deteriorate quickly, indicating dismal outcomes. Patients with severe neurocognitive compromise may have a poor neurological prognosis despite an effective response to treatment. Further validation studies should be conducted to examine the neurological prognosis of PCNSL patients with poor neurological function at baseline who were treated successfully with chemotherapy, as well as to determine the possible causes of and prevent poor neurological status in these patients. Our study suggests that administering early treatment in PCNSL patients and avoiding unnecessary delays are necessary to achieve optimal neurocognitive recovery.
Acknowledgements
Not applicable.
Funding
This work was supported by the Singapore Ministry of Health's National Medical Research Council of Singapore (grant no. NMRC/FLWSHP/054/2017-00), SHF-Foundation (grant no. SHF/FG653P/2017) and SingHealth Duke-NUS Academic Medical Centre and Oncology ACP (grant no. 08-FY2017/P1/14-A28).
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analysed during the present study.
Authors' contributions
RMHL and JYC conceptualized the study and wrote the manuscript. RMHL acquired, analysed and interpreted the data. JYC enrolled the study patients, obtained their consent and treated them. Both authors have confirmed the authenticity of all raw data, as well as read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Singhealth Centralised Institutional Review Board (CIRB 2018/3084). Written informed consent was obtained from all the participants and/or their legal guardians.
Patient consent for publication
Written informed consent was obtained from the patients for the publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 T1-weighted MRI images reveal the anatomical involvement of PCNSL at various junctures of treatment. (A) Complete responses to chemotherapy were observed in case 1, (B) partial response to chemotherapy was observed in case 2 and (C) complete responses to chemotherapy were observed in case 3. The red arrows indicate the initial sites of disease. PCNSL, primary CNS lymphoma.
Table I Clinical characteristics and treatment outcomes of patients with PCNSL.
ID Age at diagnosis (years) Gender Significant comorbidities Presenting symptoms Histology Anatomical location Treatment regimen GCS (at presentation) GCS (before treatment) Time to treatment End of treatment responseb GCS (post- treatment)
1 73 Male Hypertension Diabetes mellitus Hyperlipidaemia Ischaemic heart disease Lethargy Drowsiness Behaviour change DLBCL, non-GCB Basal ganglia Thalamus Midbrain Periventricular Corpus callosum High-dose methotrexate based (2.5 g/m2) for 4 cycles E3V1M1a E2V2M1 2 months Complete response E2V2M1
2 42 Male Nil Diplopia Poor visual acuity DLBCL, non-GCB Optic chiasma, optic nerves and tract Midbrain and pons Hypothalamus High-dose metho trexate based (2.5 g/m2) for 5 cycles E3V4M6 E1VTM1 6 months Partial response E2V1M1
3 68 Male Hypertension Hyperlipidaemia Stroke Unsteady gait Memory impairment Slow speech DLBCL, GCB Periventricular Corpus callosum Corona radiata High-dose methotrexate based (2.5 g/m2) for 5 cycles E4V4M6 E1V1M1 12 days Complete response E1V1M1
aNon-purposeful movements observed;
bAssessed using International PCNSL Collaborative Group (IPCG) criteria [17]; PCNSL, primary CNS lymphoma; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; GCS, Glasgow Coma Scale. | 4 CYCLES | DrugDosageText | CC BY-NC-ND | 33575028 | 18,923,316 | 2021-03 |
What was the dosage of drug 'DEXAMETHASONE'? | Absence of meaningful neurocognitive recovery in comatose patients with primary central nervous system lymphoma despite an effective response to chemotherapy: Case reports.
Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that occurs in patients who are elderly and immunocompromised. The most common treatment for PCNSL is high-dose methotrexate-based chemotherapy. Studies have suggested that the radiological response to high-dose methotrexate-based chemotherapy is associated with improved neurocognitive ability that remains stable upon follow-up. However, no study involving patients with an extremely poor neurological status before chemotherapy initiation has been reported, and the neurological prognosis of this group of patients remains unknown. The current case study described 3 patients with PCNSL diagnosed via biopsy who had comatose neurological states due to disease progression prior to treatment. All patients were treated with high-dose methotrexate-based chemotherapy. However, although effective radiological responses to treatment were achieved, no meaningful neurological or cognitive recovery was documented. Patients with PCNSL exhibiting a baseline comatose state have a poor neurological prognosis even with an effective tumour response to chemotherapy. Therefore, rapid detection and prompt treatment are crucial in patients with this disease.
Introduction
Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma that is usually confined to the brain, leptomeninges, spine, cerebrospinal fluid and eyes without evidence of systemic spread (1). PCNSL represents approximately 4% of all newly diagnosed central nervous system (CNS) tumours (2,3), and most seem to be of late or post-germinal centre B-cell origin (4,5). Immunodeficiency due to congenital immunodeficiency syndromes such as ataxia-telangiectasia and Wiskott-Aldrich syndrome, as well as secondary causes such as acquired immunodeficiency syndrome and iatrogenic immunosuppression for transplant procedures, has been implicated in the development of PCNSL (6).
The prognosis of PCNSL has improved substantially in recent years, particularly in immunocompetent patients (7). However, treatment of PCSNL may cause neurotoxicity and compromise health-related quality of life. Studies have suggested that patients treated with combined high-dose methotrexate chemotherapy and consolidation whole-brain radiotherapy (WBRT) in the treatment of PCNSL develop worse neurotoxicity and cognitive dysfunction than those treated with chemotherapy alone (8-12). Thus, consolidation WBRT is often withheld unless necessary, particularly in elderly patients (13). Conversely, cognition, as measured by mini-mental state examination (MMSE) scores, frequently improves following the successful treatment of PCNSL with chemotherapy with or without immunotherapy (rituximab) and remains stable on follow-up (10,14-16). However, currently, no study has described the neurological prognosis of PCNSL patients with a very poor neurocognitive function at baseline.
In this study, we reviewed the cases of 3 patients with neuroimaging- and biopsy-proven PCNSL who had baseline comatose neurological states at presentation (Table I). All 3 were treated with high-dose methotrexate-based chemotherapy only without WBRT and achieved either a partial or complete response to treatment, as assessed using International PCNSL Collaborative Group criteria (17).
Case reports
Case 1
A 73-year-old Chinese man presented with worsening lethargy and drowsiness, together with behavioural changes for 1 month. He had a medical history of hypertension, diabetes mellitus, hyperlipidaemia and ischaemic heart disease. During his initial admission, magnetic resonance imaging (MRI) of the brain revealed multiple foci of abnormal enhancement with low to heterogeneous T2 signals in a periventricular distribution, including the ependymal margins of both lateral ventricles, infundibular recess of the 3rd ventricle and pituitary stalk. These findings were highly suggestive of PCNSL. Despite these findings, the patient declined further work-up and was discharged against medical advice. He was subsequently re-admitted a month later for progressive drowsiness and fever. Neurological examination revealed a severely depressed level of consciousness with a Glasgow Coma Scale (GCS) of E3V1M1. Imaging of the brain showed interval disease progression and obstructive hydrocephalus. The patient subsequently underwent an external ventricular drain insertion, followed by stereotactic biopsy of the right caudate region two weeks later.
Histological evaluation confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal centre B-cell like (non-GCB) subtype. He was administered dexamethasone, procarbazine, vincristine and high-dose methotrexate (2.5 g/m2) (18). At the point of treatment initiation, the GCS remained poor at E2V2M1. The time from the initial presentation to time of treatment initiation was 2 months. Because chemotherapy was complicated by repeated infective episodes, including pyelonephritis, colitis and pneumonia, only 4 cycles were administered (up to week 8). Brain MRI performed at the end of treatment showed no residual tumour or interval new tumour, indicating a complete response (Fig. 1A).
Despite the complete response of the lymphoma to chemotherapy, the patient's neurocognitive status did not improve and the GCS remained poor at E2V2M1. The patient eventually died of relapsed disease 8 months later.
Case 2
A 42-year-old Bruneian man with no significant medical history initially presented with diplopia and was referred to the National Cancer Centre, Singapore, for suspected PCNSL on preliminary brain imaging. Physical examination revealed a GCS of E3V4M6, cranial nerve III, IV and VI palsy bilaterally, a fixed left pupil and extremely poor visual acuity with inability to visualize light bilaterally. Mild left hemiparesis was also evident. Brain MRI revealed homogeneously enhancing lesions in the optic chiasma, optic nerves and tract, midbrain and pons, and hypothalamus.
Stereotactic biopsy of the left suprasellar lesion confirmed DLBCL, non-GCB type. Unfortunately, the patient became progressively drowsier because of the interval enlargement of the known suprasellar mass associated with an increasing mass effect and worsening hydrocephalus. The patient subsequently underwent ventriculoperitoneal shunt insertion and tracheostomy, while his GCS continued to deteriorate to E1VTM1. He was administered high-dose methotrexate-based chemotherapy for 5 cycles based on the protocol by Shah et al (rituximab, vincristine, procarbazine and methotrexate 2.5 g/m2) (19). The time from the initial presentation to the start of treatment was 6 months. Post-treatment brain MRI showed a stable hypothalamus lesion and marked improvement in the lesions in the right temporal lobe, bilateral basal ganglia and brainstem, indicating an effective partial response to treatment (Fig. 1B).
Despite the overall response to treatment, the patient did not achieve significant improvement in cognition or physical function. His post-treatment GCS remained low at E2V1M1. Thereafter, he was managed with best supportive care alone at a hospice.
Case 3
A 68-year-old Chinese man with a significant medical history of hypertension, hyperlipidaemia and stroke presented with an unsteady gait with frequent falls, impairment of semantic memory and slow speech. His physical examination was unremarkable, and he had no gross neurological deficits. His GCS was E4V4M6. Brain MRI showed lobulated semi-confluent enhancing lesions at the bilateral periventricular regions involving the corpus callosum and corona radiata.
Stereotactic biopsy of the left frontal periventricular region revealed DLBCL, GCB type. Post operatively, he was administered levetiracetam and dexamethasone because he had mild fasciculations of his right thigh and twitching of his left biceps suggestive of a provoked seizure. He was intubated when his GCS subsequently deteriorated to E1V1M1, following which a tracheostomy was performed. Subsequently, he was administered high-dose methotrexate-based chemotherapy for 5 cycles including rituximab, vincristine and methotrexate (2.5 g/m2) but not procarbazine. Post-treatment brain MRI revealed complete resolution of the lesions along the periventricular region and corpus callosum, indicating a complete response to treatment (Fig. 1C).
Similar to cases 1 and 2, despite an effective tumour response to chemotherapy, he remained in a comatose state with a GCS of 3 and died 8 months later.
Discussion
We described the cases of 3 patients with extremely poor neurological statuses before treatment initiation. All 3 patients did not achieve meaningful neurological recovery despite an effective tumour response to chemotherapy, as evidenced by the low post-treatment GCS of 5, 4 and 3 for cases 1, 2 and 3, respectively. These findings contrast those of earlier studies that reported an improvement in cognitive function following the successful treatment of PCNSL (10,14-16). Although these cohorts generally comprise patients with grossly intact neurological and cognitive function (median MMSE range, 22-23), our study is novel because the 3 patients had extremely poor neurocognitive function at baseline with a GCS score of 5 or below before treatment initiation.
The GCS decreased in all 3 patients in the short time frame between the initial presentation and start of treatment, ranging from 12 days to 6 months. In case 1, treatment was delayed because the patient had initially requested for discharge against medical advice, whereas the delay in case 2 was due to the patient being referred from an overseas hospital. In case 3, treatment was promptly commenced. Thus, PCNSL is an aggressive disease with an unpredictable clinical course. A sharp decrease in the GCS representing disease progression of PCNSL may indicate a poor neurological prognosis even if the tumour responds well to chemotherapy. In such a scenario, best supportive care focusing on the quality of life may be considered and weighed carefully against aggressive chemotherapy with curative intent.
Although cases 1 and 3 involved elderly Chinese patients older than 65 years, case 2 involved a young Bruneian man aged only 42 years at diagnosis. Despite the differences in both age and race, all 3 patients had similarly poor neurological outcomes at the end of chemotherapy treatment. This supports the hypothesis that a poor neurocognitive status before treatment is a poor prognostic indicator for the post-treatment neurological outcome across various demographical factors such and age and race.
In conclusion, the neurocognitive status of PCNSL patients can deteriorate quickly, indicating dismal outcomes. Patients with severe neurocognitive compromise may have a poor neurological prognosis despite an effective response to treatment. Further validation studies should be conducted to examine the neurological prognosis of PCNSL patients with poor neurological function at baseline who were treated successfully with chemotherapy, as well as to determine the possible causes of and prevent poor neurological status in these patients. Our study suggests that administering early treatment in PCNSL patients and avoiding unnecessary delays are necessary to achieve optimal neurocognitive recovery.
Acknowledgements
Not applicable.
Funding
This work was supported by the Singapore Ministry of Health's National Medical Research Council of Singapore (grant no. NMRC/FLWSHP/054/2017-00), SHF-Foundation (grant no. SHF/FG653P/2017) and SingHealth Duke-NUS Academic Medical Centre and Oncology ACP (grant no. 08-FY2017/P1/14-A28).
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analysed during the present study.
Authors' contributions
RMHL and JYC conceptualized the study and wrote the manuscript. RMHL acquired, analysed and interpreted the data. JYC enrolled the study patients, obtained their consent and treated them. Both authors have confirmed the authenticity of all raw data, as well as read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Singhealth Centralised Institutional Review Board (CIRB 2018/3084). Written informed consent was obtained from all the participants and/or their legal guardians.
Patient consent for publication
Written informed consent was obtained from the patients for the publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 T1-weighted MRI images reveal the anatomical involvement of PCNSL at various junctures of treatment. (A) Complete responses to chemotherapy were observed in case 1, (B) partial response to chemotherapy was observed in case 2 and (C) complete responses to chemotherapy were observed in case 3. The red arrows indicate the initial sites of disease. PCNSL, primary CNS lymphoma.
Table I Clinical characteristics and treatment outcomes of patients with PCNSL.
ID Age at diagnosis (years) Gender Significant comorbidities Presenting symptoms Histology Anatomical location Treatment regimen GCS (at presentation) GCS (before treatment) Time to treatment End of treatment responseb GCS (post- treatment)
1 73 Male Hypertension Diabetes mellitus Hyperlipidaemia Ischaemic heart disease Lethargy Drowsiness Behaviour change DLBCL, non-GCB Basal ganglia Thalamus Midbrain Periventricular Corpus callosum High-dose methotrexate based (2.5 g/m2) for 4 cycles E3V1M1a E2V2M1 2 months Complete response E2V2M1
2 42 Male Nil Diplopia Poor visual acuity DLBCL, non-GCB Optic chiasma, optic nerves and tract Midbrain and pons Hypothalamus High-dose metho trexate based (2.5 g/m2) for 5 cycles E3V4M6 E1VTM1 6 months Partial response E2V1M1
3 68 Male Hypertension Hyperlipidaemia Stroke Unsteady gait Memory impairment Slow speech DLBCL, GCB Periventricular Corpus callosum Corona radiata High-dose methotrexate based (2.5 g/m2) for 5 cycles E4V4M6 E1V1M1 12 days Complete response E1V1M1
aNon-purposeful movements observed;
bAssessed using International PCNSL Collaborative Group (IPCG) criteria [17]; PCNSL, primary CNS lymphoma; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; GCS, Glasgow Coma Scale. | DOSAGE: 4 CYCLES | DrugDosageText | CC BY-NC-ND | 33575028 | 18,924,319 | 2021-03 |
What was the dosage of drug 'VINCRISTINE SULFATE'? | Absence of meaningful neurocognitive recovery in comatose patients with primary central nervous system lymphoma despite an effective response to chemotherapy: Case reports.
Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that occurs in patients who are elderly and immunocompromised. The most common treatment for PCNSL is high-dose methotrexate-based chemotherapy. Studies have suggested that the radiological response to high-dose methotrexate-based chemotherapy is associated with improved neurocognitive ability that remains stable upon follow-up. However, no study involving patients with an extremely poor neurological status before chemotherapy initiation has been reported, and the neurological prognosis of this group of patients remains unknown. The current case study described 3 patients with PCNSL diagnosed via biopsy who had comatose neurological states due to disease progression prior to treatment. All patients were treated with high-dose methotrexate-based chemotherapy. However, although effective radiological responses to treatment were achieved, no meaningful neurological or cognitive recovery was documented. Patients with PCNSL exhibiting a baseline comatose state have a poor neurological prognosis even with an effective tumour response to chemotherapy. Therefore, rapid detection and prompt treatment are crucial in patients with this disease.
Introduction
Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma that is usually confined to the brain, leptomeninges, spine, cerebrospinal fluid and eyes without evidence of systemic spread (1). PCNSL represents approximately 4% of all newly diagnosed central nervous system (CNS) tumours (2,3), and most seem to be of late or post-germinal centre B-cell origin (4,5). Immunodeficiency due to congenital immunodeficiency syndromes such as ataxia-telangiectasia and Wiskott-Aldrich syndrome, as well as secondary causes such as acquired immunodeficiency syndrome and iatrogenic immunosuppression for transplant procedures, has been implicated in the development of PCNSL (6).
The prognosis of PCNSL has improved substantially in recent years, particularly in immunocompetent patients (7). However, treatment of PCSNL may cause neurotoxicity and compromise health-related quality of life. Studies have suggested that patients treated with combined high-dose methotrexate chemotherapy and consolidation whole-brain radiotherapy (WBRT) in the treatment of PCNSL develop worse neurotoxicity and cognitive dysfunction than those treated with chemotherapy alone (8-12). Thus, consolidation WBRT is often withheld unless necessary, particularly in elderly patients (13). Conversely, cognition, as measured by mini-mental state examination (MMSE) scores, frequently improves following the successful treatment of PCNSL with chemotherapy with or without immunotherapy (rituximab) and remains stable on follow-up (10,14-16). However, currently, no study has described the neurological prognosis of PCNSL patients with a very poor neurocognitive function at baseline.
In this study, we reviewed the cases of 3 patients with neuroimaging- and biopsy-proven PCNSL who had baseline comatose neurological states at presentation (Table I). All 3 were treated with high-dose methotrexate-based chemotherapy only without WBRT and achieved either a partial or complete response to treatment, as assessed using International PCNSL Collaborative Group criteria (17).
Case reports
Case 1
A 73-year-old Chinese man presented with worsening lethargy and drowsiness, together with behavioural changes for 1 month. He had a medical history of hypertension, diabetes mellitus, hyperlipidaemia and ischaemic heart disease. During his initial admission, magnetic resonance imaging (MRI) of the brain revealed multiple foci of abnormal enhancement with low to heterogeneous T2 signals in a periventricular distribution, including the ependymal margins of both lateral ventricles, infundibular recess of the 3rd ventricle and pituitary stalk. These findings were highly suggestive of PCNSL. Despite these findings, the patient declined further work-up and was discharged against medical advice. He was subsequently re-admitted a month later for progressive drowsiness and fever. Neurological examination revealed a severely depressed level of consciousness with a Glasgow Coma Scale (GCS) of E3V1M1. Imaging of the brain showed interval disease progression and obstructive hydrocephalus. The patient subsequently underwent an external ventricular drain insertion, followed by stereotactic biopsy of the right caudate region two weeks later.
Histological evaluation confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal centre B-cell like (non-GCB) subtype. He was administered dexamethasone, procarbazine, vincristine and high-dose methotrexate (2.5 g/m2) (18). At the point of treatment initiation, the GCS remained poor at E2V2M1. The time from the initial presentation to time of treatment initiation was 2 months. Because chemotherapy was complicated by repeated infective episodes, including pyelonephritis, colitis and pneumonia, only 4 cycles were administered (up to week 8). Brain MRI performed at the end of treatment showed no residual tumour or interval new tumour, indicating a complete response (Fig. 1A).
Despite the complete response of the lymphoma to chemotherapy, the patient's neurocognitive status did not improve and the GCS remained poor at E2V2M1. The patient eventually died of relapsed disease 8 months later.
Case 2
A 42-year-old Bruneian man with no significant medical history initially presented with diplopia and was referred to the National Cancer Centre, Singapore, for suspected PCNSL on preliminary brain imaging. Physical examination revealed a GCS of E3V4M6, cranial nerve III, IV and VI palsy bilaterally, a fixed left pupil and extremely poor visual acuity with inability to visualize light bilaterally. Mild left hemiparesis was also evident. Brain MRI revealed homogeneously enhancing lesions in the optic chiasma, optic nerves and tract, midbrain and pons, and hypothalamus.
Stereotactic biopsy of the left suprasellar lesion confirmed DLBCL, non-GCB type. Unfortunately, the patient became progressively drowsier because of the interval enlargement of the known suprasellar mass associated with an increasing mass effect and worsening hydrocephalus. The patient subsequently underwent ventriculoperitoneal shunt insertion and tracheostomy, while his GCS continued to deteriorate to E1VTM1. He was administered high-dose methotrexate-based chemotherapy for 5 cycles based on the protocol by Shah et al (rituximab, vincristine, procarbazine and methotrexate 2.5 g/m2) (19). The time from the initial presentation to the start of treatment was 6 months. Post-treatment brain MRI showed a stable hypothalamus lesion and marked improvement in the lesions in the right temporal lobe, bilateral basal ganglia and brainstem, indicating an effective partial response to treatment (Fig. 1B).
Despite the overall response to treatment, the patient did not achieve significant improvement in cognition or physical function. His post-treatment GCS remained low at E2V1M1. Thereafter, he was managed with best supportive care alone at a hospice.
Case 3
A 68-year-old Chinese man with a significant medical history of hypertension, hyperlipidaemia and stroke presented with an unsteady gait with frequent falls, impairment of semantic memory and slow speech. His physical examination was unremarkable, and he had no gross neurological deficits. His GCS was E4V4M6. Brain MRI showed lobulated semi-confluent enhancing lesions at the bilateral periventricular regions involving the corpus callosum and corona radiata.
Stereotactic biopsy of the left frontal periventricular region revealed DLBCL, GCB type. Post operatively, he was administered levetiracetam and dexamethasone because he had mild fasciculations of his right thigh and twitching of his left biceps suggestive of a provoked seizure. He was intubated when his GCS subsequently deteriorated to E1V1M1, following which a tracheostomy was performed. Subsequently, he was administered high-dose methotrexate-based chemotherapy for 5 cycles including rituximab, vincristine and methotrexate (2.5 g/m2) but not procarbazine. Post-treatment brain MRI revealed complete resolution of the lesions along the periventricular region and corpus callosum, indicating a complete response to treatment (Fig. 1C).
Similar to cases 1 and 2, despite an effective tumour response to chemotherapy, he remained in a comatose state with a GCS of 3 and died 8 months later.
Discussion
We described the cases of 3 patients with extremely poor neurological statuses before treatment initiation. All 3 patients did not achieve meaningful neurological recovery despite an effective tumour response to chemotherapy, as evidenced by the low post-treatment GCS of 5, 4 and 3 for cases 1, 2 and 3, respectively. These findings contrast those of earlier studies that reported an improvement in cognitive function following the successful treatment of PCNSL (10,14-16). Although these cohorts generally comprise patients with grossly intact neurological and cognitive function (median MMSE range, 22-23), our study is novel because the 3 patients had extremely poor neurocognitive function at baseline with a GCS score of 5 or below before treatment initiation.
The GCS decreased in all 3 patients in the short time frame between the initial presentation and start of treatment, ranging from 12 days to 6 months. In case 1, treatment was delayed because the patient had initially requested for discharge against medical advice, whereas the delay in case 2 was due to the patient being referred from an overseas hospital. In case 3, treatment was promptly commenced. Thus, PCNSL is an aggressive disease with an unpredictable clinical course. A sharp decrease in the GCS representing disease progression of PCNSL may indicate a poor neurological prognosis even if the tumour responds well to chemotherapy. In such a scenario, best supportive care focusing on the quality of life may be considered and weighed carefully against aggressive chemotherapy with curative intent.
Although cases 1 and 3 involved elderly Chinese patients older than 65 years, case 2 involved a young Bruneian man aged only 42 years at diagnosis. Despite the differences in both age and race, all 3 patients had similarly poor neurological outcomes at the end of chemotherapy treatment. This supports the hypothesis that a poor neurocognitive status before treatment is a poor prognostic indicator for the post-treatment neurological outcome across various demographical factors such and age and race.
In conclusion, the neurocognitive status of PCNSL patients can deteriorate quickly, indicating dismal outcomes. Patients with severe neurocognitive compromise may have a poor neurological prognosis despite an effective response to treatment. Further validation studies should be conducted to examine the neurological prognosis of PCNSL patients with poor neurological function at baseline who were treated successfully with chemotherapy, as well as to determine the possible causes of and prevent poor neurological status in these patients. Our study suggests that administering early treatment in PCNSL patients and avoiding unnecessary delays are necessary to achieve optimal neurocognitive recovery.
Acknowledgements
Not applicable.
Funding
This work was supported by the Singapore Ministry of Health's National Medical Research Council of Singapore (grant no. NMRC/FLWSHP/054/2017-00), SHF-Foundation (grant no. SHF/FG653P/2017) and SingHealth Duke-NUS Academic Medical Centre and Oncology ACP (grant no. 08-FY2017/P1/14-A28).
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analysed during the present study.
Authors' contributions
RMHL and JYC conceptualized the study and wrote the manuscript. RMHL acquired, analysed and interpreted the data. JYC enrolled the study patients, obtained their consent and treated them. Both authors have confirmed the authenticity of all raw data, as well as read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Singhealth Centralised Institutional Review Board (CIRB 2018/3084). Written informed consent was obtained from all the participants and/or their legal guardians.
Patient consent for publication
Written informed consent was obtained from the patients for the publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 T1-weighted MRI images reveal the anatomical involvement of PCNSL at various junctures of treatment. (A) Complete responses to chemotherapy were observed in case 1, (B) partial response to chemotherapy was observed in case 2 and (C) complete responses to chemotherapy were observed in case 3. The red arrows indicate the initial sites of disease. PCNSL, primary CNS lymphoma.
Table I Clinical characteristics and treatment outcomes of patients with PCNSL.
ID Age at diagnosis (years) Gender Significant comorbidities Presenting symptoms Histology Anatomical location Treatment regimen GCS (at presentation) GCS (before treatment) Time to treatment End of treatment responseb GCS (post- treatment)
1 73 Male Hypertension Diabetes mellitus Hyperlipidaemia Ischaemic heart disease Lethargy Drowsiness Behaviour change DLBCL, non-GCB Basal ganglia Thalamus Midbrain Periventricular Corpus callosum High-dose methotrexate based (2.5 g/m2) for 4 cycles E3V1M1a E2V2M1 2 months Complete response E2V2M1
2 42 Male Nil Diplopia Poor visual acuity DLBCL, non-GCB Optic chiasma, optic nerves and tract Midbrain and pons Hypothalamus High-dose metho trexate based (2.5 g/m2) for 5 cycles E3V4M6 E1VTM1 6 months Partial response E2V1M1
3 68 Male Hypertension Hyperlipidaemia Stroke Unsteady gait Memory impairment Slow speech DLBCL, GCB Periventricular Corpus callosum Corona radiata High-dose methotrexate based (2.5 g/m2) for 5 cycles E4V4M6 E1V1M1 12 days Complete response E1V1M1
aNon-purposeful movements observed;
bAssessed using International PCNSL Collaborative Group (IPCG) criteria [17]; PCNSL, primary CNS lymphoma; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; GCS, Glasgow Coma Scale. | 4 CYCLES | DrugDosageText | CC BY-NC-ND | 33575028 | 18,923,316 | 2021-03 |
What was the dosage of drug 'VINCRISTINE'? | Absence of meaningful neurocognitive recovery in comatose patients with primary central nervous system lymphoma despite an effective response to chemotherapy: Case reports.
Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that occurs in patients who are elderly and immunocompromised. The most common treatment for PCNSL is high-dose methotrexate-based chemotherapy. Studies have suggested that the radiological response to high-dose methotrexate-based chemotherapy is associated with improved neurocognitive ability that remains stable upon follow-up. However, no study involving patients with an extremely poor neurological status before chemotherapy initiation has been reported, and the neurological prognosis of this group of patients remains unknown. The current case study described 3 patients with PCNSL diagnosed via biopsy who had comatose neurological states due to disease progression prior to treatment. All patients were treated with high-dose methotrexate-based chemotherapy. However, although effective radiological responses to treatment were achieved, no meaningful neurological or cognitive recovery was documented. Patients with PCNSL exhibiting a baseline comatose state have a poor neurological prognosis even with an effective tumour response to chemotherapy. Therefore, rapid detection and prompt treatment are crucial in patients with this disease.
Introduction
Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma that is usually confined to the brain, leptomeninges, spine, cerebrospinal fluid and eyes without evidence of systemic spread (1). PCNSL represents approximately 4% of all newly diagnosed central nervous system (CNS) tumours (2,3), and most seem to be of late or post-germinal centre B-cell origin (4,5). Immunodeficiency due to congenital immunodeficiency syndromes such as ataxia-telangiectasia and Wiskott-Aldrich syndrome, as well as secondary causes such as acquired immunodeficiency syndrome and iatrogenic immunosuppression for transplant procedures, has been implicated in the development of PCNSL (6).
The prognosis of PCNSL has improved substantially in recent years, particularly in immunocompetent patients (7). However, treatment of PCSNL may cause neurotoxicity and compromise health-related quality of life. Studies have suggested that patients treated with combined high-dose methotrexate chemotherapy and consolidation whole-brain radiotherapy (WBRT) in the treatment of PCNSL develop worse neurotoxicity and cognitive dysfunction than those treated with chemotherapy alone (8-12). Thus, consolidation WBRT is often withheld unless necessary, particularly in elderly patients (13). Conversely, cognition, as measured by mini-mental state examination (MMSE) scores, frequently improves following the successful treatment of PCNSL with chemotherapy with or without immunotherapy (rituximab) and remains stable on follow-up (10,14-16). However, currently, no study has described the neurological prognosis of PCNSL patients with a very poor neurocognitive function at baseline.
In this study, we reviewed the cases of 3 patients with neuroimaging- and biopsy-proven PCNSL who had baseline comatose neurological states at presentation (Table I). All 3 were treated with high-dose methotrexate-based chemotherapy only without WBRT and achieved either a partial or complete response to treatment, as assessed using International PCNSL Collaborative Group criteria (17).
Case reports
Case 1
A 73-year-old Chinese man presented with worsening lethargy and drowsiness, together with behavioural changes for 1 month. He had a medical history of hypertension, diabetes mellitus, hyperlipidaemia and ischaemic heart disease. During his initial admission, magnetic resonance imaging (MRI) of the brain revealed multiple foci of abnormal enhancement with low to heterogeneous T2 signals in a periventricular distribution, including the ependymal margins of both lateral ventricles, infundibular recess of the 3rd ventricle and pituitary stalk. These findings were highly suggestive of PCNSL. Despite these findings, the patient declined further work-up and was discharged against medical advice. He was subsequently re-admitted a month later for progressive drowsiness and fever. Neurological examination revealed a severely depressed level of consciousness with a Glasgow Coma Scale (GCS) of E3V1M1. Imaging of the brain showed interval disease progression and obstructive hydrocephalus. The patient subsequently underwent an external ventricular drain insertion, followed by stereotactic biopsy of the right caudate region two weeks later.
Histological evaluation confirmed diffuse large B-cell lymphoma (DLBCL), non-germinal centre B-cell like (non-GCB) subtype. He was administered dexamethasone, procarbazine, vincristine and high-dose methotrexate (2.5 g/m2) (18). At the point of treatment initiation, the GCS remained poor at E2V2M1. The time from the initial presentation to time of treatment initiation was 2 months. Because chemotherapy was complicated by repeated infective episodes, including pyelonephritis, colitis and pneumonia, only 4 cycles were administered (up to week 8). Brain MRI performed at the end of treatment showed no residual tumour or interval new tumour, indicating a complete response (Fig. 1A).
Despite the complete response of the lymphoma to chemotherapy, the patient's neurocognitive status did not improve and the GCS remained poor at E2V2M1. The patient eventually died of relapsed disease 8 months later.
Case 2
A 42-year-old Bruneian man with no significant medical history initially presented with diplopia and was referred to the National Cancer Centre, Singapore, for suspected PCNSL on preliminary brain imaging. Physical examination revealed a GCS of E3V4M6, cranial nerve III, IV and VI palsy bilaterally, a fixed left pupil and extremely poor visual acuity with inability to visualize light bilaterally. Mild left hemiparesis was also evident. Brain MRI revealed homogeneously enhancing lesions in the optic chiasma, optic nerves and tract, midbrain and pons, and hypothalamus.
Stereotactic biopsy of the left suprasellar lesion confirmed DLBCL, non-GCB type. Unfortunately, the patient became progressively drowsier because of the interval enlargement of the known suprasellar mass associated with an increasing mass effect and worsening hydrocephalus. The patient subsequently underwent ventriculoperitoneal shunt insertion and tracheostomy, while his GCS continued to deteriorate to E1VTM1. He was administered high-dose methotrexate-based chemotherapy for 5 cycles based on the protocol by Shah et al (rituximab, vincristine, procarbazine and methotrexate 2.5 g/m2) (19). The time from the initial presentation to the start of treatment was 6 months. Post-treatment brain MRI showed a stable hypothalamus lesion and marked improvement in the lesions in the right temporal lobe, bilateral basal ganglia and brainstem, indicating an effective partial response to treatment (Fig. 1B).
Despite the overall response to treatment, the patient did not achieve significant improvement in cognition or physical function. His post-treatment GCS remained low at E2V1M1. Thereafter, he was managed with best supportive care alone at a hospice.
Case 3
A 68-year-old Chinese man with a significant medical history of hypertension, hyperlipidaemia and stroke presented with an unsteady gait with frequent falls, impairment of semantic memory and slow speech. His physical examination was unremarkable, and he had no gross neurological deficits. His GCS was E4V4M6. Brain MRI showed lobulated semi-confluent enhancing lesions at the bilateral periventricular regions involving the corpus callosum and corona radiata.
Stereotactic biopsy of the left frontal periventricular region revealed DLBCL, GCB type. Post operatively, he was administered levetiracetam and dexamethasone because he had mild fasciculations of his right thigh and twitching of his left biceps suggestive of a provoked seizure. He was intubated when his GCS subsequently deteriorated to E1V1M1, following which a tracheostomy was performed. Subsequently, he was administered high-dose methotrexate-based chemotherapy for 5 cycles including rituximab, vincristine and methotrexate (2.5 g/m2) but not procarbazine. Post-treatment brain MRI revealed complete resolution of the lesions along the periventricular region and corpus callosum, indicating a complete response to treatment (Fig. 1C).
Similar to cases 1 and 2, despite an effective tumour response to chemotherapy, he remained in a comatose state with a GCS of 3 and died 8 months later.
Discussion
We described the cases of 3 patients with extremely poor neurological statuses before treatment initiation. All 3 patients did not achieve meaningful neurological recovery despite an effective tumour response to chemotherapy, as evidenced by the low post-treatment GCS of 5, 4 and 3 for cases 1, 2 and 3, respectively. These findings contrast those of earlier studies that reported an improvement in cognitive function following the successful treatment of PCNSL (10,14-16). Although these cohorts generally comprise patients with grossly intact neurological and cognitive function (median MMSE range, 22-23), our study is novel because the 3 patients had extremely poor neurocognitive function at baseline with a GCS score of 5 or below before treatment initiation.
The GCS decreased in all 3 patients in the short time frame between the initial presentation and start of treatment, ranging from 12 days to 6 months. In case 1, treatment was delayed because the patient had initially requested for discharge against medical advice, whereas the delay in case 2 was due to the patient being referred from an overseas hospital. In case 3, treatment was promptly commenced. Thus, PCNSL is an aggressive disease with an unpredictable clinical course. A sharp decrease in the GCS representing disease progression of PCNSL may indicate a poor neurological prognosis even if the tumour responds well to chemotherapy. In such a scenario, best supportive care focusing on the quality of life may be considered and weighed carefully against aggressive chemotherapy with curative intent.
Although cases 1 and 3 involved elderly Chinese patients older than 65 years, case 2 involved a young Bruneian man aged only 42 years at diagnosis. Despite the differences in both age and race, all 3 patients had similarly poor neurological outcomes at the end of chemotherapy treatment. This supports the hypothesis that a poor neurocognitive status before treatment is a poor prognostic indicator for the post-treatment neurological outcome across various demographical factors such and age and race.
In conclusion, the neurocognitive status of PCNSL patients can deteriorate quickly, indicating dismal outcomes. Patients with severe neurocognitive compromise may have a poor neurological prognosis despite an effective response to treatment. Further validation studies should be conducted to examine the neurological prognosis of PCNSL patients with poor neurological function at baseline who were treated successfully with chemotherapy, as well as to determine the possible causes of and prevent poor neurological status in these patients. Our study suggests that administering early treatment in PCNSL patients and avoiding unnecessary delays are necessary to achieve optimal neurocognitive recovery.
Acknowledgements
Not applicable.
Funding
This work was supported by the Singapore Ministry of Health's National Medical Research Council of Singapore (grant no. NMRC/FLWSHP/054/2017-00), SHF-Foundation (grant no. SHF/FG653P/2017) and SingHealth Duke-NUS Academic Medical Centre and Oncology ACP (grant no. 08-FY2017/P1/14-A28).
Availability of data and materials
Data sharing is not applicable to this article, as no datasets were generated or analysed during the present study.
Authors' contributions
RMHL and JYC conceptualized the study and wrote the manuscript. RMHL acquired, analysed and interpreted the data. JYC enrolled the study patients, obtained their consent and treated them. Both authors have confirmed the authenticity of all raw data, as well as read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Singhealth Centralised Institutional Review Board (CIRB 2018/3084). Written informed consent was obtained from all the participants and/or their legal guardians.
Patient consent for publication
Written informed consent was obtained from the patients for the publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 T1-weighted MRI images reveal the anatomical involvement of PCNSL at various junctures of treatment. (A) Complete responses to chemotherapy were observed in case 1, (B) partial response to chemotherapy was observed in case 2 and (C) complete responses to chemotherapy were observed in case 3. The red arrows indicate the initial sites of disease. PCNSL, primary CNS lymphoma.
Table I Clinical characteristics and treatment outcomes of patients with PCNSL.
ID Age at diagnosis (years) Gender Significant comorbidities Presenting symptoms Histology Anatomical location Treatment regimen GCS (at presentation) GCS (before treatment) Time to treatment End of treatment responseb GCS (post- treatment)
1 73 Male Hypertension Diabetes mellitus Hyperlipidaemia Ischaemic heart disease Lethargy Drowsiness Behaviour change DLBCL, non-GCB Basal ganglia Thalamus Midbrain Periventricular Corpus callosum High-dose methotrexate based (2.5 g/m2) for 4 cycles E3V1M1a E2V2M1 2 months Complete response E2V2M1
2 42 Male Nil Diplopia Poor visual acuity DLBCL, non-GCB Optic chiasma, optic nerves and tract Midbrain and pons Hypothalamus High-dose metho trexate based (2.5 g/m2) for 5 cycles E3V4M6 E1VTM1 6 months Partial response E2V1M1
3 68 Male Hypertension Hyperlipidaemia Stroke Unsteady gait Memory impairment Slow speech DLBCL, GCB Periventricular Corpus callosum Corona radiata High-dose methotrexate based (2.5 g/m2) for 5 cycles E4V4M6 E1V1M1 12 days Complete response E1V1M1
aNon-purposeful movements observed;
bAssessed using International PCNSL Collaborative Group (IPCG) criteria [17]; PCNSL, primary CNS lymphoma; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; GCS, Glasgow Coma Scale. | DOSAGE: 4 CYCLES | DrugDosageText | CC BY-NC-ND | 33575028 | 18,924,319 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF.
This case outlines recurrent neutropenia after fourteen years of successful clozapine use. The patient has a diagnosis of treatment-resistant schizophrenia which has been complicated by sensitivity to side effects of haloperidol and past failure of antipsychotics to manage her symptoms. It was necessary for our patient to follow a complicated treatment path involving close monitoring of blood levels, admissions, the initiation of lithium and the regular use of filgrastim (Neupogen), granulocyte colony stimulating factor (G-CSF). Following a failure of rescue filgrastim to increase her neutrophil levels, a management protocol was designed with input from the on-site hematology team. This protocol involved the use of filgrastim on a regular prophylactic basis. This management plan has worked for the patient who has been able to continue use of clozapine and has not suffered from any neutropenic episodes in over six months.
1. Background
Treatment-resistant schizophrenia is an enduring and challenging illness which affects twenty to thirty-three percent of the treatment-resistant population or one third of patients with schizophrenia [1, 2]. Treatment-resistant schizophrenia is a pervasive disorder known to cause challenges in management for treating clinicians in psychiatric practice.
Treatment resistance is due to the limited variety of antipsychotic treatments and can result in much personal, social, and economic burden [3]. In attempting to solve the problem of resistance associated with antipsychotic treatment, clozapine has become the gold standard and has been shown to benefit the achievement and maintenance of stability in patients with treatment-resistant schizophrenia [4].
Clozapine's ability to work on various molecular targets, including 5HT2A, a1-adrenergic, muscarinic, D1, and D2, has the advantage of improve efficacy and reliability in treating psychosis when compared with more classic treatments [5].
However, in keeping with this broad mechanism of action, clozapine is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures [6]. Other possible side effects include metabolic syndrome, anticholinergic effects, sedation, other blood dyscrasias, and delirium [7]. Neutropenia is the most common life-threatening side effect of clozapine use, and an absolute neutrophil count of less than one thousand and five hundred/mm can result in increased chance of infection when the immune system does not have the needed neutrophil capacity to challenge the infection [7]. Such side effects necessitate close monitoring of blood results and suspicion of any new onset physical changes or symptoms. The incidence of agranulocytosis and neutropenia is the highest within the first six to eighteen weeks of commencing clozapine [8]. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine, preexisting benign inherited neutropenia, and human leukocyte antigen haplotypes [7, 9]. The mechanism behind clozapine-induced agranulocytosis and neutropenia is currently unclear, although studies have shown that there are genetic factors at play [10].
Certain phenotypes may take years to manifest, and this may partly explain neutropenia that develops in long-term users of clozapine [11]. In addition, there are multiple proposed immunological mechanisms leading to leukocyte depletion [10]. Neutropenia may also be due to extrinsic causes, for example, specific antibiotic groups, compounded by clozapine use [10].
Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [12]. Filgrastim works most effectively when prescribed prophylactically [12]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [12]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date. This case provides an insight into the challenges clinicians and clients face managing late onset neutropenia in clozapine use as indicated for treatment-resistant schizophrenia.
2. Case Presentation
A 41-year-old female with treatment-resistant schizophrenia was admitted to an acute mental health unit in Ireland due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia (red light), with an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Deterioration in her mental state began to manifest day five postclozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep. Paliperidone resulted in a lack of improvement to the mental state, and her symptoms remained troubling. Our patient was observed to exhibit vague paranoid thinking, was guarded on interaction, and seemed anxious with pressured speech. This was noted to be in keeping with previous relapses.
The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes. Prior to this first neutropenic episode, our patient maintained reasonable levels of social functioning and was in the process of completing a night-time college course while utilizing previous qualifications in a volunteering capacity by day. She lived independently and in her free time was physically active and a nonsmoker, with a keen interest in running and participation in distance running events. She had coped well with the loss of her mother a few years previously.
A diagnosis of schizophrenia was established for this lady at the age of twenty-six with symptoms of paranoia, odd behaviors, and beliefs. She was commenced on clozapine in that same year as an in-patient following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. There was no contributing family history of psychosis. Episodes of clozapine-induced neutropenia posed a risk to continued use of clozapine, which had aided her in leading a fulfilling and busy lifestyle to date.
3. Investigations
Differential causes for deterioration in the mental state and/or neutropenia were ruled out. Full physical examination was performed with blood testing to rule out infection or other disease processes impacting immunity or hematopoiesis. This patient had never experienced neutropenic episodes prior to starting clozapine and for many years while taking clozapine which ruled out a cause of cyclic neutropenia or any other genetic conditions. The patient had full viral and autoimmune blood screening completed which produced negative results. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained via trephine biopsy which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.
4. Treatment
Following admission in late January, our patient remained neutropenic for a number of weeks. To correct her white blood cell count filgrastim, G-CSF (Neupogen) 30 MU was prescribed on February eleventh while an in-patient (Figure 1). This resulted in a white cell count which increased from 3.4 × 109/L to 6.5 × 109/L and ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. Filgrastim was prescribed in conjunction with in-house hematology advice and administered by the nursing staff. One month posttreatment with Neupogen, our patient's white cells fell once again to 2.4 with ANC of 1.64 × 109/L which required a further dose of filgrastim. Lithium was started in March 2018 in an attempt to increase and maintain leukocyte counts. Lithium 800 mg once daily seemed to result in an improvement in our patient's leukocyte count averaging between 3.3 × 109/L and 4.4 × 109/L. Initially, efforts were made to avoid a clozapine rechallenge but combination antipsychotic treatment proved to be ineffective, and our patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while she remained an in-patient.
The patient responded well to clozapine rechallenge, and hematology specialists advised on safe reinstatement of clozapine. Unfortunately, clozapine use continued to cause recurrent neutropenic results (Figure 1). Discontinuation of clozapine consequently lead to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.
A filgrastim treatment protocol was created for our patient as part of a multidisciplinary approach, commencement of which corresponded with a period of baseline ANC stability (Figure 2). Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol was developed with hematology input to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment has been achieved (Figure 3). This lady's current prescription of filgrastim is 30 MU up to three times per week.
5. Outcome and Follow-Up
Although the initial incident of neutropenia does indicate an increased risk of further neutropenic episodes, maintenance of mental health and social functioning is an achievable priority for our patient at the current time. She is utilizing biweekly filgrastim prophylactically. This regimen in combination with lithium has maintained white cell and neutrophil count in the amber/green range and has thus far facilitated continuous use of clozapine over the past six months approximately. The patient has been counseled with regard to the possible short-term and long-term side effects of filgrastim, and the patient decided to continue the use of filgrastim which allows ongoing use of clozapine. Continued input of hematology is needed with regard to prophylactic use of filgrastim and its unclear risk of contributing to leukemia. With sustained and uninterrupted clozapine treatment, our patient's mental state has stabilized with mild residual symptoms.
6. Discussion
Research suggests that, on discontinuation of clozapine, neutropenia takes an average of fourteen to twenty-two days to resolve and can resolve spontaneously [8]. In the case discussed, consistent stability in leukocyte and neutrophil counts has been difficult. However, reference ranges above normal were achieved quickly in the days following each administration of filgrastim. In the literature, recommendations for persistent neutropenia include coprescription of lithium or GM-CSF with clozapine [8, 13]. Research into cases recommenced on clozapine and coprescribed GM-CSF has demonstrated a 78% success rate compared with coprescription of lithium which correlates with a 60% success rate [12]. Lithium works by increasing the WBC count by approximately 2 × 109/L, and the effectiveness of a low dosage of lithium avoids toxic effects. The exact mechanism by which lithium increases granulocytes is unknown. However, research has shown that this mechanism involves GM-CSF production as opposed to granulocyte redistribution from the bone marrow [14]. Myles et al. [12] recommend that GM-CSF can be used as a preventative measure during clozapine use.
Cytokines such as G-CSF and GM-CSF are effective in stimulating granulocyte production, which shortens the duration of agranulocytosis [14]. Bone marrow precursor cell levels need to be sufficient prior to cytokine use [12]. There is scope for coadministration of cytokines and lithium in severe neutropenia or refractory cases and conveniently, reliable patients can be coached to self-administer injections of G-CSF [12]. There is no known contraindication to the continuation of lithium treatment and regular filgrastim injections in conjunction with clozapine as part of long-term treatment [12].
Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count [15]. Past criteria have proven too rigid, resulting in patients avoiding retrial of clozapine in treatment-resistant schizophrenia [15]. Mild-moderate cases of neutropenia have been shown to be a common and benign finding [15].
7. Learning Points/Take Home Messages
Late-onset neutropenia is a risk of long-term clozapine use; therefore, vigilance is always required, and guidelines should be followed in anticipation of this event
Filgrastim can be used safely to maintain neutrophil levels, in addition to lithium and clozapine
Schedules of filgrastim can be individualized with expert input from hematology and close monitoring
Data Availability
Data used to support the findings of this study are included within the article.
Additional Points
Adapted from patient. I was worried that the blood levels would not become normal, and that I would have to stop taking clozapine. It had suited me up until there was a problem with my blood levels. I was able to enjoy life. I am relieved that with my current medications, I can continue to take clozapine, and I have been able to renew my interests since. I am happy for my case to be shared in this report if it helps others who may have a similar problem taking clozapine.
Ethical Approval
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008. The authors assert that ethical approval for publication of this case report was not required by their local ethics committee.
Disclosure
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors, Dr. Eimear O' Neill, Dr. Deirdre Carolan, Dr. Sarah Anne Kennedy, and Dr. Sandra Barry, do not have any conflicts of interest to report.
Figure 1 Neutrophil serum level from 22nd of January to 10th of December 2018. Figure 1 displays the neutrophil level by serum testing from 22nd of January to 10th of December 2018. The x axis demonstrates dates of sampling, and the y axis corresponds with absolute neutrophil count (ANC) ×109/L. Initially, there is a period of neutropenia (1.0 × 109/L-2.0 × 109/L). Filgrastim, G-CSF 30 MU, was prescribed on February 10th resulting in an ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. A further neutropenic episode occurred on March 4th with ANC 1.64 × 109/L. Lithium was commenced on March 10th. Clozapine rechallenge in September corresponded with further deterioration in ANC measurements prompting close liaison with hematology to devise a filgrastim treatment protocol.
Figure 2 Neutrophil serum level from 2nd of January to 20th of September 2019. Figure 2 displays the neutrophil level by serum testing from 2nd January to 20th September 2019. The x axis demonstrates dates of sampling, and the y axis corresponds with the absolute neutrophil count ×109/L. Commencement of the filgrastim treatment protocol in March 2019 corresponds with a period of stability in baseline ANC with fewer episodes of neutropenia. Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol developed to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result.
Figure 3 Administration of filgrastim resulting in increases in neutrophil levels. Figure 3 demonstrates the administration of filgrastim 30 MU, given as needed in response to neutropenia occurring from March 2019, in keeping with the patient specific protocol supported by hematology. The x axis shows the timeline of the filgrastim administration, and the y axis displays the absolute neutrophil count ×109/L. The blue columns represent the ANC prior to giving filgrastim, and the orange columns represent ANCs one day postfilgrastim administration. Green light results indicating safe ANCs are seen from July 2019 utilizing prophylactic filgrastim up to three times weekly. | CLOZAPINE, PALIPERIDONE, ZOPICLONE | DrugsGivenReaction | CC BY | 33575054 | 18,985,980 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF.
This case outlines recurrent neutropenia after fourteen years of successful clozapine use. The patient has a diagnosis of treatment-resistant schizophrenia which has been complicated by sensitivity to side effects of haloperidol and past failure of antipsychotics to manage her symptoms. It was necessary for our patient to follow a complicated treatment path involving close monitoring of blood levels, admissions, the initiation of lithium and the regular use of filgrastim (Neupogen), granulocyte colony stimulating factor (G-CSF). Following a failure of rescue filgrastim to increase her neutrophil levels, a management protocol was designed with input from the on-site hematology team. This protocol involved the use of filgrastim on a regular prophylactic basis. This management plan has worked for the patient who has been able to continue use of clozapine and has not suffered from any neutropenic episodes in over six months.
1. Background
Treatment-resistant schizophrenia is an enduring and challenging illness which affects twenty to thirty-three percent of the treatment-resistant population or one third of patients with schizophrenia [1, 2]. Treatment-resistant schizophrenia is a pervasive disorder known to cause challenges in management for treating clinicians in psychiatric practice.
Treatment resistance is due to the limited variety of antipsychotic treatments and can result in much personal, social, and economic burden [3]. In attempting to solve the problem of resistance associated with antipsychotic treatment, clozapine has become the gold standard and has been shown to benefit the achievement and maintenance of stability in patients with treatment-resistant schizophrenia [4].
Clozapine's ability to work on various molecular targets, including 5HT2A, a1-adrenergic, muscarinic, D1, and D2, has the advantage of improve efficacy and reliability in treating psychosis when compared with more classic treatments [5].
However, in keeping with this broad mechanism of action, clozapine is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures [6]. Other possible side effects include metabolic syndrome, anticholinergic effects, sedation, other blood dyscrasias, and delirium [7]. Neutropenia is the most common life-threatening side effect of clozapine use, and an absolute neutrophil count of less than one thousand and five hundred/mm can result in increased chance of infection when the immune system does not have the needed neutrophil capacity to challenge the infection [7]. Such side effects necessitate close monitoring of blood results and suspicion of any new onset physical changes or symptoms. The incidence of agranulocytosis and neutropenia is the highest within the first six to eighteen weeks of commencing clozapine [8]. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine, preexisting benign inherited neutropenia, and human leukocyte antigen haplotypes [7, 9]. The mechanism behind clozapine-induced agranulocytosis and neutropenia is currently unclear, although studies have shown that there are genetic factors at play [10].
Certain phenotypes may take years to manifest, and this may partly explain neutropenia that develops in long-term users of clozapine [11]. In addition, there are multiple proposed immunological mechanisms leading to leukocyte depletion [10]. Neutropenia may also be due to extrinsic causes, for example, specific antibiotic groups, compounded by clozapine use [10].
Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [12]. Filgrastim works most effectively when prescribed prophylactically [12]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [12]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date. This case provides an insight into the challenges clinicians and clients face managing late onset neutropenia in clozapine use as indicated for treatment-resistant schizophrenia.
2. Case Presentation
A 41-year-old female with treatment-resistant schizophrenia was admitted to an acute mental health unit in Ireland due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia (red light), with an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Deterioration in her mental state began to manifest day five postclozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep. Paliperidone resulted in a lack of improvement to the mental state, and her symptoms remained troubling. Our patient was observed to exhibit vague paranoid thinking, was guarded on interaction, and seemed anxious with pressured speech. This was noted to be in keeping with previous relapses.
The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes. Prior to this first neutropenic episode, our patient maintained reasonable levels of social functioning and was in the process of completing a night-time college course while utilizing previous qualifications in a volunteering capacity by day. She lived independently and in her free time was physically active and a nonsmoker, with a keen interest in running and participation in distance running events. She had coped well with the loss of her mother a few years previously.
A diagnosis of schizophrenia was established for this lady at the age of twenty-six with symptoms of paranoia, odd behaviors, and beliefs. She was commenced on clozapine in that same year as an in-patient following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. There was no contributing family history of psychosis. Episodes of clozapine-induced neutropenia posed a risk to continued use of clozapine, which had aided her in leading a fulfilling and busy lifestyle to date.
3. Investigations
Differential causes for deterioration in the mental state and/or neutropenia were ruled out. Full physical examination was performed with blood testing to rule out infection or other disease processes impacting immunity or hematopoiesis. This patient had never experienced neutropenic episodes prior to starting clozapine and for many years while taking clozapine which ruled out a cause of cyclic neutropenia or any other genetic conditions. The patient had full viral and autoimmune blood screening completed which produced negative results. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained via trephine biopsy which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.
4. Treatment
Following admission in late January, our patient remained neutropenic for a number of weeks. To correct her white blood cell count filgrastim, G-CSF (Neupogen) 30 MU was prescribed on February eleventh while an in-patient (Figure 1). This resulted in a white cell count which increased from 3.4 × 109/L to 6.5 × 109/L and ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. Filgrastim was prescribed in conjunction with in-house hematology advice and administered by the nursing staff. One month posttreatment with Neupogen, our patient's white cells fell once again to 2.4 with ANC of 1.64 × 109/L which required a further dose of filgrastim. Lithium was started in March 2018 in an attempt to increase and maintain leukocyte counts. Lithium 800 mg once daily seemed to result in an improvement in our patient's leukocyte count averaging between 3.3 × 109/L and 4.4 × 109/L. Initially, efforts were made to avoid a clozapine rechallenge but combination antipsychotic treatment proved to be ineffective, and our patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while she remained an in-patient.
The patient responded well to clozapine rechallenge, and hematology specialists advised on safe reinstatement of clozapine. Unfortunately, clozapine use continued to cause recurrent neutropenic results (Figure 1). Discontinuation of clozapine consequently lead to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.
A filgrastim treatment protocol was created for our patient as part of a multidisciplinary approach, commencement of which corresponded with a period of baseline ANC stability (Figure 2). Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol was developed with hematology input to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment has been achieved (Figure 3). This lady's current prescription of filgrastim is 30 MU up to three times per week.
5. Outcome and Follow-Up
Although the initial incident of neutropenia does indicate an increased risk of further neutropenic episodes, maintenance of mental health and social functioning is an achievable priority for our patient at the current time. She is utilizing biweekly filgrastim prophylactically. This regimen in combination with lithium has maintained white cell and neutrophil count in the amber/green range and has thus far facilitated continuous use of clozapine over the past six months approximately. The patient has been counseled with regard to the possible short-term and long-term side effects of filgrastim, and the patient decided to continue the use of filgrastim which allows ongoing use of clozapine. Continued input of hematology is needed with regard to prophylactic use of filgrastim and its unclear risk of contributing to leukemia. With sustained and uninterrupted clozapine treatment, our patient's mental state has stabilized with mild residual symptoms.
6. Discussion
Research suggests that, on discontinuation of clozapine, neutropenia takes an average of fourteen to twenty-two days to resolve and can resolve spontaneously [8]. In the case discussed, consistent stability in leukocyte and neutrophil counts has been difficult. However, reference ranges above normal were achieved quickly in the days following each administration of filgrastim. In the literature, recommendations for persistent neutropenia include coprescription of lithium or GM-CSF with clozapine [8, 13]. Research into cases recommenced on clozapine and coprescribed GM-CSF has demonstrated a 78% success rate compared with coprescription of lithium which correlates with a 60% success rate [12]. Lithium works by increasing the WBC count by approximately 2 × 109/L, and the effectiveness of a low dosage of lithium avoids toxic effects. The exact mechanism by which lithium increases granulocytes is unknown. However, research has shown that this mechanism involves GM-CSF production as opposed to granulocyte redistribution from the bone marrow [14]. Myles et al. [12] recommend that GM-CSF can be used as a preventative measure during clozapine use.
Cytokines such as G-CSF and GM-CSF are effective in stimulating granulocyte production, which shortens the duration of agranulocytosis [14]. Bone marrow precursor cell levels need to be sufficient prior to cytokine use [12]. There is scope for coadministration of cytokines and lithium in severe neutropenia or refractory cases and conveniently, reliable patients can be coached to self-administer injections of G-CSF [12]. There is no known contraindication to the continuation of lithium treatment and regular filgrastim injections in conjunction with clozapine as part of long-term treatment [12].
Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count [15]. Past criteria have proven too rigid, resulting in patients avoiding retrial of clozapine in treatment-resistant schizophrenia [15]. Mild-moderate cases of neutropenia have been shown to be a common and benign finding [15].
7. Learning Points/Take Home Messages
Late-onset neutropenia is a risk of long-term clozapine use; therefore, vigilance is always required, and guidelines should be followed in anticipation of this event
Filgrastim can be used safely to maintain neutrophil levels, in addition to lithium and clozapine
Schedules of filgrastim can be individualized with expert input from hematology and close monitoring
Data Availability
Data used to support the findings of this study are included within the article.
Additional Points
Adapted from patient. I was worried that the blood levels would not become normal, and that I would have to stop taking clozapine. It had suited me up until there was a problem with my blood levels. I was able to enjoy life. I am relieved that with my current medications, I can continue to take clozapine, and I have been able to renew my interests since. I am happy for my case to be shared in this report if it helps others who may have a similar problem taking clozapine.
Ethical Approval
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008. The authors assert that ethical approval for publication of this case report was not required by their local ethics committee.
Disclosure
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors, Dr. Eimear O' Neill, Dr. Deirdre Carolan, Dr. Sarah Anne Kennedy, and Dr. Sandra Barry, do not have any conflicts of interest to report.
Figure 1 Neutrophil serum level from 22nd of January to 10th of December 2018. Figure 1 displays the neutrophil level by serum testing from 22nd of January to 10th of December 2018. The x axis demonstrates dates of sampling, and the y axis corresponds with absolute neutrophil count (ANC) ×109/L. Initially, there is a period of neutropenia (1.0 × 109/L-2.0 × 109/L). Filgrastim, G-CSF 30 MU, was prescribed on February 10th resulting in an ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. A further neutropenic episode occurred on March 4th with ANC 1.64 × 109/L. Lithium was commenced on March 10th. Clozapine rechallenge in September corresponded with further deterioration in ANC measurements prompting close liaison with hematology to devise a filgrastim treatment protocol.
Figure 2 Neutrophil serum level from 2nd of January to 20th of September 2019. Figure 2 displays the neutrophil level by serum testing from 2nd January to 20th September 2019. The x axis demonstrates dates of sampling, and the y axis corresponds with the absolute neutrophil count ×109/L. Commencement of the filgrastim treatment protocol in March 2019 corresponds with a period of stability in baseline ANC with fewer episodes of neutropenia. Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol developed to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result.
Figure 3 Administration of filgrastim resulting in increases in neutrophil levels. Figure 3 demonstrates the administration of filgrastim 30 MU, given as needed in response to neutropenia occurring from March 2019, in keeping with the patient specific protocol supported by hematology. The x axis shows the timeline of the filgrastim administration, and the y axis displays the absolute neutrophil count ×109/L. The blue columns represent the ANC prior to giving filgrastim, and the orange columns represent ANCs one day postfilgrastim administration. Green light results indicating safe ANCs are seen from July 2019 utilizing prophylactic filgrastim up to three times weekly. | CLOZAPINE, PALIPERIDONE, ZOPICLONE | DrugsGivenReaction | CC BY | 33575054 | 18,985,980 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Schizophrenia'. | Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF.
This case outlines recurrent neutropenia after fourteen years of successful clozapine use. The patient has a diagnosis of treatment-resistant schizophrenia which has been complicated by sensitivity to side effects of haloperidol and past failure of antipsychotics to manage her symptoms. It was necessary for our patient to follow a complicated treatment path involving close monitoring of blood levels, admissions, the initiation of lithium and the regular use of filgrastim (Neupogen), granulocyte colony stimulating factor (G-CSF). Following a failure of rescue filgrastim to increase her neutrophil levels, a management protocol was designed with input from the on-site hematology team. This protocol involved the use of filgrastim on a regular prophylactic basis. This management plan has worked for the patient who has been able to continue use of clozapine and has not suffered from any neutropenic episodes in over six months.
1. Background
Treatment-resistant schizophrenia is an enduring and challenging illness which affects twenty to thirty-three percent of the treatment-resistant population or one third of patients with schizophrenia [1, 2]. Treatment-resistant schizophrenia is a pervasive disorder known to cause challenges in management for treating clinicians in psychiatric practice.
Treatment resistance is due to the limited variety of antipsychotic treatments and can result in much personal, social, and economic burden [3]. In attempting to solve the problem of resistance associated with antipsychotic treatment, clozapine has become the gold standard and has been shown to benefit the achievement and maintenance of stability in patients with treatment-resistant schizophrenia [4].
Clozapine's ability to work on various molecular targets, including 5HT2A, a1-adrenergic, muscarinic, D1, and D2, has the advantage of improve efficacy and reliability in treating psychosis when compared with more classic treatments [5].
However, in keeping with this broad mechanism of action, clozapine is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures [6]. Other possible side effects include metabolic syndrome, anticholinergic effects, sedation, other blood dyscrasias, and delirium [7]. Neutropenia is the most common life-threatening side effect of clozapine use, and an absolute neutrophil count of less than one thousand and five hundred/mm can result in increased chance of infection when the immune system does not have the needed neutrophil capacity to challenge the infection [7]. Such side effects necessitate close monitoring of blood results and suspicion of any new onset physical changes or symptoms. The incidence of agranulocytosis and neutropenia is the highest within the first six to eighteen weeks of commencing clozapine [8]. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine, preexisting benign inherited neutropenia, and human leukocyte antigen haplotypes [7, 9]. The mechanism behind clozapine-induced agranulocytosis and neutropenia is currently unclear, although studies have shown that there are genetic factors at play [10].
Certain phenotypes may take years to manifest, and this may partly explain neutropenia that develops in long-term users of clozapine [11]. In addition, there are multiple proposed immunological mechanisms leading to leukocyte depletion [10]. Neutropenia may also be due to extrinsic causes, for example, specific antibiotic groups, compounded by clozapine use [10].
Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [12]. Filgrastim works most effectively when prescribed prophylactically [12]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [12]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date. This case provides an insight into the challenges clinicians and clients face managing late onset neutropenia in clozapine use as indicated for treatment-resistant schizophrenia.
2. Case Presentation
A 41-year-old female with treatment-resistant schizophrenia was admitted to an acute mental health unit in Ireland due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia (red light), with an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Deterioration in her mental state began to manifest day five postclozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep. Paliperidone resulted in a lack of improvement to the mental state, and her symptoms remained troubling. Our patient was observed to exhibit vague paranoid thinking, was guarded on interaction, and seemed anxious with pressured speech. This was noted to be in keeping with previous relapses.
The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes. Prior to this first neutropenic episode, our patient maintained reasonable levels of social functioning and was in the process of completing a night-time college course while utilizing previous qualifications in a volunteering capacity by day. She lived independently and in her free time was physically active and a nonsmoker, with a keen interest in running and participation in distance running events. She had coped well with the loss of her mother a few years previously.
A diagnosis of schizophrenia was established for this lady at the age of twenty-six with symptoms of paranoia, odd behaviors, and beliefs. She was commenced on clozapine in that same year as an in-patient following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. There was no contributing family history of psychosis. Episodes of clozapine-induced neutropenia posed a risk to continued use of clozapine, which had aided her in leading a fulfilling and busy lifestyle to date.
3. Investigations
Differential causes for deterioration in the mental state and/or neutropenia were ruled out. Full physical examination was performed with blood testing to rule out infection or other disease processes impacting immunity or hematopoiesis. This patient had never experienced neutropenic episodes prior to starting clozapine and for many years while taking clozapine which ruled out a cause of cyclic neutropenia or any other genetic conditions. The patient had full viral and autoimmune blood screening completed which produced negative results. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained via trephine biopsy which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.
4. Treatment
Following admission in late January, our patient remained neutropenic for a number of weeks. To correct her white blood cell count filgrastim, G-CSF (Neupogen) 30 MU was prescribed on February eleventh while an in-patient (Figure 1). This resulted in a white cell count which increased from 3.4 × 109/L to 6.5 × 109/L and ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. Filgrastim was prescribed in conjunction with in-house hematology advice and administered by the nursing staff. One month posttreatment with Neupogen, our patient's white cells fell once again to 2.4 with ANC of 1.64 × 109/L which required a further dose of filgrastim. Lithium was started in March 2018 in an attempt to increase and maintain leukocyte counts. Lithium 800 mg once daily seemed to result in an improvement in our patient's leukocyte count averaging between 3.3 × 109/L and 4.4 × 109/L. Initially, efforts were made to avoid a clozapine rechallenge but combination antipsychotic treatment proved to be ineffective, and our patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while she remained an in-patient.
The patient responded well to clozapine rechallenge, and hematology specialists advised on safe reinstatement of clozapine. Unfortunately, clozapine use continued to cause recurrent neutropenic results (Figure 1). Discontinuation of clozapine consequently lead to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.
A filgrastim treatment protocol was created for our patient as part of a multidisciplinary approach, commencement of which corresponded with a period of baseline ANC stability (Figure 2). Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol was developed with hematology input to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment has been achieved (Figure 3). This lady's current prescription of filgrastim is 30 MU up to three times per week.
5. Outcome and Follow-Up
Although the initial incident of neutropenia does indicate an increased risk of further neutropenic episodes, maintenance of mental health and social functioning is an achievable priority for our patient at the current time. She is utilizing biweekly filgrastim prophylactically. This regimen in combination with lithium has maintained white cell and neutrophil count in the amber/green range and has thus far facilitated continuous use of clozapine over the past six months approximately. The patient has been counseled with regard to the possible short-term and long-term side effects of filgrastim, and the patient decided to continue the use of filgrastim which allows ongoing use of clozapine. Continued input of hematology is needed with regard to prophylactic use of filgrastim and its unclear risk of contributing to leukemia. With sustained and uninterrupted clozapine treatment, our patient's mental state has stabilized with mild residual symptoms.
6. Discussion
Research suggests that, on discontinuation of clozapine, neutropenia takes an average of fourteen to twenty-two days to resolve and can resolve spontaneously [8]. In the case discussed, consistent stability in leukocyte and neutrophil counts has been difficult. However, reference ranges above normal were achieved quickly in the days following each administration of filgrastim. In the literature, recommendations for persistent neutropenia include coprescription of lithium or GM-CSF with clozapine [8, 13]. Research into cases recommenced on clozapine and coprescribed GM-CSF has demonstrated a 78% success rate compared with coprescription of lithium which correlates with a 60% success rate [12]. Lithium works by increasing the WBC count by approximately 2 × 109/L, and the effectiveness of a low dosage of lithium avoids toxic effects. The exact mechanism by which lithium increases granulocytes is unknown. However, research has shown that this mechanism involves GM-CSF production as opposed to granulocyte redistribution from the bone marrow [14]. Myles et al. [12] recommend that GM-CSF can be used as a preventative measure during clozapine use.
Cytokines such as G-CSF and GM-CSF are effective in stimulating granulocyte production, which shortens the duration of agranulocytosis [14]. Bone marrow precursor cell levels need to be sufficient prior to cytokine use [12]. There is scope for coadministration of cytokines and lithium in severe neutropenia or refractory cases and conveniently, reliable patients can be coached to self-administer injections of G-CSF [12]. There is no known contraindication to the continuation of lithium treatment and regular filgrastim injections in conjunction with clozapine as part of long-term treatment [12].
Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count [15]. Past criteria have proven too rigid, resulting in patients avoiding retrial of clozapine in treatment-resistant schizophrenia [15]. Mild-moderate cases of neutropenia have been shown to be a common and benign finding [15].
7. Learning Points/Take Home Messages
Late-onset neutropenia is a risk of long-term clozapine use; therefore, vigilance is always required, and guidelines should be followed in anticipation of this event
Filgrastim can be used safely to maintain neutrophil levels, in addition to lithium and clozapine
Schedules of filgrastim can be individualized with expert input from hematology and close monitoring
Data Availability
Data used to support the findings of this study are included within the article.
Additional Points
Adapted from patient. I was worried that the blood levels would not become normal, and that I would have to stop taking clozapine. It had suited me up until there was a problem with my blood levels. I was able to enjoy life. I am relieved that with my current medications, I can continue to take clozapine, and I have been able to renew my interests since. I am happy for my case to be shared in this report if it helps others who may have a similar problem taking clozapine.
Ethical Approval
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008. The authors assert that ethical approval for publication of this case report was not required by their local ethics committee.
Disclosure
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors, Dr. Eimear O' Neill, Dr. Deirdre Carolan, Dr. Sarah Anne Kennedy, and Dr. Sandra Barry, do not have any conflicts of interest to report.
Figure 1 Neutrophil serum level from 22nd of January to 10th of December 2018. Figure 1 displays the neutrophil level by serum testing from 22nd of January to 10th of December 2018. The x axis demonstrates dates of sampling, and the y axis corresponds with absolute neutrophil count (ANC) ×109/L. Initially, there is a period of neutropenia (1.0 × 109/L-2.0 × 109/L). Filgrastim, G-CSF 30 MU, was prescribed on February 10th resulting in an ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. A further neutropenic episode occurred on March 4th with ANC 1.64 × 109/L. Lithium was commenced on March 10th. Clozapine rechallenge in September corresponded with further deterioration in ANC measurements prompting close liaison with hematology to devise a filgrastim treatment protocol.
Figure 2 Neutrophil serum level from 2nd of January to 20th of September 2019. Figure 2 displays the neutrophil level by serum testing from 2nd January to 20th September 2019. The x axis demonstrates dates of sampling, and the y axis corresponds with the absolute neutrophil count ×109/L. Commencement of the filgrastim treatment protocol in March 2019 corresponds with a period of stability in baseline ANC with fewer episodes of neutropenia. Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol developed to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result.
Figure 3 Administration of filgrastim resulting in increases in neutrophil levels. Figure 3 demonstrates the administration of filgrastim 30 MU, given as needed in response to neutropenia occurring from March 2019, in keeping with the patient specific protocol supported by hematology. The x axis shows the timeline of the filgrastim administration, and the y axis displays the absolute neutrophil count ×109/L. The blue columns represent the ANC prior to giving filgrastim, and the orange columns represent ANCs one day postfilgrastim administration. Green light results indicating safe ANCs are seen from July 2019 utilizing prophylactic filgrastim up to three times weekly. | HALOPERIDOL, OLANZAPINE, QUETIAPINE | DrugsGivenReaction | CC BY | 33575054 | 18,965,251 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF.
This case outlines recurrent neutropenia after fourteen years of successful clozapine use. The patient has a diagnosis of treatment-resistant schizophrenia which has been complicated by sensitivity to side effects of haloperidol and past failure of antipsychotics to manage her symptoms. It was necessary for our patient to follow a complicated treatment path involving close monitoring of blood levels, admissions, the initiation of lithium and the regular use of filgrastim (Neupogen), granulocyte colony stimulating factor (G-CSF). Following a failure of rescue filgrastim to increase her neutrophil levels, a management protocol was designed with input from the on-site hematology team. This protocol involved the use of filgrastim on a regular prophylactic basis. This management plan has worked for the patient who has been able to continue use of clozapine and has not suffered from any neutropenic episodes in over six months.
1. Background
Treatment-resistant schizophrenia is an enduring and challenging illness which affects twenty to thirty-three percent of the treatment-resistant population or one third of patients with schizophrenia [1, 2]. Treatment-resistant schizophrenia is a pervasive disorder known to cause challenges in management for treating clinicians in psychiatric practice.
Treatment resistance is due to the limited variety of antipsychotic treatments and can result in much personal, social, and economic burden [3]. In attempting to solve the problem of resistance associated with antipsychotic treatment, clozapine has become the gold standard and has been shown to benefit the achievement and maintenance of stability in patients with treatment-resistant schizophrenia [4].
Clozapine's ability to work on various molecular targets, including 5HT2A, a1-adrenergic, muscarinic, D1, and D2, has the advantage of improve efficacy and reliability in treating psychosis when compared with more classic treatments [5].
However, in keeping with this broad mechanism of action, clozapine is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures [6]. Other possible side effects include metabolic syndrome, anticholinergic effects, sedation, other blood dyscrasias, and delirium [7]. Neutropenia is the most common life-threatening side effect of clozapine use, and an absolute neutrophil count of less than one thousand and five hundred/mm can result in increased chance of infection when the immune system does not have the needed neutrophil capacity to challenge the infection [7]. Such side effects necessitate close monitoring of blood results and suspicion of any new onset physical changes or symptoms. The incidence of agranulocytosis and neutropenia is the highest within the first six to eighteen weeks of commencing clozapine [8]. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine, preexisting benign inherited neutropenia, and human leukocyte antigen haplotypes [7, 9]. The mechanism behind clozapine-induced agranulocytosis and neutropenia is currently unclear, although studies have shown that there are genetic factors at play [10].
Certain phenotypes may take years to manifest, and this may partly explain neutropenia that develops in long-term users of clozapine [11]. In addition, there are multiple proposed immunological mechanisms leading to leukocyte depletion [10]. Neutropenia may also be due to extrinsic causes, for example, specific antibiotic groups, compounded by clozapine use [10].
Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [12]. Filgrastim works most effectively when prescribed prophylactically [12]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [12]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date. This case provides an insight into the challenges clinicians and clients face managing late onset neutropenia in clozapine use as indicated for treatment-resistant schizophrenia.
2. Case Presentation
A 41-year-old female with treatment-resistant schizophrenia was admitted to an acute mental health unit in Ireland due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia (red light), with an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Deterioration in her mental state began to manifest day five postclozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep. Paliperidone resulted in a lack of improvement to the mental state, and her symptoms remained troubling. Our patient was observed to exhibit vague paranoid thinking, was guarded on interaction, and seemed anxious with pressured speech. This was noted to be in keeping with previous relapses.
The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes. Prior to this first neutropenic episode, our patient maintained reasonable levels of social functioning and was in the process of completing a night-time college course while utilizing previous qualifications in a volunteering capacity by day. She lived independently and in her free time was physically active and a nonsmoker, with a keen interest in running and participation in distance running events. She had coped well with the loss of her mother a few years previously.
A diagnosis of schizophrenia was established for this lady at the age of twenty-six with symptoms of paranoia, odd behaviors, and beliefs. She was commenced on clozapine in that same year as an in-patient following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. There was no contributing family history of psychosis. Episodes of clozapine-induced neutropenia posed a risk to continued use of clozapine, which had aided her in leading a fulfilling and busy lifestyle to date.
3. Investigations
Differential causes for deterioration in the mental state and/or neutropenia were ruled out. Full physical examination was performed with blood testing to rule out infection or other disease processes impacting immunity or hematopoiesis. This patient had never experienced neutropenic episodes prior to starting clozapine and for many years while taking clozapine which ruled out a cause of cyclic neutropenia or any other genetic conditions. The patient had full viral and autoimmune blood screening completed which produced negative results. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained via trephine biopsy which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.
4. Treatment
Following admission in late January, our patient remained neutropenic for a number of weeks. To correct her white blood cell count filgrastim, G-CSF (Neupogen) 30 MU was prescribed on February eleventh while an in-patient (Figure 1). This resulted in a white cell count which increased from 3.4 × 109/L to 6.5 × 109/L and ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. Filgrastim was prescribed in conjunction with in-house hematology advice and administered by the nursing staff. One month posttreatment with Neupogen, our patient's white cells fell once again to 2.4 with ANC of 1.64 × 109/L which required a further dose of filgrastim. Lithium was started in March 2018 in an attempt to increase and maintain leukocyte counts. Lithium 800 mg once daily seemed to result in an improvement in our patient's leukocyte count averaging between 3.3 × 109/L and 4.4 × 109/L. Initially, efforts were made to avoid a clozapine rechallenge but combination antipsychotic treatment proved to be ineffective, and our patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while she remained an in-patient.
The patient responded well to clozapine rechallenge, and hematology specialists advised on safe reinstatement of clozapine. Unfortunately, clozapine use continued to cause recurrent neutropenic results (Figure 1). Discontinuation of clozapine consequently lead to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.
A filgrastim treatment protocol was created for our patient as part of a multidisciplinary approach, commencement of which corresponded with a period of baseline ANC stability (Figure 2). Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol was developed with hematology input to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment has been achieved (Figure 3). This lady's current prescription of filgrastim is 30 MU up to three times per week.
5. Outcome and Follow-Up
Although the initial incident of neutropenia does indicate an increased risk of further neutropenic episodes, maintenance of mental health and social functioning is an achievable priority for our patient at the current time. She is utilizing biweekly filgrastim prophylactically. This regimen in combination with lithium has maintained white cell and neutrophil count in the amber/green range and has thus far facilitated continuous use of clozapine over the past six months approximately. The patient has been counseled with regard to the possible short-term and long-term side effects of filgrastim, and the patient decided to continue the use of filgrastim which allows ongoing use of clozapine. Continued input of hematology is needed with regard to prophylactic use of filgrastim and its unclear risk of contributing to leukemia. With sustained and uninterrupted clozapine treatment, our patient's mental state has stabilized with mild residual symptoms.
6. Discussion
Research suggests that, on discontinuation of clozapine, neutropenia takes an average of fourteen to twenty-two days to resolve and can resolve spontaneously [8]. In the case discussed, consistent stability in leukocyte and neutrophil counts has been difficult. However, reference ranges above normal were achieved quickly in the days following each administration of filgrastim. In the literature, recommendations for persistent neutropenia include coprescription of lithium or GM-CSF with clozapine [8, 13]. Research into cases recommenced on clozapine and coprescribed GM-CSF has demonstrated a 78% success rate compared with coprescription of lithium which correlates with a 60% success rate [12]. Lithium works by increasing the WBC count by approximately 2 × 109/L, and the effectiveness of a low dosage of lithium avoids toxic effects. The exact mechanism by which lithium increases granulocytes is unknown. However, research has shown that this mechanism involves GM-CSF production as opposed to granulocyte redistribution from the bone marrow [14]. Myles et al. [12] recommend that GM-CSF can be used as a preventative measure during clozapine use.
Cytokines such as G-CSF and GM-CSF are effective in stimulating granulocyte production, which shortens the duration of agranulocytosis [14]. Bone marrow precursor cell levels need to be sufficient prior to cytokine use [12]. There is scope for coadministration of cytokines and lithium in severe neutropenia or refractory cases and conveniently, reliable patients can be coached to self-administer injections of G-CSF [12]. There is no known contraindication to the continuation of lithium treatment and regular filgrastim injections in conjunction with clozapine as part of long-term treatment [12].
Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count [15]. Past criteria have proven too rigid, resulting in patients avoiding retrial of clozapine in treatment-resistant schizophrenia [15]. Mild-moderate cases of neutropenia have been shown to be a common and benign finding [15].
7. Learning Points/Take Home Messages
Late-onset neutropenia is a risk of long-term clozapine use; therefore, vigilance is always required, and guidelines should be followed in anticipation of this event
Filgrastim can be used safely to maintain neutrophil levels, in addition to lithium and clozapine
Schedules of filgrastim can be individualized with expert input from hematology and close monitoring
Data Availability
Data used to support the findings of this study are included within the article.
Additional Points
Adapted from patient. I was worried that the blood levels would not become normal, and that I would have to stop taking clozapine. It had suited me up until there was a problem with my blood levels. I was able to enjoy life. I am relieved that with my current medications, I can continue to take clozapine, and I have been able to renew my interests since. I am happy for my case to be shared in this report if it helps others who may have a similar problem taking clozapine.
Ethical Approval
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008. The authors assert that ethical approval for publication of this case report was not required by their local ethics committee.
Disclosure
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors, Dr. Eimear O' Neill, Dr. Deirdre Carolan, Dr. Sarah Anne Kennedy, and Dr. Sandra Barry, do not have any conflicts of interest to report.
Figure 1 Neutrophil serum level from 22nd of January to 10th of December 2018. Figure 1 displays the neutrophil level by serum testing from 22nd of January to 10th of December 2018. The x axis demonstrates dates of sampling, and the y axis corresponds with absolute neutrophil count (ANC) ×109/L. Initially, there is a period of neutropenia (1.0 × 109/L-2.0 × 109/L). Filgrastim, G-CSF 30 MU, was prescribed on February 10th resulting in an ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. A further neutropenic episode occurred on March 4th with ANC 1.64 × 109/L. Lithium was commenced on March 10th. Clozapine rechallenge in September corresponded with further deterioration in ANC measurements prompting close liaison with hematology to devise a filgrastim treatment protocol.
Figure 2 Neutrophil serum level from 2nd of January to 20th of September 2019. Figure 2 displays the neutrophil level by serum testing from 2nd January to 20th September 2019. The x axis demonstrates dates of sampling, and the y axis corresponds with the absolute neutrophil count ×109/L. Commencement of the filgrastim treatment protocol in March 2019 corresponds with a period of stability in baseline ANC with fewer episodes of neutropenia. Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol developed to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result.
Figure 3 Administration of filgrastim resulting in increases in neutrophil levels. Figure 3 demonstrates the administration of filgrastim 30 MU, given as needed in response to neutropenia occurring from March 2019, in keeping with the patient specific protocol supported by hematology. The x axis shows the timeline of the filgrastim administration, and the y axis displays the absolute neutrophil count ×109/L. The blue columns represent the ANC prior to giving filgrastim, and the orange columns represent ANCs one day postfilgrastim administration. Green light results indicating safe ANCs are seen from July 2019 utilizing prophylactic filgrastim up to three times weekly. | HALOPERIDOL, OLANZAPINE, QUETIAPINE | DrugsGivenReaction | CC BY | 33575054 | 18,965,251 | 2021 |
What was the dosage of drug 'PALIPERIDONE'? | Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF.
This case outlines recurrent neutropenia after fourteen years of successful clozapine use. The patient has a diagnosis of treatment-resistant schizophrenia which has been complicated by sensitivity to side effects of haloperidol and past failure of antipsychotics to manage her symptoms. It was necessary for our patient to follow a complicated treatment path involving close monitoring of blood levels, admissions, the initiation of lithium and the regular use of filgrastim (Neupogen), granulocyte colony stimulating factor (G-CSF). Following a failure of rescue filgrastim to increase her neutrophil levels, a management protocol was designed with input from the on-site hematology team. This protocol involved the use of filgrastim on a regular prophylactic basis. This management plan has worked for the patient who has been able to continue use of clozapine and has not suffered from any neutropenic episodes in over six months.
1. Background
Treatment-resistant schizophrenia is an enduring and challenging illness which affects twenty to thirty-three percent of the treatment-resistant population or one third of patients with schizophrenia [1, 2]. Treatment-resistant schizophrenia is a pervasive disorder known to cause challenges in management for treating clinicians in psychiatric practice.
Treatment resistance is due to the limited variety of antipsychotic treatments and can result in much personal, social, and economic burden [3]. In attempting to solve the problem of resistance associated with antipsychotic treatment, clozapine has become the gold standard and has been shown to benefit the achievement and maintenance of stability in patients with treatment-resistant schizophrenia [4].
Clozapine's ability to work on various molecular targets, including 5HT2A, a1-adrenergic, muscarinic, D1, and D2, has the advantage of improve efficacy and reliability in treating psychosis when compared with more classic treatments [5].
However, in keeping with this broad mechanism of action, clozapine is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures [6]. Other possible side effects include metabolic syndrome, anticholinergic effects, sedation, other blood dyscrasias, and delirium [7]. Neutropenia is the most common life-threatening side effect of clozapine use, and an absolute neutrophil count of less than one thousand and five hundred/mm can result in increased chance of infection when the immune system does not have the needed neutrophil capacity to challenge the infection [7]. Such side effects necessitate close monitoring of blood results and suspicion of any new onset physical changes or symptoms. The incidence of agranulocytosis and neutropenia is the highest within the first six to eighteen weeks of commencing clozapine [8]. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine, preexisting benign inherited neutropenia, and human leukocyte antigen haplotypes [7, 9]. The mechanism behind clozapine-induced agranulocytosis and neutropenia is currently unclear, although studies have shown that there are genetic factors at play [10].
Certain phenotypes may take years to manifest, and this may partly explain neutropenia that develops in long-term users of clozapine [11]. In addition, there are multiple proposed immunological mechanisms leading to leukocyte depletion [10]. Neutropenia may also be due to extrinsic causes, for example, specific antibiotic groups, compounded by clozapine use [10].
Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [12]. Filgrastim works most effectively when prescribed prophylactically [12]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [12]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date. This case provides an insight into the challenges clinicians and clients face managing late onset neutropenia in clozapine use as indicated for treatment-resistant schizophrenia.
2. Case Presentation
A 41-year-old female with treatment-resistant schizophrenia was admitted to an acute mental health unit in Ireland due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia (red light), with an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Deterioration in her mental state began to manifest day five postclozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep. Paliperidone resulted in a lack of improvement to the mental state, and her symptoms remained troubling. Our patient was observed to exhibit vague paranoid thinking, was guarded on interaction, and seemed anxious with pressured speech. This was noted to be in keeping with previous relapses.
The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes. Prior to this first neutropenic episode, our patient maintained reasonable levels of social functioning and was in the process of completing a night-time college course while utilizing previous qualifications in a volunteering capacity by day. She lived independently and in her free time was physically active and a nonsmoker, with a keen interest in running and participation in distance running events. She had coped well with the loss of her mother a few years previously.
A diagnosis of schizophrenia was established for this lady at the age of twenty-six with symptoms of paranoia, odd behaviors, and beliefs. She was commenced on clozapine in that same year as an in-patient following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. There was no contributing family history of psychosis. Episodes of clozapine-induced neutropenia posed a risk to continued use of clozapine, which had aided her in leading a fulfilling and busy lifestyle to date.
3. Investigations
Differential causes for deterioration in the mental state and/or neutropenia were ruled out. Full physical examination was performed with blood testing to rule out infection or other disease processes impacting immunity or hematopoiesis. This patient had never experienced neutropenic episodes prior to starting clozapine and for many years while taking clozapine which ruled out a cause of cyclic neutropenia or any other genetic conditions. The patient had full viral and autoimmune blood screening completed which produced negative results. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained via trephine biopsy which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.
4. Treatment
Following admission in late January, our patient remained neutropenic for a number of weeks. To correct her white blood cell count filgrastim, G-CSF (Neupogen) 30 MU was prescribed on February eleventh while an in-patient (Figure 1). This resulted in a white cell count which increased from 3.4 × 109/L to 6.5 × 109/L and ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. Filgrastim was prescribed in conjunction with in-house hematology advice and administered by the nursing staff. One month posttreatment with Neupogen, our patient's white cells fell once again to 2.4 with ANC of 1.64 × 109/L which required a further dose of filgrastim. Lithium was started in March 2018 in an attempt to increase and maintain leukocyte counts. Lithium 800 mg once daily seemed to result in an improvement in our patient's leukocyte count averaging between 3.3 × 109/L and 4.4 × 109/L. Initially, efforts were made to avoid a clozapine rechallenge but combination antipsychotic treatment proved to be ineffective, and our patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while she remained an in-patient.
The patient responded well to clozapine rechallenge, and hematology specialists advised on safe reinstatement of clozapine. Unfortunately, clozapine use continued to cause recurrent neutropenic results (Figure 1). Discontinuation of clozapine consequently lead to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.
A filgrastim treatment protocol was created for our patient as part of a multidisciplinary approach, commencement of which corresponded with a period of baseline ANC stability (Figure 2). Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol was developed with hematology input to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment has been achieved (Figure 3). This lady's current prescription of filgrastim is 30 MU up to three times per week.
5. Outcome and Follow-Up
Although the initial incident of neutropenia does indicate an increased risk of further neutropenic episodes, maintenance of mental health and social functioning is an achievable priority for our patient at the current time. She is utilizing biweekly filgrastim prophylactically. This regimen in combination with lithium has maintained white cell and neutrophil count in the amber/green range and has thus far facilitated continuous use of clozapine over the past six months approximately. The patient has been counseled with regard to the possible short-term and long-term side effects of filgrastim, and the patient decided to continue the use of filgrastim which allows ongoing use of clozapine. Continued input of hematology is needed with regard to prophylactic use of filgrastim and its unclear risk of contributing to leukemia. With sustained and uninterrupted clozapine treatment, our patient's mental state has stabilized with mild residual symptoms.
6. Discussion
Research suggests that, on discontinuation of clozapine, neutropenia takes an average of fourteen to twenty-two days to resolve and can resolve spontaneously [8]. In the case discussed, consistent stability in leukocyte and neutrophil counts has been difficult. However, reference ranges above normal were achieved quickly in the days following each administration of filgrastim. In the literature, recommendations for persistent neutropenia include coprescription of lithium or GM-CSF with clozapine [8, 13]. Research into cases recommenced on clozapine and coprescribed GM-CSF has demonstrated a 78% success rate compared with coprescription of lithium which correlates with a 60% success rate [12]. Lithium works by increasing the WBC count by approximately 2 × 109/L, and the effectiveness of a low dosage of lithium avoids toxic effects. The exact mechanism by which lithium increases granulocytes is unknown. However, research has shown that this mechanism involves GM-CSF production as opposed to granulocyte redistribution from the bone marrow [14]. Myles et al. [12] recommend that GM-CSF can be used as a preventative measure during clozapine use.
Cytokines such as G-CSF and GM-CSF are effective in stimulating granulocyte production, which shortens the duration of agranulocytosis [14]. Bone marrow precursor cell levels need to be sufficient prior to cytokine use [12]. There is scope for coadministration of cytokines and lithium in severe neutropenia or refractory cases and conveniently, reliable patients can be coached to self-administer injections of G-CSF [12]. There is no known contraindication to the continuation of lithium treatment and regular filgrastim injections in conjunction with clozapine as part of long-term treatment [12].
Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count [15]. Past criteria have proven too rigid, resulting in patients avoiding retrial of clozapine in treatment-resistant schizophrenia [15]. Mild-moderate cases of neutropenia have been shown to be a common and benign finding [15].
7. Learning Points/Take Home Messages
Late-onset neutropenia is a risk of long-term clozapine use; therefore, vigilance is always required, and guidelines should be followed in anticipation of this event
Filgrastim can be used safely to maintain neutrophil levels, in addition to lithium and clozapine
Schedules of filgrastim can be individualized with expert input from hematology and close monitoring
Data Availability
Data used to support the findings of this study are included within the article.
Additional Points
Adapted from patient. I was worried that the blood levels would not become normal, and that I would have to stop taking clozapine. It had suited me up until there was a problem with my blood levels. I was able to enjoy life. I am relieved that with my current medications, I can continue to take clozapine, and I have been able to renew my interests since. I am happy for my case to be shared in this report if it helps others who may have a similar problem taking clozapine.
Ethical Approval
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008. The authors assert that ethical approval for publication of this case report was not required by their local ethics committee.
Disclosure
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors, Dr. Eimear O' Neill, Dr. Deirdre Carolan, Dr. Sarah Anne Kennedy, and Dr. Sandra Barry, do not have any conflicts of interest to report.
Figure 1 Neutrophil serum level from 22nd of January to 10th of December 2018. Figure 1 displays the neutrophil level by serum testing from 22nd of January to 10th of December 2018. The x axis demonstrates dates of sampling, and the y axis corresponds with absolute neutrophil count (ANC) ×109/L. Initially, there is a period of neutropenia (1.0 × 109/L-2.0 × 109/L). Filgrastim, G-CSF 30 MU, was prescribed on February 10th resulting in an ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. A further neutropenic episode occurred on March 4th with ANC 1.64 × 109/L. Lithium was commenced on March 10th. Clozapine rechallenge in September corresponded with further deterioration in ANC measurements prompting close liaison with hematology to devise a filgrastim treatment protocol.
Figure 2 Neutrophil serum level from 2nd of January to 20th of September 2019. Figure 2 displays the neutrophil level by serum testing from 2nd January to 20th September 2019. The x axis demonstrates dates of sampling, and the y axis corresponds with the absolute neutrophil count ×109/L. Commencement of the filgrastim treatment protocol in March 2019 corresponds with a period of stability in baseline ANC with fewer episodes of neutropenia. Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol developed to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result.
Figure 3 Administration of filgrastim resulting in increases in neutrophil levels. Figure 3 demonstrates the administration of filgrastim 30 MU, given as needed in response to neutropenia occurring from March 2019, in keeping with the patient specific protocol supported by hematology. The x axis shows the timeline of the filgrastim administration, and the y axis displays the absolute neutrophil count ×109/L. The blue columns represent the ANC prior to giving filgrastim, and the orange columns represent ANCs one day postfilgrastim administration. Green light results indicating safe ANCs are seen from July 2019 utilizing prophylactic filgrastim up to three times weekly. | DOSE INCREASED | DrugDosageText | CC BY | 33575054 | 18,985,980 | 2021 |
What was the dosage of drug 'ZOPICLONE'? | Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF.
This case outlines recurrent neutropenia after fourteen years of successful clozapine use. The patient has a diagnosis of treatment-resistant schizophrenia which has been complicated by sensitivity to side effects of haloperidol and past failure of antipsychotics to manage her symptoms. It was necessary for our patient to follow a complicated treatment path involving close monitoring of blood levels, admissions, the initiation of lithium and the regular use of filgrastim (Neupogen), granulocyte colony stimulating factor (G-CSF). Following a failure of rescue filgrastim to increase her neutrophil levels, a management protocol was designed with input from the on-site hematology team. This protocol involved the use of filgrastim on a regular prophylactic basis. This management plan has worked for the patient who has been able to continue use of clozapine and has not suffered from any neutropenic episodes in over six months.
1. Background
Treatment-resistant schizophrenia is an enduring and challenging illness which affects twenty to thirty-three percent of the treatment-resistant population or one third of patients with schizophrenia [1, 2]. Treatment-resistant schizophrenia is a pervasive disorder known to cause challenges in management for treating clinicians in psychiatric practice.
Treatment resistance is due to the limited variety of antipsychotic treatments and can result in much personal, social, and economic burden [3]. In attempting to solve the problem of resistance associated with antipsychotic treatment, clozapine has become the gold standard and has been shown to benefit the achievement and maintenance of stability in patients with treatment-resistant schizophrenia [4].
Clozapine's ability to work on various molecular targets, including 5HT2A, a1-adrenergic, muscarinic, D1, and D2, has the advantage of improve efficacy and reliability in treating psychosis when compared with more classic treatments [5].
However, in keeping with this broad mechanism of action, clozapine is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures [6]. Other possible side effects include metabolic syndrome, anticholinergic effects, sedation, other blood dyscrasias, and delirium [7]. Neutropenia is the most common life-threatening side effect of clozapine use, and an absolute neutrophil count of less than one thousand and five hundred/mm can result in increased chance of infection when the immune system does not have the needed neutrophil capacity to challenge the infection [7]. Such side effects necessitate close monitoring of blood results and suspicion of any new onset physical changes or symptoms. The incidence of agranulocytosis and neutropenia is the highest within the first six to eighteen weeks of commencing clozapine [8]. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine, preexisting benign inherited neutropenia, and human leukocyte antigen haplotypes [7, 9]. The mechanism behind clozapine-induced agranulocytosis and neutropenia is currently unclear, although studies have shown that there are genetic factors at play [10].
Certain phenotypes may take years to manifest, and this may partly explain neutropenia that develops in long-term users of clozapine [11]. In addition, there are multiple proposed immunological mechanisms leading to leukocyte depletion [10]. Neutropenia may also be due to extrinsic causes, for example, specific antibiotic groups, compounded by clozapine use [10].
Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [12]. Filgrastim works most effectively when prescribed prophylactically [12]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [12]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date. This case provides an insight into the challenges clinicians and clients face managing late onset neutropenia in clozapine use as indicated for treatment-resistant schizophrenia.
2. Case Presentation
A 41-year-old female with treatment-resistant schizophrenia was admitted to an acute mental health unit in Ireland due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia (red light), with an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Deterioration in her mental state began to manifest day five postclozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep. Paliperidone resulted in a lack of improvement to the mental state, and her symptoms remained troubling. Our patient was observed to exhibit vague paranoid thinking, was guarded on interaction, and seemed anxious with pressured speech. This was noted to be in keeping with previous relapses.
The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes. Prior to this first neutropenic episode, our patient maintained reasonable levels of social functioning and was in the process of completing a night-time college course while utilizing previous qualifications in a volunteering capacity by day. She lived independently and in her free time was physically active and a nonsmoker, with a keen interest in running and participation in distance running events. She had coped well with the loss of her mother a few years previously.
A diagnosis of schizophrenia was established for this lady at the age of twenty-six with symptoms of paranoia, odd behaviors, and beliefs. She was commenced on clozapine in that same year as an in-patient following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. There was no contributing family history of psychosis. Episodes of clozapine-induced neutropenia posed a risk to continued use of clozapine, which had aided her in leading a fulfilling and busy lifestyle to date.
3. Investigations
Differential causes for deterioration in the mental state and/or neutropenia were ruled out. Full physical examination was performed with blood testing to rule out infection or other disease processes impacting immunity or hematopoiesis. This patient had never experienced neutropenic episodes prior to starting clozapine and for many years while taking clozapine which ruled out a cause of cyclic neutropenia or any other genetic conditions. The patient had full viral and autoimmune blood screening completed which produced negative results. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained via trephine biopsy which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.
4. Treatment
Following admission in late January, our patient remained neutropenic for a number of weeks. To correct her white blood cell count filgrastim, G-CSF (Neupogen) 30 MU was prescribed on February eleventh while an in-patient (Figure 1). This resulted in a white cell count which increased from 3.4 × 109/L to 6.5 × 109/L and ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. Filgrastim was prescribed in conjunction with in-house hematology advice and administered by the nursing staff. One month posttreatment with Neupogen, our patient's white cells fell once again to 2.4 with ANC of 1.64 × 109/L which required a further dose of filgrastim. Lithium was started in March 2018 in an attempt to increase and maintain leukocyte counts. Lithium 800 mg once daily seemed to result in an improvement in our patient's leukocyte count averaging between 3.3 × 109/L and 4.4 × 109/L. Initially, efforts were made to avoid a clozapine rechallenge but combination antipsychotic treatment proved to be ineffective, and our patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while she remained an in-patient.
The patient responded well to clozapine rechallenge, and hematology specialists advised on safe reinstatement of clozapine. Unfortunately, clozapine use continued to cause recurrent neutropenic results (Figure 1). Discontinuation of clozapine consequently lead to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.
A filgrastim treatment protocol was created for our patient as part of a multidisciplinary approach, commencement of which corresponded with a period of baseline ANC stability (Figure 2). Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol was developed with hematology input to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment has been achieved (Figure 3). This lady's current prescription of filgrastim is 30 MU up to three times per week.
5. Outcome and Follow-Up
Although the initial incident of neutropenia does indicate an increased risk of further neutropenic episodes, maintenance of mental health and social functioning is an achievable priority for our patient at the current time. She is utilizing biweekly filgrastim prophylactically. This regimen in combination with lithium has maintained white cell and neutrophil count in the amber/green range and has thus far facilitated continuous use of clozapine over the past six months approximately. The patient has been counseled with regard to the possible short-term and long-term side effects of filgrastim, and the patient decided to continue the use of filgrastim which allows ongoing use of clozapine. Continued input of hematology is needed with regard to prophylactic use of filgrastim and its unclear risk of contributing to leukemia. With sustained and uninterrupted clozapine treatment, our patient's mental state has stabilized with mild residual symptoms.
6. Discussion
Research suggests that, on discontinuation of clozapine, neutropenia takes an average of fourteen to twenty-two days to resolve and can resolve spontaneously [8]. In the case discussed, consistent stability in leukocyte and neutrophil counts has been difficult. However, reference ranges above normal were achieved quickly in the days following each administration of filgrastim. In the literature, recommendations for persistent neutropenia include coprescription of lithium or GM-CSF with clozapine [8, 13]. Research into cases recommenced on clozapine and coprescribed GM-CSF has demonstrated a 78% success rate compared with coprescription of lithium which correlates with a 60% success rate [12]. Lithium works by increasing the WBC count by approximately 2 × 109/L, and the effectiveness of a low dosage of lithium avoids toxic effects. The exact mechanism by which lithium increases granulocytes is unknown. However, research has shown that this mechanism involves GM-CSF production as opposed to granulocyte redistribution from the bone marrow [14]. Myles et al. [12] recommend that GM-CSF can be used as a preventative measure during clozapine use.
Cytokines such as G-CSF and GM-CSF are effective in stimulating granulocyte production, which shortens the duration of agranulocytosis [14]. Bone marrow precursor cell levels need to be sufficient prior to cytokine use [12]. There is scope for coadministration of cytokines and lithium in severe neutropenia or refractory cases and conveniently, reliable patients can be coached to self-administer injections of G-CSF [12]. There is no known contraindication to the continuation of lithium treatment and regular filgrastim injections in conjunction with clozapine as part of long-term treatment [12].
Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count [15]. Past criteria have proven too rigid, resulting in patients avoiding retrial of clozapine in treatment-resistant schizophrenia [15]. Mild-moderate cases of neutropenia have been shown to be a common and benign finding [15].
7. Learning Points/Take Home Messages
Late-onset neutropenia is a risk of long-term clozapine use; therefore, vigilance is always required, and guidelines should be followed in anticipation of this event
Filgrastim can be used safely to maintain neutrophil levels, in addition to lithium and clozapine
Schedules of filgrastim can be individualized with expert input from hematology and close monitoring
Data Availability
Data used to support the findings of this study are included within the article.
Additional Points
Adapted from patient. I was worried that the blood levels would not become normal, and that I would have to stop taking clozapine. It had suited me up until there was a problem with my blood levels. I was able to enjoy life. I am relieved that with my current medications, I can continue to take clozapine, and I have been able to renew my interests since. I am happy for my case to be shared in this report if it helps others who may have a similar problem taking clozapine.
Ethical Approval
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008. The authors assert that ethical approval for publication of this case report was not required by their local ethics committee.
Disclosure
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors, Dr. Eimear O' Neill, Dr. Deirdre Carolan, Dr. Sarah Anne Kennedy, and Dr. Sandra Barry, do not have any conflicts of interest to report.
Figure 1 Neutrophil serum level from 22nd of January to 10th of December 2018. Figure 1 displays the neutrophil level by serum testing from 22nd of January to 10th of December 2018. The x axis demonstrates dates of sampling, and the y axis corresponds with absolute neutrophil count (ANC) ×109/L. Initially, there is a period of neutropenia (1.0 × 109/L-2.0 × 109/L). Filgrastim, G-CSF 30 MU, was prescribed on February 10th resulting in an ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. A further neutropenic episode occurred on March 4th with ANC 1.64 × 109/L. Lithium was commenced on March 10th. Clozapine rechallenge in September corresponded with further deterioration in ANC measurements prompting close liaison with hematology to devise a filgrastim treatment protocol.
Figure 2 Neutrophil serum level from 2nd of January to 20th of September 2019. Figure 2 displays the neutrophil level by serum testing from 2nd January to 20th September 2019. The x axis demonstrates dates of sampling, and the y axis corresponds with the absolute neutrophil count ×109/L. Commencement of the filgrastim treatment protocol in March 2019 corresponds with a period of stability in baseline ANC with fewer episodes of neutropenia. Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol developed to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result.
Figure 3 Administration of filgrastim resulting in increases in neutrophil levels. Figure 3 demonstrates the administration of filgrastim 30 MU, given as needed in response to neutropenia occurring from March 2019, in keeping with the patient specific protocol supported by hematology. The x axis shows the timeline of the filgrastim administration, and the y axis displays the absolute neutrophil count ×109/L. The blue columns represent the ANC prior to giving filgrastim, and the orange columns represent ANCs one day postfilgrastim administration. Green light results indicating safe ANCs are seen from July 2019 utilizing prophylactic filgrastim up to three times weekly. | DOSE INCREASED | DrugDosageText | CC BY | 33575054 | 18,985,980 | 2021 |
What was the outcome of reaction 'Neutropenia'? | Late-Onset Neutropenia in Long-Term Clozapine Use and Its Management Utilizing Prophylactic G-CSF.
This case outlines recurrent neutropenia after fourteen years of successful clozapine use. The patient has a diagnosis of treatment-resistant schizophrenia which has been complicated by sensitivity to side effects of haloperidol and past failure of antipsychotics to manage her symptoms. It was necessary for our patient to follow a complicated treatment path involving close monitoring of blood levels, admissions, the initiation of lithium and the regular use of filgrastim (Neupogen), granulocyte colony stimulating factor (G-CSF). Following a failure of rescue filgrastim to increase her neutrophil levels, a management protocol was designed with input from the on-site hematology team. This protocol involved the use of filgrastim on a regular prophylactic basis. This management plan has worked for the patient who has been able to continue use of clozapine and has not suffered from any neutropenic episodes in over six months.
1. Background
Treatment-resistant schizophrenia is an enduring and challenging illness which affects twenty to thirty-three percent of the treatment-resistant population or one third of patients with schizophrenia [1, 2]. Treatment-resistant schizophrenia is a pervasive disorder known to cause challenges in management for treating clinicians in psychiatric practice.
Treatment resistance is due to the limited variety of antipsychotic treatments and can result in much personal, social, and economic burden [3]. In attempting to solve the problem of resistance associated with antipsychotic treatment, clozapine has become the gold standard and has been shown to benefit the achievement and maintenance of stability in patients with treatment-resistant schizophrenia [4].
Clozapine's ability to work on various molecular targets, including 5HT2A, a1-adrenergic, muscarinic, D1, and D2, has the advantage of improve efficacy and reliability in treating psychosis when compared with more classic treatments [5].
However, in keeping with this broad mechanism of action, clozapine is also associated with increased risk of serious side effects including neutropenia, agranulocytosis, myocarditis, pericarditis, bowel obstruction, and seizures [6]. Other possible side effects include metabolic syndrome, anticholinergic effects, sedation, other blood dyscrasias, and delirium [7]. Neutropenia is the most common life-threatening side effect of clozapine use, and an absolute neutrophil count of less than one thousand and five hundred/mm can result in increased chance of infection when the immune system does not have the needed neutrophil capacity to challenge the infection [7]. Such side effects necessitate close monitoring of blood results and suspicion of any new onset physical changes or symptoms. The incidence of agranulocytosis and neutropenia is the highest within the first six to eighteen weeks of commencing clozapine [8]. Further risk factors may include dosage of clozapine used, female gender, use of certain medications in addition to clozapine, preexisting benign inherited neutropenia, and human leukocyte antigen haplotypes [7, 9]. The mechanism behind clozapine-induced agranulocytosis and neutropenia is currently unclear, although studies have shown that there are genetic factors at play [10].
Certain phenotypes may take years to manifest, and this may partly explain neutropenia that develops in long-term users of clozapine [11]. In addition, there are multiple proposed immunological mechanisms leading to leukocyte depletion [10]. Neutropenia may also be due to extrinsic causes, for example, specific antibiotic groups, compounded by clozapine use [10].
Research has shown that filgrastim can be used with lithium to induce neutrophilia in patients with clozapine-induced neutropenia [12]. Filgrastim works most effectively when prescribed prophylactically [12]. It is important that hematology specialists are involved, patient education is advocated, and blood monitoring is adhered to in utilizing such strategies to avoid neutropenia [12]. There has been limited published data on the use of regular dosing of filgrastim in the management of clozapine-induced neutropenia in Ireland to date. This case provides an insight into the challenges clinicians and clients face managing late onset neutropenia in clozapine use as indicated for treatment-resistant schizophrenia.
2. Case Presentation
A 41-year-old female with treatment-resistant schizophrenia was admitted to an acute mental health unit in Ireland due to deterioration in her mental state. This was secondary to discontinuation of treatment with clozapine (600 mg per day) twelve days previously when routine blood monitoring indicated neutropenia (red light), with an absolute neutrophil count (ANC) of less than 0.5 × 109/L. Deterioration in her mental state began to manifest day five postclozapine discontinuation, despite starting and increasing doses of paliperidone and zopiclone to aide sleep. Paliperidone resulted in a lack of improvement to the mental state, and her symptoms remained troubling. Our patient was observed to exhibit vague paranoid thinking, was guarded on interaction, and seemed anxious with pressured speech. This was noted to be in keeping with previous relapses.
The patient had been taking clozapine with full compliance, no admissions and stable mental state for fourteen years, and without previous neutropenic episodes. Prior to this first neutropenic episode, our patient maintained reasonable levels of social functioning and was in the process of completing a night-time college course while utilizing previous qualifications in a volunteering capacity by day. She lived independently and in her free time was physically active and a nonsmoker, with a keen interest in running and participation in distance running events. She had coped well with the loss of her mother a few years previously.
A diagnosis of schizophrenia was established for this lady at the age of twenty-six with symptoms of paranoia, odd behaviors, and beliefs. She was commenced on clozapine in that same year as an in-patient following failure of olanzapine, haloperidol, and quetiapine to improve her symptoms. There was no contributing family history of psychosis. Episodes of clozapine-induced neutropenia posed a risk to continued use of clozapine, which had aided her in leading a fulfilling and busy lifestyle to date.
3. Investigations
Differential causes for deterioration in the mental state and/or neutropenia were ruled out. Full physical examination was performed with blood testing to rule out infection or other disease processes impacting immunity or hematopoiesis. This patient had never experienced neutropenic episodes prior to starting clozapine and for many years while taking clozapine which ruled out a cause of cyclic neutropenia or any other genetic conditions. The patient had full viral and autoimmune blood screening completed which produced negative results. Prior to commencing prophylactic use of filgrastim, a bone marrow aspirate was obtained via trephine biopsy which showed some mild reactive changes thought to be secondary to use of rescue filgrastim.
4. Treatment
Following admission in late January, our patient remained neutropenic for a number of weeks. To correct her white blood cell count filgrastim, G-CSF (Neupogen) 30 MU was prescribed on February eleventh while an in-patient (Figure 1). This resulted in a white cell count which increased from 3.4 × 109/L to 6.5 × 109/L and ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. Filgrastim was prescribed in conjunction with in-house hematology advice and administered by the nursing staff. One month posttreatment with Neupogen, our patient's white cells fell once again to 2.4 with ANC of 1.64 × 109/L which required a further dose of filgrastim. Lithium was started in March 2018 in an attempt to increase and maintain leukocyte counts. Lithium 800 mg once daily seemed to result in an improvement in our patient's leukocyte count averaging between 3.3 × 109/L and 4.4 × 109/L. Initially, efforts were made to avoid a clozapine rechallenge but combination antipsychotic treatment proved to be ineffective, and our patient's mental state continued to deteriorate. Thus, clozapine rechallenge was reconsidered while she remained an in-patient.
The patient responded well to clozapine rechallenge, and hematology specialists advised on safe reinstatement of clozapine. Unfortunately, clozapine use continued to cause recurrent neutropenic results (Figure 1). Discontinuation of clozapine consequently lead to an acute deterioration in the mental state that began to manifest within 24-48 hours. As a result, treatment aims shifted over time with the need to minimize time off clozapine treatment being superseded by the need to maintain continuous clozapine treatment.
A filgrastim treatment protocol was created for our patient as part of a multidisciplinary approach, commencement of which corresponded with a period of baseline ANC stability (Figure 2). Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol was developed with hematology input to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result. It was only with this latter prophylactic use of filgrastim that continuous maintenance of clozapine treatment has been achieved (Figure 3). This lady's current prescription of filgrastim is 30 MU up to three times per week.
5. Outcome and Follow-Up
Although the initial incident of neutropenia does indicate an increased risk of further neutropenic episodes, maintenance of mental health and social functioning is an achievable priority for our patient at the current time. She is utilizing biweekly filgrastim prophylactically. This regimen in combination with lithium has maintained white cell and neutrophil count in the amber/green range and has thus far facilitated continuous use of clozapine over the past six months approximately. The patient has been counseled with regard to the possible short-term and long-term side effects of filgrastim, and the patient decided to continue the use of filgrastim which allows ongoing use of clozapine. Continued input of hematology is needed with regard to prophylactic use of filgrastim and its unclear risk of contributing to leukemia. With sustained and uninterrupted clozapine treatment, our patient's mental state has stabilized with mild residual symptoms.
6. Discussion
Research suggests that, on discontinuation of clozapine, neutropenia takes an average of fourteen to twenty-two days to resolve and can resolve spontaneously [8]. In the case discussed, consistent stability in leukocyte and neutrophil counts has been difficult. However, reference ranges above normal were achieved quickly in the days following each administration of filgrastim. In the literature, recommendations for persistent neutropenia include coprescription of lithium or GM-CSF with clozapine [8, 13]. Research into cases recommenced on clozapine and coprescribed GM-CSF has demonstrated a 78% success rate compared with coprescription of lithium which correlates with a 60% success rate [12]. Lithium works by increasing the WBC count by approximately 2 × 109/L, and the effectiveness of a low dosage of lithium avoids toxic effects. The exact mechanism by which lithium increases granulocytes is unknown. However, research has shown that this mechanism involves GM-CSF production as opposed to granulocyte redistribution from the bone marrow [14]. Myles et al. [12] recommend that GM-CSF can be used as a preventative measure during clozapine use.
Cytokines such as G-CSF and GM-CSF are effective in stimulating granulocyte production, which shortens the duration of agranulocytosis [14]. Bone marrow precursor cell levels need to be sufficient prior to cytokine use [12]. There is scope for coadministration of cytokines and lithium in severe neutropenia or refractory cases and conveniently, reliable patients can be coached to self-administer injections of G-CSF [12]. There is no known contraindication to the continuation of lithium treatment and regular filgrastim injections in conjunction with clozapine as part of long-term treatment [12].
Best practice will continue to change in an attempt to avoid and treat clozapine-induced neutropenia. Recent research debates the need to consider intervention in cases of mild-moderate neutropenia, and the latest FDA guidelines, 2015, recommend that neutropenia be monitored using absolute neutrophil count only without surveillance of the total white cell count [15]. Past criteria have proven too rigid, resulting in patients avoiding retrial of clozapine in treatment-resistant schizophrenia [15]. Mild-moderate cases of neutropenia have been shown to be a common and benign finding [15].
7. Learning Points/Take Home Messages
Late-onset neutropenia is a risk of long-term clozapine use; therefore, vigilance is always required, and guidelines should be followed in anticipation of this event
Filgrastim can be used safely to maintain neutrophil levels, in addition to lithium and clozapine
Schedules of filgrastim can be individualized with expert input from hematology and close monitoring
Data Availability
Data used to support the findings of this study are included within the article.
Additional Points
Adapted from patient. I was worried that the blood levels would not become normal, and that I would have to stop taking clozapine. It had suited me up until there was a problem with my blood levels. I was able to enjoy life. I am relieved that with my current medications, I can continue to take clozapine, and I have been able to renew my interests since. I am happy for my case to be shared in this report if it helps others who may have a similar problem taking clozapine.
Ethical Approval
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008. The authors assert that ethical approval for publication of this case report was not required by their local ethics committee.
Disclosure
This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of Interest
The authors, Dr. Eimear O' Neill, Dr. Deirdre Carolan, Dr. Sarah Anne Kennedy, and Dr. Sandra Barry, do not have any conflicts of interest to report.
Figure 1 Neutrophil serum level from 22nd of January to 10th of December 2018. Figure 1 displays the neutrophil level by serum testing from 22nd of January to 10th of December 2018. The x axis demonstrates dates of sampling, and the y axis corresponds with absolute neutrophil count (ANC) ×109/L. Initially, there is a period of neutropenia (1.0 × 109/L-2.0 × 109/L). Filgrastim, G-CSF 30 MU, was prescribed on February 10th resulting in an ANC which increased from 1.78 × 109/L to 4.8 × 109/L one day later. A further neutropenic episode occurred on March 4th with ANC 1.64 × 109/L. Lithium was commenced on March 10th. Clozapine rechallenge in September corresponded with further deterioration in ANC measurements prompting close liaison with hematology to devise a filgrastim treatment protocol.
Figure 2 Neutrophil serum level from 2nd of January to 20th of September 2019. Figure 2 displays the neutrophil level by serum testing from 2nd January to 20th September 2019. The x axis demonstrates dates of sampling, and the y axis corresponds with the absolute neutrophil count ×109/L. Commencement of the filgrastim treatment protocol in March 2019 corresponds with a period of stability in baseline ANC with fewer episodes of neutropenia. Initially, hematology supported use of filgrastim if red light monitoring result was received. This protocol developed to include use of filgrastim given an amber light result and ultimately biweekly prophylactic use of filgrastim to avoid a red light result.
Figure 3 Administration of filgrastim resulting in increases in neutrophil levels. Figure 3 demonstrates the administration of filgrastim 30 MU, given as needed in response to neutropenia occurring from March 2019, in keeping with the patient specific protocol supported by hematology. The x axis shows the timeline of the filgrastim administration, and the y axis displays the absolute neutrophil count ×109/L. The blue columns represent the ANC prior to giving filgrastim, and the orange columns represent ANCs one day postfilgrastim administration. Green light results indicating safe ANCs are seen from July 2019 utilizing prophylactic filgrastim up to three times weekly. | Recovered | ReactionOutcome | CC BY | 33575054 | 18,985,980 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'COVID-19'. | SARS-CoV-2 Infection (COVID-19) and Herpes Simplex Virus-1 Conjunctivitis: Concurrent Viral Infections or a Cause-Effect Result?
The pulmonary effects of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease (COVID-19), are well documented; however, more evidence is needed to understand its effect on multiple organ systems. We present the case of a 69-year-old male with dyspnea for two weeks and bilateral conjunctivitis who tested positive for SARS-CoV-2. He was found to be hypoxic, requiring supplemental oxygen. On hospital day two, he complained of worsening left eye pain with the development of a left lower eyelid ulcer. He underwent a CT of facial bones, which showed findings consistent with pre-septal cellulitis and abscess. Samples from bilateral conjunctival secretions and left lower eyelid ulcer tested positive for herpes simplex virus-1 (HSV-1), and negative for SARS-CoV-2. He received supportive care, antibiotics, and famciclovir with almost complete resolution of his ocular complaints. This case illustrates an atypical COVID-19 presentation and raises concern as to how this virus modulates the immune system, allowing for concurrent viral infections.
Introduction
Coronavirus disease 2019 (COVID-19) is primarily a respiratory infection; however, it is now known to affect multiple organs, including the eye [1]. Due to the novelty of the virus, there are scarce data on COVID-19-related ocular infections in the medical literature. One study conducted in China noted that 31.6% of COVID-19-infected patients had ocular manifestations consistent with conjunctivitis [2]. However, the initial presentation of COVID-19 being an ocular manifestation seems rare. Other viruses such as herpes simplex are known to commonly present with ocular manifestations, with the latter having an annual incidence of 11.8 new cases for every 100,000 population [3]. In fact, the reactivation of latent herpes simplex virus (HSV) in the sensory ganglia may lead to initial or recurrent disease, typically monocular [3].
Case presentation
A 69-year-old Caucasian male with a medical history of type II diabetes mellitus, coronary artery disease, peripheral arterial disease, and stage III squamous cell lung cancer receiving weekly docetaxel presented to the ER in March 2020 with complaints of progressive dyspnea, cough, and scant white sputum for 14 days. He was a personal care aide who worked in a rehabilitation facility where multiple staff and patients had tested positive for COVID-19. Upon presentation, he was afebrile, normotensive, and hypoxemic, requiring 2 liters of oxygen via nasal cannula. He also reported bilateral eye pain, more significant in the left eye than the right, with associated bilateral conjunctival erythema, pruritus, chemosis, and foreign body sensation. He denied any blurry vision, changes in visual acuity, or previous ocular problems. Of note, the patient was enrolled in a double-blinded, randomized placebo-controlled trial with sarilumab on hospital day two (illness day 15) for the management of COVID-19. The patient electively self-withdrew from the trial three days post-infusion (drug versus placebo) administration due to personal reasons, unrelated to any safety concerns.
The patient tested positive for COVID-19 via a nasopharyngeal swab polymerase chain reaction (PCR). Laboratory workup revealed a normal white blood cell count, with normal neutrophil and lymphocyte counts. However, mild thrombocytopenia and vitamin D deficiency were noted. He presented with mild to moderate elevation in C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 level. His procalcitonin level, however, was mildly elevated (Table 1).
Table 1 Lab values at admission
Laboratory test Value at admission (reference range)
C-reactive protein 12.09 mg/dL (<0.5 mg/dL)
D-Dimer 2.0 mg/L (<0.5 mg/L)
Ferritin 824 ng/mL (21.81–274.66 ng/mL)
Hemoglobin A1c 8.3% (4.0–6.5%)
Interleukin 6 59 pg/mL (<5 pg/mL)
Lactic acid 2.5 mmol/L (0.5–2.2 mmol/L)
Lactic dehydrogenase 398 μ/l (125–220 μ/L)
Platelet count 103 103/μL (142.0–424.0 103/μL)
Procalcitonin 0.13 ng/ml (0.0–0.07 ng/mL)
Troponin 0.013 (0.000–0.023)
Vitamin D 23.2 ng/mL (>30 ng/mL)
White blood cell 4.38 103/μL (4.6–10.2 103/μL)
His chest X-ray at admission was unrevealing; however, a CT angiography (CTA) of his chest was negative for pulmonary embolism but revealed bilateral nodular and confluent sub-pleural and peri-bronchovascular ground-glass opacities. On the second day of admission (illness day 15), his left eye swelling and pain were noted to have worsened, with the development of a small ulcerative lesion anterior to the left lower eyelid (Figure 1).
Figure 1 Right and left eye (panel A and B, respectively) showing bilateral periorbital and conjunctival erythema, and a shallow ulcer in the left lower eyelid anteriorly (panel B)
A CT of facial bones showed a left-sided pre-septal and facial swelling consistent with cellulitis, and suggestive of a subdermal fluid collection measuring 1.5 x 0.4 x 0.9 cm, concerning for a superficial abscess (Figure 2). He was thus started on vancomycin and ceftriaxone.
Figure 2 CT facial bones with contrast showing left-sided pre-septal cellulitis and probable subdermal fluid collection (yellow arrow)
CT: computed tomography
His clinical presentation was most compatible with acute viral follicular conjunctivitis. For diagnostic purposes, conjunctival swabs were obtained from both eyes on hospital day seven (illness day 21), including a swab of the ulcer at the left lower eyelid. All the specimens were positive for HSV-1 PCR, and negative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), Adenovirus, and varicella-zoster virus (VZV) PCR.
His moderately severe SARS-CoV-2 infection was managed with a five-day course of hydroxychloroquine based on the limited evidence available at the time, in addition to supportive care. For the confirmed HSV-1 conjunctivitis, he was provided with a seven-day course of famciclovir and supportive care using artificial tears, cold compresses, and olopatadine hydrochloride ophthalmic solutions 0.1% every five to eight hours. The intravenous antimicrobial regimen targeting his pre-septal cellulitis was transitioned to oral cephalexin and doxycycline with instructions to complete 14 days of therapy.
During his inpatient stay, his oxygen requirements improved, along with his ocular symptoms. He was reached via telephone on post-discharge day six for continuity of care; he stated that he continued to notice some shortness of breath on exertion, though his ocular complaints had almost completely resolved.
Discussion
Coronaviruses had been previously reported to be associated with conjunctivitis in humans but deemed to be mild and rare [4,5]. However, ocular complications of SARS-CoV-2 have not been widely reported. A study performed in the province of Hubei in China by Wu et al. found that 31.6% of COVID-19 patients (n=39) had ocular manifestations consistent with conjunctivitis. A meta-analysis conducted by Loffredo et al., including three studies of 1,167 patients with COVID-19, found that only 3% of patients with severe disease and 0.7% of patients with non-severe disease had conjunctivitis. In SARS-CoV-2 conjunctivitis, patients can present with ocular redness, irritation, foreign body sensation, tearing, and chemosis [2,5,6]. Our patient presented with all of the above characteristics. In addition, our patient did not experience blurred vision, which is consistent with other studies [2,5].
Clinical examination findings of SARS-CoV-2 conjunctivitis are mostly consistent with mild follicular conjunctivitis as observed in several other studies [4,5,7]. Similarly, our patient's exam findings were consistent with acute viral follicular conjunctivitis, likely related to COVID-19 with superimposed HSV-1 reactivation. The potential false-negative COVID-19 PCR test of the conjunctival swabs can be explained by poor sample collection, scarcity of viral RNA in conjunctival fluid, or test error. Of note, Wu et al. reported that only 16.7% of their COVID-19-positive patients under study had positive results for SARS-CoV-2 on PCR from both conjunctivae. This implies that perhaps not all COVID-19-related conjunctivitis will have positive SARS-CoV-2 PCR upon testing of conjunctival swabs. Conjunctivitis can rarely present as an initial manifestation of COVID-19, and ocular symptoms more commonly affect patients with severe systemic diseases [2,5,8]. Moreover, patients with ocular symptoms have been reported to present with higher white blood cell and neutrophil counts, higher levels of procalcitonin, CRP, and LDH compared to patients without ocular symptoms [2]. Our patient did have neutrophilia, elevated CRP, and LDH, but a mild elevation of procalcitonin, and his COVID-19 was deemed moderate in severity. Even though there is a low prevalence of SARS-CoV-2 nucleotides in tears, just like SARS-CoV-1, it is possible to transmit via the eyes [2,5]. Furthermore, in order to demonstrate that the genome detected corresponds to the infectious virus, Colavita et al inoculated Vero-6 cells with ocular samples positive for SARS-CoV-2 RNA, and cytopathic effects were observed five days post-inoculum [1]. It has been suggested that viral loads in conjunctival specimens gradually decrease over time, with less potential for transmissibility accompanied by improvement of the ocular symptoms [4]. Several authors have reported outcomes ranging from improvement to resolution of symptoms by the third week of illness [1,4]. Significantly, ocular manifestations of COVID-19 conjunctivitis are thought to be self-limited, and there are currently no reports of sight-threatening manifestations.
In our case, the patient had several risk factors for immunosuppression, including age, multiple comorbidities, and the use of antineoplastic therapy. Furthermore, we believe that multiple factors led to his HSV-1 reactivation, including recent use of the cytotoxic agent for his underlying lung malignancy, and his underlying SARS-CoV-2 infection. In addition, our patient had bilateral ocular disease, whereas HSV-1 conjunctivitis is almost always unilateral [9]. One hypothesis is that the initial COVID-19 conjunctivitis led to repeated eye-rubbing and trauma resulting in HSV-1 reactivation complicated by superimposed bacterial infection and autoinoculation of the other eye. Corneal staining with fluorescein was not performed for the evaluation of herpetic keratitis.
HSV conjunctivitis has been deemed to be the second most common cause of viral conjunctivitis after Adenovirus infection, and also the most serious one [6,9]. In one study conducted in a Minnesota county, the annual incidence of herpes eye symptoms was found to be 11.8 new cases for every 100,000 population [3]. With HSV, vesicles may appear on the face or eyelids and vision may be affected [6]. Supportive care for both COVID-19 and HSV-1 conjunctivitis are indicated, with the use of preservative-free artificial tears, antihistamine eye drops, and cold compresses. A short course of topical antibiotics can be added to prevent or treat bacterial superinfection [5]. For HSV conjunctivitis, topical antivirals like acyclovir have been used, and most patients achieve resolution within 14-30 days [6]. For our immunosuppressed patient, a systemic option was preferred over a topical antiviral, in addition to supportive care, yielding excellent results. Although atypical manifestations of COVID-19 infections including ocular manifestations were not looked into during the initial phase of the pandemic, it has now become critical to consider the possibility of COVID-19 infection in multiple organ systems, as well as the risk of co-infections including reactivation of viruses, based on the evolving evidence. This would tremendously help us in taking good care of these patients as well as to timely put preventative measures in place to control its spread both in the healthcare settings and among the population at large.
Conclusions
Conjunctivitis is an atypical presentation of COVID-19 and can present with eye redness, ocular irritation, foreign body sensation, tearing, and chemosis. Detection of viral RNA in tears may not always be possible for diagnostic purposes. Nonetheless, COVID-19 conjunctivitis can in most instances be managed with a trial of frequent preservative-free artificial tears, cold compresses, and lubricating ophthalmic ointment. A short course of topical antibiotics can be added to prevent or treat bacterial superinfection. Lastly, HSV-1 should be on the differential diagnosis for any immunocompromised patient that presents with COVID-19 conjunctivitis.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | DOCETAXEL | DrugsGivenReaction | CC BY | 33575153 | 18,984,996 | 2021-01-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ophthalmic herpes simplex'. | SARS-CoV-2 Infection (COVID-19) and Herpes Simplex Virus-1 Conjunctivitis: Concurrent Viral Infections or a Cause-Effect Result?
The pulmonary effects of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease (COVID-19), are well documented; however, more evidence is needed to understand its effect on multiple organ systems. We present the case of a 69-year-old male with dyspnea for two weeks and bilateral conjunctivitis who tested positive for SARS-CoV-2. He was found to be hypoxic, requiring supplemental oxygen. On hospital day two, he complained of worsening left eye pain with the development of a left lower eyelid ulcer. He underwent a CT of facial bones, which showed findings consistent with pre-septal cellulitis and abscess. Samples from bilateral conjunctival secretions and left lower eyelid ulcer tested positive for herpes simplex virus-1 (HSV-1), and negative for SARS-CoV-2. He received supportive care, antibiotics, and famciclovir with almost complete resolution of his ocular complaints. This case illustrates an atypical COVID-19 presentation and raises concern as to how this virus modulates the immune system, allowing for concurrent viral infections.
Introduction
Coronavirus disease 2019 (COVID-19) is primarily a respiratory infection; however, it is now known to affect multiple organs, including the eye [1]. Due to the novelty of the virus, there are scarce data on COVID-19-related ocular infections in the medical literature. One study conducted in China noted that 31.6% of COVID-19-infected patients had ocular manifestations consistent with conjunctivitis [2]. However, the initial presentation of COVID-19 being an ocular manifestation seems rare. Other viruses such as herpes simplex are known to commonly present with ocular manifestations, with the latter having an annual incidence of 11.8 new cases for every 100,000 population [3]. In fact, the reactivation of latent herpes simplex virus (HSV) in the sensory ganglia may lead to initial or recurrent disease, typically monocular [3].
Case presentation
A 69-year-old Caucasian male with a medical history of type II diabetes mellitus, coronary artery disease, peripheral arterial disease, and stage III squamous cell lung cancer receiving weekly docetaxel presented to the ER in March 2020 with complaints of progressive dyspnea, cough, and scant white sputum for 14 days. He was a personal care aide who worked in a rehabilitation facility where multiple staff and patients had tested positive for COVID-19. Upon presentation, he was afebrile, normotensive, and hypoxemic, requiring 2 liters of oxygen via nasal cannula. He also reported bilateral eye pain, more significant in the left eye than the right, with associated bilateral conjunctival erythema, pruritus, chemosis, and foreign body sensation. He denied any blurry vision, changes in visual acuity, or previous ocular problems. Of note, the patient was enrolled in a double-blinded, randomized placebo-controlled trial with sarilumab on hospital day two (illness day 15) for the management of COVID-19. The patient electively self-withdrew from the trial three days post-infusion (drug versus placebo) administration due to personal reasons, unrelated to any safety concerns.
The patient tested positive for COVID-19 via a nasopharyngeal swab polymerase chain reaction (PCR). Laboratory workup revealed a normal white blood cell count, with normal neutrophil and lymphocyte counts. However, mild thrombocytopenia and vitamin D deficiency were noted. He presented with mild to moderate elevation in C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 level. His procalcitonin level, however, was mildly elevated (Table 1).
Table 1 Lab values at admission
Laboratory test Value at admission (reference range)
C-reactive protein 12.09 mg/dL (<0.5 mg/dL)
D-Dimer 2.0 mg/L (<0.5 mg/L)
Ferritin 824 ng/mL (21.81–274.66 ng/mL)
Hemoglobin A1c 8.3% (4.0–6.5%)
Interleukin 6 59 pg/mL (<5 pg/mL)
Lactic acid 2.5 mmol/L (0.5–2.2 mmol/L)
Lactic dehydrogenase 398 μ/l (125–220 μ/L)
Platelet count 103 103/μL (142.0–424.0 103/μL)
Procalcitonin 0.13 ng/ml (0.0–0.07 ng/mL)
Troponin 0.013 (0.000–0.023)
Vitamin D 23.2 ng/mL (>30 ng/mL)
White blood cell 4.38 103/μL (4.6–10.2 103/μL)
His chest X-ray at admission was unrevealing; however, a CT angiography (CTA) of his chest was negative for pulmonary embolism but revealed bilateral nodular and confluent sub-pleural and peri-bronchovascular ground-glass opacities. On the second day of admission (illness day 15), his left eye swelling and pain were noted to have worsened, with the development of a small ulcerative lesion anterior to the left lower eyelid (Figure 1).
Figure 1 Right and left eye (panel A and B, respectively) showing bilateral periorbital and conjunctival erythema, and a shallow ulcer in the left lower eyelid anteriorly (panel B)
A CT of facial bones showed a left-sided pre-septal and facial swelling consistent with cellulitis, and suggestive of a subdermal fluid collection measuring 1.5 x 0.4 x 0.9 cm, concerning for a superficial abscess (Figure 2). He was thus started on vancomycin and ceftriaxone.
Figure 2 CT facial bones with contrast showing left-sided pre-septal cellulitis and probable subdermal fluid collection (yellow arrow)
CT: computed tomography
His clinical presentation was most compatible with acute viral follicular conjunctivitis. For diagnostic purposes, conjunctival swabs were obtained from both eyes on hospital day seven (illness day 21), including a swab of the ulcer at the left lower eyelid. All the specimens were positive for HSV-1 PCR, and negative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), Adenovirus, and varicella-zoster virus (VZV) PCR.
His moderately severe SARS-CoV-2 infection was managed with a five-day course of hydroxychloroquine based on the limited evidence available at the time, in addition to supportive care. For the confirmed HSV-1 conjunctivitis, he was provided with a seven-day course of famciclovir and supportive care using artificial tears, cold compresses, and olopatadine hydrochloride ophthalmic solutions 0.1% every five to eight hours. The intravenous antimicrobial regimen targeting his pre-septal cellulitis was transitioned to oral cephalexin and doxycycline with instructions to complete 14 days of therapy.
During his inpatient stay, his oxygen requirements improved, along with his ocular symptoms. He was reached via telephone on post-discharge day six for continuity of care; he stated that he continued to notice some shortness of breath on exertion, though his ocular complaints had almost completely resolved.
Discussion
Coronaviruses had been previously reported to be associated with conjunctivitis in humans but deemed to be mild and rare [4,5]. However, ocular complications of SARS-CoV-2 have not been widely reported. A study performed in the province of Hubei in China by Wu et al. found that 31.6% of COVID-19 patients (n=39) had ocular manifestations consistent with conjunctivitis. A meta-analysis conducted by Loffredo et al., including three studies of 1,167 patients with COVID-19, found that only 3% of patients with severe disease and 0.7% of patients with non-severe disease had conjunctivitis. In SARS-CoV-2 conjunctivitis, patients can present with ocular redness, irritation, foreign body sensation, tearing, and chemosis [2,5,6]. Our patient presented with all of the above characteristics. In addition, our patient did not experience blurred vision, which is consistent with other studies [2,5].
Clinical examination findings of SARS-CoV-2 conjunctivitis are mostly consistent with mild follicular conjunctivitis as observed in several other studies [4,5,7]. Similarly, our patient's exam findings were consistent with acute viral follicular conjunctivitis, likely related to COVID-19 with superimposed HSV-1 reactivation. The potential false-negative COVID-19 PCR test of the conjunctival swabs can be explained by poor sample collection, scarcity of viral RNA in conjunctival fluid, or test error. Of note, Wu et al. reported that only 16.7% of their COVID-19-positive patients under study had positive results for SARS-CoV-2 on PCR from both conjunctivae. This implies that perhaps not all COVID-19-related conjunctivitis will have positive SARS-CoV-2 PCR upon testing of conjunctival swabs. Conjunctivitis can rarely present as an initial manifestation of COVID-19, and ocular symptoms more commonly affect patients with severe systemic diseases [2,5,8]. Moreover, patients with ocular symptoms have been reported to present with higher white blood cell and neutrophil counts, higher levels of procalcitonin, CRP, and LDH compared to patients without ocular symptoms [2]. Our patient did have neutrophilia, elevated CRP, and LDH, but a mild elevation of procalcitonin, and his COVID-19 was deemed moderate in severity. Even though there is a low prevalence of SARS-CoV-2 nucleotides in tears, just like SARS-CoV-1, it is possible to transmit via the eyes [2,5]. Furthermore, in order to demonstrate that the genome detected corresponds to the infectious virus, Colavita et al inoculated Vero-6 cells with ocular samples positive for SARS-CoV-2 RNA, and cytopathic effects were observed five days post-inoculum [1]. It has been suggested that viral loads in conjunctival specimens gradually decrease over time, with less potential for transmissibility accompanied by improvement of the ocular symptoms [4]. Several authors have reported outcomes ranging from improvement to resolution of symptoms by the third week of illness [1,4]. Significantly, ocular manifestations of COVID-19 conjunctivitis are thought to be self-limited, and there are currently no reports of sight-threatening manifestations.
In our case, the patient had several risk factors for immunosuppression, including age, multiple comorbidities, and the use of antineoplastic therapy. Furthermore, we believe that multiple factors led to his HSV-1 reactivation, including recent use of the cytotoxic agent for his underlying lung malignancy, and his underlying SARS-CoV-2 infection. In addition, our patient had bilateral ocular disease, whereas HSV-1 conjunctivitis is almost always unilateral [9]. One hypothesis is that the initial COVID-19 conjunctivitis led to repeated eye-rubbing and trauma resulting in HSV-1 reactivation complicated by superimposed bacterial infection and autoinoculation of the other eye. Corneal staining with fluorescein was not performed for the evaluation of herpetic keratitis.
HSV conjunctivitis has been deemed to be the second most common cause of viral conjunctivitis after Adenovirus infection, and also the most serious one [6,9]. In one study conducted in a Minnesota county, the annual incidence of herpes eye symptoms was found to be 11.8 new cases for every 100,000 population [3]. With HSV, vesicles may appear on the face or eyelids and vision may be affected [6]. Supportive care for both COVID-19 and HSV-1 conjunctivitis are indicated, with the use of preservative-free artificial tears, antihistamine eye drops, and cold compresses. A short course of topical antibiotics can be added to prevent or treat bacterial superinfection [5]. For HSV conjunctivitis, topical antivirals like acyclovir have been used, and most patients achieve resolution within 14-30 days [6]. For our immunosuppressed patient, a systemic option was preferred over a topical antiviral, in addition to supportive care, yielding excellent results. Although atypical manifestations of COVID-19 infections including ocular manifestations were not looked into during the initial phase of the pandemic, it has now become critical to consider the possibility of COVID-19 infection in multiple organ systems, as well as the risk of co-infections including reactivation of viruses, based on the evolving evidence. This would tremendously help us in taking good care of these patients as well as to timely put preventative measures in place to control its spread both in the healthcare settings and among the population at large.
Conclusions
Conjunctivitis is an atypical presentation of COVID-19 and can present with eye redness, ocular irritation, foreign body sensation, tearing, and chemosis. Detection of viral RNA in tears may not always be possible for diagnostic purposes. Nonetheless, COVID-19 conjunctivitis can in most instances be managed with a trial of frequent preservative-free artificial tears, cold compresses, and lubricating ophthalmic ointment. A short course of topical antibiotics can be added to prevent or treat bacterial superinfection. Lastly, HSV-1 should be on the differential diagnosis for any immunocompromised patient that presents with COVID-19 conjunctivitis.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | DOCETAXEL | DrugsGivenReaction | CC BY | 33575153 | 18,984,996 | 2021-01-09 |
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