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Introduction: Mucocutaneous eruptions are associated with many viral processes and present as erythema multiforme (EM), reactive infectious mucocutaneous eruption (RIME), Stevens Johnson syndrome (SJS) or toxic epidermal necrosis (TEN). Limited reports have described the association of COVID-19 and mucocutaneous eruptions in children and adults to date. Method(s): This was a multicenter descriptive case series performed at six tertiary medical centers. Inclusion required a clinical diagnosis of EM, RIME, SJS or TEN and a positive COVID-19 test (rapid antigen or PCR) less than 4 weeks prior to onset of dermatologic manifestation. Data was collected at time of each patient encounter. Result(s): A total of 7 patients met criteria and had a median age of 15 years for pediatric patients (<18 years of age) and 36 years for adult patients (>18 years of age). Patients were found to have a diagnosis of RIME in 85.7% of cases. Oral mucosal involvement was the most common clinical finding (100%), followed by ocular (57.1%), urogenital (57.1%) and skin (42.9%) involvement. 71.4% of cases required hospitalization for their cutaneous eruption. No patients died from their inflammatory condition. Discussion(s): This case series highlights the development of mucocutaneous eruptions in association with COVID-19 infection. Within our cohort, RIME was the most commonly identified COVID-associated eruption. These findings provide additional evidence that abnormalities in host immune response to viral pathogens play a role in severe mucocutaneous blistering conditions. Further investigation will aid our understanding of this disease to improve diagnostics and advance targeted treatments for patients in the future.
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"Kawasaki was an icon in the paediatric world,” Jane Burns, professor and director of the Kawasaki Disease Research Centre at the University of California San Diego School of Medicine, told The BMJ. In 1949 he became a staff paediatrician at the Red Cross Hospital outside Tokyo and began to undertake research. ” "Ten years after starting at the Japanese Red Cross Central Hospital (now the Japanese Red Cross Medical Centre) in Tokyo, I examined on 5 January 1961 a boy aged four years and three months with a curious clinical symptom complex I had never seen,” he explained.3 "The patient had a high fever of about two weeks' duration, marked bilateral conjunctival hyperaemia without discharge, reddening dry fissured lips, diffuse redness of the mucous membrane of oral cavity, strawberry like tongue, left non-purulent cervical adenopathy, polymorphous erythema on the body, and marked redness of palms and soles, with indurative oedema of hands and feet following desquamation from the fingertips.”
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Objectives: A 14-year-old female patient presents with marked haemorrhagic, adherent crusting of the upper and lower lip and enoral vesicles and erosions. Two weeks before, she had suffered from a respiratory tract infection. She did not take antibiotics but ibuprofen. One week later, she described a swelling and crusting of the upper and lower lips. Urogenital mucosa was also erosive. There was no ocular involvement. Another week later, cocard-like single lesions with partly central blister formation developed. A flaccid blister of 15 mm in diameter was detected in the left ear helix. In total, there was a limited cutaneous involvement of <10% BSA. The girl was admitted to the paediatric clinic. Method(s): Due to mucocutaneous eruptions, bullous lesions and multimucosal involvement, we assumed a Steven-Johnson syndrome or reactive infectious mucocutaneous eruption (RIME). Intravenous rehydration and prophylactic administration of cefotaxime and aciclovir were given. She was balanced and given analgesia with novalgin. The recent increased intake of ibuprofen was discontinued. Local therapy included mometasone cream and serasept dressings. During the inpatient stay, the general condition stabilised and the skin efflorescence's showed a clear regression. Result(s): The microbiological smears for COVID-19, HSV, VZV, mycoplasma, and chlamydia were negative. Discussion(s): As adult classifications for blistering severe cutaneous adverse reactions are limited applicable in children, Ramien et al. proposed revised paediatric-focused clinical criteria 2021. They leave traditional definitions of EEM, SJS and TEN. But they distinguish erythema multiforme (EM) for classic targets with/without mucosal involvement, RIME for cases with mucosal predominance and a respiratory infection trigger, and drug-induced epidermal necrolysis (DEN) for cases caused by medications. (Ramien BJD 2021) There are no current guidelines for RIME therapy. A reasonable management approach includes symptomatic therapy, treatment of identifiable infectious triggers (if possible), consulting urologists, ophthalmologists and gynaecologists (if necessary), immunosuppression, and psychological support. (Ramien ClinExpDermatol 2021).
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A case report of 52-years-old male with erythema nodosum, fever and malaise that developed seven days after second dose of mRNA vaccine Comirnaty (Pfizer-BioNTech) against coronavirus SARS-CoV-2. The most common causes of erythema nodosum were ruled out and the patient was treated with systemic corticotherapy with a very good effect. Because of the time association between the development of erythema nodosum and the second dose of mRNA vaccine, findings of high titres of anti-SARS-CoV-2 IgG antibodies in the blood, the case was reported to national regulation authority (State Institute for Drug Control) as a possible side effect of the mRNA vaccine Comirnaty.Copyright © 2021, EEZY Publishing, s.r.o.. All rights reserved.
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Introduction: Several studies have evaluated the occurrence of oral lesions and changes in sensory functions in patients positive for COVID-19. Objective(s): To evaluate the manifestations of COVID-19, emphasizing olfactory and gustatory changes, xerostomia, and oral lesions. Material(s) and Method(s): A cross-sectional and observational study was conducted. Approved by the Institutional Ethics Committee (#46151121.6.0000.5141). All patients were diagnosed by reverse transcription-polymerase chain reaction assay (RT-PCR) and considered to have mild symptoms, according to the latest WHO joint report. The patients were evaluated at a reference Service for COVID-19 in Minas Gerais, Brazil. The oral cavity was evaluated for each patient on the second and seventh days. Result(s): A total of 414 patients older than 18 years were evaluated. One hundred thirty-nine presented at least one of the studied conditions, oral lesions (19.08%) were the most frequently observed, followed by gustatory disorders (18.11%), xerostomia (14.25%), and olfactory dysfunction (14%). Among the oral lesions, there were various anatomical locations and clinical presentations. The occurrence involving lips and tongue represented 49 oral lesions, the most prevalent being, respectively, ulcerations (n=51), candidiasis (n=8), and erythema or red plaques (n=7). Fifty patients died. Conclusion(s): This study represents, to date, the largest case series of oral lesions in Brazilian patients with COVID-19, and oral alterations were observed in an expressive percentage of patients with COVID-19. However, it cannot be concluded that SARS-CoV-2 directly causes them.
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BackgroundVaccination has been recommended in the midst of the COVID-19 pandemic, but some patients are not vaccinated due to concerns about adverse reactions.ObjectivesThe purpose of this study is to investigate the adverse reactions in rheumatic diseases and to guide the decision-making of patients and physicians.MethodsA questionnaire was sent to patients with rheumatic diseases, and patients who could be counted as of September 2021, when they consented to this study, were surveyed.ResultsThe subjects were 123 (male:female=10:113), 84 with rheumatoid arthritis and 39 with other immune diseases. The therapeutic agents used were PSL 31(25.2%), MTX 65(52.8%), NSAID/COX inhibitors 28(22.8%), bDMARDs 42(34.1%). adverse reactions after the first and second vaccination were fever 17(13.8%)/50(40.7%), joint symptoms 7(5.7%)/22(17.9%), local injection reactions (pain/irritation) 22(17.9%), local injection reactions (pain/erythema) 93(75.6)/98(79.7), systemic skin symptoms 0(0%)/2(1.6%), other symptoms (malaise, myalgia, etc.) 59(48.0%)/85(69.1%), and treatment intensification 5(4.1%)/12(9.7%). These responses differed in occurrence only for fever with and without PSL medication (22.5%: 47.3% (p=0.02)).The odds ratio for disease worsening after the first dose of vaccine and again after the second dose was 33.5 (p<0.01).ConclusionNo specific adverse reactions other than the commonly known ones were observed, but some patients experienced worsening of symptoms after vaccination, requiring intensified treatment. Based on the results of this study, we believe that adverse reactions to vaccination are acceptable. We plan to accumulate more cases and analyze them in the future.The exacerbation of disease after the first vaccination would predict the exacerbation after the second vaccination.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background The clinical condition of epidemic dropsy is caused by the consumption of edible oils contaminated with Argemone mexicana oil. Two of the most toxic alkaloids found in argemone oil are sanguinarine and dehydrosanguinarine, which cause capillary dilation, proliferation, and increased permeability. Extreme cardiac decompensation leading to congestive heart failure and glaucoma resulting in blindness are the most serious consequences of epidemic dropsy. Materials and methods All patients attending the medicine department of Tezpur Medical College and Hospital with clinical features of epidemic dropsy were included in the study after obtaining informed consent. All patients, after a complete history, underwent a thorough clinical examination, and findings were recorded using a pre-formed proforma. Along with routine blood examination, patients were also evaluated with echocardiography, ECG, and chest X-ray. Cooking oil samples obtained from patients were investigated for the presence of sanguinarine in a standardized laboratory with the help of the district authority. The statistical analysis was done using MS Excel 2017. Results Out of 38 patients, 36 were male (94.7%), and only two were female (5.2%). Male to female ratio was 18:1. This difference in sex ratio may be due to the fact that only severely ill patients attended our tertiary care hospital. In contrast, moderate and mildly ill patients were treated in local hospitals. The mean age of patients was 28.1 years, and the mean length of hospital stay was eight days. Bilateral pitting type of ankle edema was the most common clinical manifestation, and all 38 patients (100%) exhibited edema. A total of 76% of patients had dermatological manifestations. Sixty-two percent of patients had gastrointestinal manifestations. In cardiovascular manifestation, persistent tachycardia was seen in 52% of patients, pansystolic murmur was best heard in the apical area in 42% of patients, and 21 percent had evidence of a raised jugular venous pressure (JVP). Five percent of patients had pleural effusion. Sixteen percent of patients had ophthalmological manifestations. Eight patients (21%) required ICU care. The in-hospital fatality rate was 10.53% (n=4). Of the expired patients, 100% were male. The most common cause of death was cardiogenic shock (75%), followed by septic shock (25%). Conclusion From our study, it was found that most of the patients were male, with an age group of 25-45 years. The most common clinical manifestation was dependent edema, along with signs of heart failure. Other common manifestations were dermatological and gastrointestinal. The severity and outcome were directly related to the delay in seeking medical consultation and diagnosis.
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Introduction: Mucinous adenocarcinomas of the appendix are defined as epithelial neoplasms often causing cystic dilation of the appendix due to accumulation of gelatinous material. Pseudomyxoma peritonei is an extremely rare complication of appendiceal mucinous adenocarcinomas with an estimated incidence rate of one to 2 people per million per year. Here-in we present a unique case of enterocutaneous fistula formation secondary to percutaneous biopsy of an enlarging omental mass in the setting of pseudomyxoma peritonei. Case Description/Methods: A 50-year-old male with a past medical history of metastatic appendiceal mucinous adenocarcinoma presented to the ED with abdominal pain, nausea, and vomiting. The patient had previously undergone 2 debulking surgeries over the past 2 years prior to admission and has since been on FOLFOX therapy. Due to the COVID pandemic, the patient did not follow-up in the 2 years period from previous admission. A CT scan was now notable for a new enlarging omental mass despite the recent debulking surgery. Given the enlarging mass, a decision was made to pursue a percutaneous biopsy of the mass due to concern for potential new malignancy. Two weeks after the biopsy, the patient presented to our facility due to worsening erythema and drainage from the biopsy site. The patient met SIRS criteria, thus broad-spectrum antibiotics were initiated. A CT of the abdomen and pelvis with oral and IV contrast was obtained, which demonstrated a 9 cm abscess or continuation of intra-abdominal multilocular cystic lesion/ pseudomyxoma peritonei. The surgical team was consulted. Patient had 100 cc of purulent and mucinous drainage expressed from biopsy site. The patient was then placed for transfer to a hospital capable of advanced surgical management for evaluation and potential resection of fistula formation. The patient had a successful reductive surgery and intraoperative chemotherapy (Figure). Discussion(s): Given the rarity of pseudomyxoma peritonei, appropriate management is not always straightforward. A literature review yielded no previous reports of enterocutaneous fistula as a complication of percutaneous drainage in the setting of pseudomyxoma peritonei. We recommend that percutaneous drainage not be sought in individuals with this diagnosis due to potential for fistula formation.
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Background/Aims Flares following COVID-19 vaccination are an emerging concern among patients with rare rheumatic disease like idiopathic inflammatory myositis (IIMs), whereas data and understanding of this is rather limited. We aimed to study the prevalence, characteristics and determinants of IIM flares following COVID-19 vaccination. Methods CoVAD (COVID-19 Vaccination In Autoimmune Diseases) surveys are global patient self-reported e-surveys from 109 countries conducted in 2021 and 2022. Flares of IIM were defined by 4 definitions;a. patient self-reported, b. physician and immunosuppression (IS) denoted, c. sign directed (new erythematous rash, or worsening myositis or arthritis), d. MCID worsening of PROMISPF10a score between the patients who had taken both surveys. Descriptive statistics and multivariate regression were used to describe the predictors of flare. Cox-regression analysis was used to differentiate flares by IIM subtypes. Results Among the 1,278 IIM patients, aged 63 (50-71) years, 276 (21.5%) were dermatomyositis, 237 (18.5%) IBM, 899 (70.3%) were female and most were Caucasian (80.8%). Flares of IIM were seen in 123/1278 (9.6%), 163/1278 (12.7%), 112/1278 (8.7%), and 16/96 (19.6%) by definitions a-d respectively with median time to flare being 71.5 (10.7- 235) days. Muscle weakness (69.1%), and fatigue (56.9%) were the most common symptoms of flare. The predictors of self-reported flare were: inactive/disease in remission prior to first dose of vaccine (OR=4.3, 95%CI=2.4-7.6), and anxiety disorder (OR=2.2, 95%CI=1.1-4.7). Rituximab use (OR=0.3, 95%CI=0.1-0.7) and IBM (OR=0.3, 95%CI=0.1-0.7) were protective. Physician defined flares were seen more often in females, mixed ethnicity, and those with asthma, ILD, and anxiety disorder (OR ranging 1.6-7.0, all p<0.05). Notably, overlap myositis (OM) had higher HR for flare compared to polymyositis (HR=2.3, 95%CI=1.2-4.4, p=0.010). Conclusion Nearly one in ten individuals with IIM develop flares after vaccination, more so among women, those with overlap myositis, and inactive disease prior to vaccination. Formal definition of flares in IIM is needed.
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Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300mg by monthly iv infusion) following application to the manufacturer's early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI);Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n=5, chilblain LE n=1, subacute cutaneous LE n=1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26;higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved >=75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p<0.001) and EQ5D-VAS (p=0.002) by three months. Lupus-QoL trended toward improvement across all domains but most strongly for fatigue (p=0.01) and pain (p=0.002) by 6 months. One patient discontinued treatment after 4 months due to polydermatomal shingles complicated by sensorineural hearing loss. Infection coincided with background prednisolone dose >15mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG <5g/L). Prolonged aciclovir treatment was required for lesion resolution. Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients.
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History: Transient and generalized adverse effects are common following COVID-19 vaccination;among other adverse effects, shoulder injuries related to vaccine administration (SIRVA) have been known to occur. In this case, a previously healthy right-hand dominant 62-year-old male presented with left shoulder pain and weakness 3 months after receiving a COVID-19 intramuscular vaccine in the left deltoid. Approximately 2 weeks after the injection, he started experiencing pain and numbness around the injection site along with ipsilateral shoulder weakness. Despite conservative management with Motrin, Medrol Dosepak, gabapentin and physical therapy (PT), the pain and weakness persisted. Physical Exam: Left Shoulder-No calor or erythema;significant atrophy of the anterior and middle deltoid muscle relative to right side;abduction 4/5;external rotation with shoulder adducted 4/5;range of motion for active forward flexion was 150 degrees and passive was 170 degrees;passive range of motion for external rotation was 70 degrees;internal rotation to the level of L5;sensation to light touch was intact. Right Shoulder-Range of motion, strength, and sensation were intact. Cervical Spine-Full ROM;no cervical paraspinal tenderness noted. Negative Spurling's and Lhermitte's tests. Differential Diagnosis: 161. Axillary Nerve Palsy 2/2 Chemical Neurotoxicity 162. Brachial Neuritis 163. Mechanical Axillary Nerve Palsy 2/2 Vaccination 164. Partial-Tear of Left Supraspinatus Tendon 165. Acromioclavicular Osteoarthritis Test Results: Left Shoulder-XR:Mild pseudo-subluxation;MRI w/o contrast: 8x9mmpartial-thickness articular surface tear of the distal supraspinatus tendon (<50%fiber thickness). Minimal subacromial bursitis. Mild acromioclavicular joint osteoarthritis. EMG/NCV: Left and Right Axillary Motor Nerves: prolonged distal onset latency;Left Deltoid: increased insertion activity, moderately increased spontaneous activity, reduced recruitment;Remaining LUE muscles without evidence of electrical instability Final Diagnosis: Axillary Nerve Palsy Secondary To Chemical Neurotoxicity from Intramuscular COVID-19 Vaccine. Discussion(s): We postulate that the neurologic deficits presented in our case may be attributed to chemical neurotoxicity to the axillary nerve following vaccination as the delayed onset of pain and weakness are most consistent with this differential. There are several cases of brachial neuritis following vaccination for the prevention of COVID- 19, however, EMG/NCV results in our patient were not consistent with brachial plexopathy. Additionally, while there have been a handful of reported cases of bursitis following COVID-19 vaccines falling under the SIRVA classification of injuries, this is the first case of reported axillary nerve neurapraxia. Outcome(s): The patient's left shoulder numbness and pain improved with PT and medical management. While mild improvement in strength was noted, weakness and atrophy persisted even on the third follow up visit 6 months after the initial appointment. He was counseled on his injury and was recommended to undergo repeat EMG testing to document recovery after his 6-month follow-up appointment. Follow-Up: The patient did not follow-up for a repeatEMG after his 6-month follow-up appointment. At that time, the patient was clinically stable, tolerating PT, and expecting recovery of his deltoid function.
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Background/Aims We report the features of chronic chilblain-like digital lesions newly presenting since the start of the covid-19 pandemic. Comparison with primary perniosis and acrocyanosis, reveals a unique phenotype which appears to be a long-covid phenomenon. Methods The case records of 26 patients with new onset persistent chilblain-like lesions presenting to the Rheumatology service of St George's University Hospital, London between Autumn 2020 and Spring 2022 were reviewed. Demographic and clinical features, serology, imaging, treatment response and outcome up to Summer 2022 were collated retrospectively. Results Chilblain-like lesions first occurred between September and March;2019/ 2020 6 cases, 2020/2021 18 cases and 2021/2022 2 cases. Mean age 35.4 (17-60) years, 88% female, 85% white, all non-smokers. Median body mass index (BMI) 20.2, range 17.0 - 33.2. BMI underweight (<18.5) in 27%. All cases reported new red-purple-blue colour changes of the fingers, some with pain, swelling and pruritis, affecting both hands in 12, one hand in 6, and both hands and feet in 8 cases. There was a past history of cold sensitivity or primary Raynaud's in 54%. Covid was confirmed in 3 cases, 2 - 8 months prior to onset of chilblain-like symptoms. Possible covid, unconfirmed, was suspected in 5 cases, 1 - 11 months earlier. Affected digits appeared diffusely erythro-cyanotic in 81%, with blotchy discrete maculo-papular erythematous lesions in 42%, some with both features. Involvement was asymmetric in 54%, thumbs spared in 69%. Complement was low in 50% (8/16), ANA positive in 26% (6/23). MRI of hands showed phalangeal bone marrow oedema in keeping with osteitis in 4 of 7 cases. More severe signs and symptoms were associated with low BMI, low C3/4 and a past history of cold sensitivity or Raynauds. Cold avoidance strategies were sufficient for 58%. Pain prompted a trial of NSAIDs, aspirin, nitrates, calcium channel blockers, hydroxychloroquine, oral or topical corticosteroid or topical tacrolimus in 42%. In general, these were minimally effective or not tolerated. 4 severe cases received sildenafil or tadalafil, effective in 2. In 27% complete remission occurred during the first summer season after symptoms commenced, median duration 6 (range 2 - 10) months. In the remaining 19 cases, chilblain-like symptoms returned or worsened in the subsequent second winter period, with 6 of 19 entering remission the following summer. For the remaining 13 persistent cases the total duration of symptoms spans more than a year, and in four cases more than 2 years. Conclusion This series illustrates a distinct chronic chilblain-like condition. Features similar to primary perniosis include female predominance, middle age, pruritic painful blotchy lesions, asymmetry and low BMI. Features in keeping with acrocyanosis include chronicity, extensive diffuse erythro-cyanotic discoloration, relative improvement in warm weather and lack of association with smoking.
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The fast development of vaccines against the novel coronavirus disease is among the most critical steps taken to control this potentially fatal viral disease. Like other vaccines, the coronavirus disease 2019 (COVID-19) vaccines can also cause unwanted reactions. Erythema multiforme (EM) is among the oral mucocutaneous side effects of COVID-19 vaccines. This study aimed to comprehensively review the reported cases of EM since the global onset of COVID-19 vaccination. Data from 31 relevant studies regarding the type and dose of COVID-19 vaccines administered, time of initiation of symptoms, age, and gender of patients, site of involvement, patients' medical history, and treatment options were extracted. In total, 90 patients were identified with EM as a side effect of COVID-19 vaccination across studies. EM had the highest frequency after receiving the first dose of mRNA vaccines in older individuals. The first symptoms of EM appeared in less than 3 days in 45% and after 3 days in 55% of patients. EM is not a common side effect of COVID-19 vaccination, and fear of its occurrence should not impede vaccination.
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Background: Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic initiation factor 4A (eIF4A), a host RNA helicase required for SARS-CoV-2 replication. In vitro, zotatifin demonstrates broad spectrum antiviral activity against all human coronaviruses tested. Zotatifin has physicochemical and pharmacokinetic (PK) properties suitable for convenient, single subcutaneous (sc) injection. This study assessed the safety, antiviral activity, and PK of zotatifin in non-hospitalized patients (pts) with mild/moderate COVID. Method(s): PROPEL is a randomized, placebo-controlled, double-blind study in non-hospitalized pts with mild/moderate COVID. At randomization, pts must have had a SARS-CoV-2 positive test within 7 days and at least 1 COVID symptom. Pts were randomized (3:1) to zotatifin or placebo sc in 3 cohorts of 12 pts each. Cohort 1, 2 and 3 received a single dose (SD) of zotatifin of 0.01. 0.02 and 0.035 mg/kg or matching placebo. Safety (adverse event (AE) and laboratory tests), antiviral activity (mid-turbinate nasal swabs and saliva), and plasma PK were collected over 30 days. The primary endpoint was safety;key secondary endpoints included SARS-CoV-2 viral load (VL) and PK. The study was not powered for statistical inferential testing. Result(s): 36 pts were enrolled across all three cohorts and completed a 30-day follow up. Data is currently available for pts in cohorts 1 and 2, 18 and 6 of whom received zotatifin and placebo, respectively. Baseline characteristics were comparable between groups. The most common AE was erythema at injection site in cohort 1 (44%) and cohort 2 (89%), vs. 0% in the zotatifin and pooled placebo groups, respectively. Other AE frequencies were comparable between zotatifin and placebo and no serious AEs were reported. The concentrationtime profile of zotatifin from cohorts 1 and 2 following sc administration was similar to that reported previously following IV administration, demonstrated a terminal elimination half-life (t1/2) of ~ 4 days, high steady-state volume of distribution (Vss) of 31 L/kg, and low plasma clearance (Cl) of 3.9 mL/min/kg. A faster time to viral RNA undetectability was observed with zotatifin vs. placebo (see Fig 1. Not statistically significant). Conclusion(s): Zotatifin was safe, well tolerated and demonstrated a trend in clinical antiviral activity in patients with mild to moderate COVID which supports further clinical development. Zotatifin sc route of administration supports a point of care treatment for COVID.
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Background: Cyclophosphamide (Cy) is used in hematopoietic stem cell transplant (HSCT) preparative regimens and lymphodepletion for chimeric antigen receptor T-cell (CAR-T) therapy. We describe a case of cyclophosphamide hypersensitivity in a pediatric patient during CAR-T therapy. Case description: A 13 year old boy was diagnosed with very high risk ALL in 2015 and had 2 isolated CNS relapses treated with intensified chemotherapy (chemo) and cranial radiation (1st relapse) and Blinatumomab with intrathecal (IT) chemo followed by sibling donor HSCT (2nd relapse). At age 19, and 18 months after HSCT, he had a 3rd CNS relapse treated with IT chemo and referral for CAR-T therapy. At our center, leukapheresis and CAR-T production (Novartis) were performed. Later, during lymphodepletion with fludarabine (Flu) and Cy, physiologic replacement hydrocortisone (HC) was briefly held to prevent interference with CAR-T function. After 3 days of Flu/Cy, he developed fever and hypotension requiring inotropic support. Hypotension and fever resolved with stress dose HC and antibiotics and was attributed to culture-negative sepsis and adrenal crisis. CAR-T infusion was subsequently delayed by skin GVHD requiring glucocorticoids and COVID-19 infection treated with convalescent plasma and nirmatrelvir/ritonavir. Physiologic HC replacement was continued when he was re-admitted for CAR-T therapy, but he again developed fever, diffuse erythema and shock in hours following the first dose of Cy necessitating stress dose HC, antibiotics, inotropes, and mechanical ventilation. Negative blood cultures and ongoing physiologic HC replacement suggested an alternative explanation for shock. Case reports of anaphylaxis to Cy metabolites implicated Cy as the causative agent so it was discontinued. After recovery, CAR-T cells were infused without complications. In the following weeks, he had no evidence of recurrent leukemia but was persistently pancytopenic. A sibling donor stem cell boost was proposed but the patient accepted only palliative care. He had several opportunistic infections before succumbing to E. coli sepsis. Discussion(s): The first episode of shock was initially attributed to adrenal crisis and sepsis, although no organism was identified. The second episode appeared anaphylactic in timing and clinical presentation with adequate HC replacement and negative cultures, suggesting Type I hypersensitivity. The patient previously received Cy uneventfully before HSCT, suggesting that the donor-derived immune system was the source of new Cy hypersensitivity. Onset of anaphylaxis within hours rather than minutes after Cy administration supports hypersensitivity to Cy metabolites rather than to the drug itself. This case highlights the importance of consideration of sensitivity to Cy metabolites as well as acquired donor-specific allergy even when alternative explanations are likely.Copyright © 2023 American Society for Transplantation and Cellular Therapy