Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial.

Background: An in silico screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods: A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Results: Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log10 viral load was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm versus the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho -0.45, p = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho -0.54, p = 0.005). Conclusion: In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients.

BABESIA MICROTI INFECTION WITH LOW-GRADE PARASITEMIA CAUSING ARDS IN AN IMMUNOCOMPETENT PATIENT

SESSION TITLE: Unusual Critical Care SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Babesiosis can have a clinical spectrum ranging from mild illness in most cases to more severe manifestations in immunosuppressed individuals or in those with high-grade parasitemia. This patient had severe babesiosis resulting in ARDS and shock in spite of being immunocompetent and having low-grade parasitemia, making it a rare presentation. CASE PRESENTATION: A 49-year-old, previously healthy woman, was admitted with high-grade fevers. Physical exam findings were normal, except for fever (103 F). Initial lab results were significant for hemolytic anemia and thrombocytopenia. Chest radiography was normal. Other microbiology studies, including COVID-19, were negative. Empiric antibiotic therapy with piperacillin-tazobactam and doxycycline was started. Peripheral smear identified rare, minute intracellular ring forms, suspicious for babesia. IV azithromycin and oral atovaquone were started. PCR was done to confirm the diagnosis and Babesia microti DNA was detected. As peripheral smear showed parasitemia of only 1% (percentage of red blood cells infected), exchange transfusion was not considered as a treatment option. Two days after admission, worsening hemodynamic and respiratory status was noted with increasing oxygen requirements. CT chest now revealed diffuse interstitial infiltrates. ARDS ensued and the patient was intubated and started on mechanical ventilation with vasopressor support. Immunodeficiency workup was normal. In view of clinical deterioration, the antimicrobials were switched from atovaquone and azithromycin to IV clindamycin and quinidine for 14 days. After a protracted ICU stay, the patient showed gradual clinical improvement, parasitemia resolved, and she was eventually discharged to a rehabilitation facility. DISCUSSION: Babesiosis is a tick-borne infectious disease endemic to the North-East and Midwest United States. Majority of the infections are self-limited. However, in immunocompromised individuals and in those with high-grade parasitemia (>10%), it manifests as a severe illness with ARDS, severe hemolysis, or shock. Diagnosis is made by identifying parasites on thin peripheral blood smears with Giemsa/Wright stains. PCR can be used for species identification and for confirming the diagnosis in cases with low-grade parasitemia (<4%). IV azithromycin plus oral atovaquone is the preferred initial regimen and IV clindamycin plus quinidine is an alternative combination that can be used in severe infection. Red blood cell exchange transfusion can be considered in patients with high-grade parasitemia or organ failure. CONCLUSIONS: Babesiosis can very rarely cause ARDS and shock in immunocompetent patients with low-grade parasitemia. Prompt diagnosis and escalation of antimicrobial regimens to clindamycin and quinidine in such cases can lead to improved clinical outcomes. Exchange transfusion can serve as a treatment option in patients with high-grade parasitemia. Reference #1: Ord RL, Lobo CA. Human babesiosis: Pathogens, prevalence, diagnosis, and treatment. Current clinical microbiology reports. 2015 Dec;2(4):173-81. Reference #2: Ripoll JG, Rizvi MS, King RL, Daniels CE. Severe Babesia microti infection presenting as multiorgan failure in an immunocompetent host. Case Reports. 2018 May 30;2018:bcr-2018. Reference #3: Sanchez E, Vannier E, Wormser GP, Hu LT. Diagnosis, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: a review. Jama. 2016 Apr 26;315(16):1767-77. DISCLOSURES: No relevant relationships by Shankar Chhetri No relevant relationships by Vasudev Malik Daliparty No relevant relationships by Preethi Dendi No relevant relationships by samer talib

A CASE OF PNEUMOCYSTIS JIROVECI PNEUMONIA MIMICKING METHOTREXATE-INDUCED PNEUMONITIS

SESSION TITLE: Procedures in Chest Infections Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is known to cause potentially life-threatening pneumonia in patients on immunosuppressive therapy. Here we describe a case of an elderly man on low dose methotrexate with PJP pneumonia initially mistaken for drug induced pneumonitis. CASE PRESENTATION: A 79 year old man with T-cell large granular lymphocytic leukemia on methotrexate, indeterminate colitis on azathioprine and sulfasalazine and interstitial lung disease was admitted for 3 week history of worsening dyspnea, lethargy and cough. On arrival his oxygen saturation was 87% on room air, requiring 5 liters oxygen via nasal canula. Lung examination was notable for bilateral crackles. Laboratory studies showed white blood cell count 12.4k/μL, lactate 2.7mmol/L, procalcitonin 0.137ng/mL, lactate dehydrogenase(LDH) 925 IU/L, 1,3 β-D glucan elevated at 154pg/mL. Infectious work up including COVID-19 testing was unremarkable. Chest radiograph showed bilateral diffuse interstitial infiltrates (figure 1) and computed tomography (CT) scan showed peripheral reticular changes and patchy ground glass opacities bilaterally (figures 2;3). He was initially treated for possible bacterial pneumonia;then with 125mg of methylprednisolone for presumed methotrexate induced pneumonitis without improvement. He underwent bronchoscopy with bronchoalveolar lavage(BAL) gram stain showing numerous histiocytes and scattered lymphocytes;no infectious organisms were isolated. PJP PCR from BAL came back positive and trimethoprim-sulfamethoxazole (TMP-SMX) was started. Despite maximum therapy he deteriorated clinically, transitioned to comfort care and expired. DISCUSSION: Diagnosis of PJP is made by visualization of cystic or trophic forms in respiratory tissue obtained via biopsy, BAL or sputum. Fungal burden is typically lower in non-HIV patients with PJP, and may result in negative BAL or sputum stain. Thus PCR testing is a useful diagnostic tool. Positive PCR alone cannot distinguish between colonization and active disease, and should be performed when clinical suspicion is high. 1,3 β-D glucan and LDH are nonspecific markers that help in presumptive diagnosis. First line therapy for PJP is TMP-SMX, with atovaquone, dapsone and pentamidine available as alternative therapies. Duration of therapy should be at least 21 days. Adjunctive corticosteroids show survival benefit in HIV-infected individuals. In severely hypoxic patients, corticosteroids are beneficial if started within 72 hours of antibiotic initiation. Their use in non-HIV PJP cases remains controversial. CONCLUSIONS: This case highlights the risk of PJP with long term methotrexate therapy. Cough, hypoxemia and bilateral interstitial infiltrates should prompt work-up for PJP. Timely recognition and early treatment are crucial to prevent mortality. Further studies are needed to assess the efficacy and provide guidelines for primary prophylaxis in this population. Reference #1: Wilson JW, Limper AH, Grys TE, Karre T, Wengenack NL, Binnicker MJ. Pneumocystis jirovecii testing by real-time polymerase chain reaction and direct examination among immunocompetent and immunosuppressed patient groups and correlation to disease specificity. Diagn Microbiol Infect Dis. 2011 Feb;69(2):145-52. doi: 10.1016/j.diagmicrobio.2010.10.021. PMID: 21251557;PMCID: PMC6855182. Reference #2: Salzer HJF, Schäfer G, Hoenigl M, Günther G, Hoffmann C, Kalsdorf B, Alanio A, Lange C. Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia. Respiration. 2018;96(1):52-65. doi: 10.1159/000487713. Epub 2018 Apr 10. PMID: 29635251 DISCLOSURES: No relevant relationships by Rutendo Jokomo-Nyakabau No relevant relationships by Richard Swaney No relevant relationships by Manasa Velagapudi

SYSTEMATIC LITERATURE REVIEW on the SCREENING and PROPHYLAXIS of CHRONIC and OPPORTUNISTIC INFECTIONS

Background: Opportunistic and chronic infections can arise in the context of treatment used for Autoimmune Rheumatic Diseases (ARDs). Although it is recognized that screening procedures and prophylactic measures must be followed, clinical practice is largely heterogeneous, with relevant recommendations not currently developed or disparately located across the literature. Objectives: To conduct a systematic literature review (SLR) focusing on the screening and prophylaxis of opportunistic and chronic infections in ARDs. This is preparatory work done by members of the respective EULAR task force (TF). Methods: Following the EULAR standardised operating procedures, we conducted an SLR with the following 5 search domains;1) Infection: infectious agents identifed by a scoping review and expert opinion (TF members), 2) Rheumatic Diseases: all ARDs, 3) Immunosuppression: all immunosuppressives/immunomodulators used in rheumatology, 4) Screening: general and specifc (e.g mantoux test) terms, 5) Prophylaxis: general and specifc (e.g trimethop-rim) terms. Articles were retrieved having the terms from domains 1 AND 2 AND 3, plus terms from domains 4 OR 5. Databases searched: Pubmed, Embase, Cochrane. Exclusion criteria: post-operative infections, pediatric ARDs, not ARDs (e.g septic arthritis), not concerning screening or prophylaxis, Covid-19 studies, articles concerning vaccinations and non-Εnglish literature. Quality of studies included was assessed as follows: Newcastle Ottawa scale for non-randomized controlled trials (RCTs), RoB-Cochrane tool for RCTs, AMSTAR2 for SLRs. Results: 5641 studies were initially retrieved (Figure 1). After title and screening and removal of duplicates, 568 full-text articles were assessed for eligibility. Finally, 293 articles were included in the SLR. Most studies were of medium quality. Reasons for exclusion are shown in Figure 1. Results categorized as per type of microbe, are as follows: For Tuberculosis;evidence suggests that tuberculin skin test (TST) is affected by treatment with glucocorticoids and conventional synthetic DMARDs (csDMARDs) and its performance is inferior to interferon gamma release assay (IGRA). Agreement between TST and IGRA is moderate to low. Conversion of TST/IGRA occurs in about 10-15% of patients treated with biologic DMARDs (bDMARDs). Various prophylactic schemes have been used for latent TB, including isoniazide for 9 months, rifampicin for 4 months, isoniazide/rifampicin for 3-4 months. For hepatitis B (HBV): there is evidence that risk of reactivation is increased in patients positive for hepatitis B surface antigen. These patients should be referred for HBV treatment. Patients who are positive for anti-HBcore antibodies, are at low risk for reactivation when treated with glucocorticoids, cDMARDs and bDMARDs but should be monitored periodically with liver function tests and HBV-viral load. Patients treated with rituximab display higher risk for HBV reactivation especially when anti-HBs titers are low. Risk for reactivation in hepatitis C RNA positive patients, treated with bDMARDs is low. However, all patients should be referred for antiviral treatment and monitored periodically. For pneumocystis jirovecii: prophylaxis with trimeth-oprim/sulfamethoxazole (alternatively with atovaquone or pentamidine) should be considered in patients treated with prednisolone: 15-30mg/day for more than 4 weeks. Few data exist for screening and prophylaxis from viruses like E B V, CMV and Varicella Zoster Virus. Expert opinion supports the screening of rare bugs like histoplasma and trypanosoma in patients considered to be at high risk (e.g living in endemic areas). Conclusion: The risk of chronic and opportunistic infections should be considered in all patients prior to treatment with immunosuppressives/immunomod-ulators. Different screening and prophylaxis approaches are described in the literature, partly determined by individual patient and disease characteristics. Collaboration between different disciplines is important.

PNEUMOCYSTIS JIROVECI PNEUMONIA IN A PATIENT WITH SARCOIDOSIS ON CHRONIC STEROIDS

CASE: A 75-year-old male with history of sarcoidosis, heart failure, atrial fibrillation, hypertension, and mitral valve replacement presented to the emergency department with dyspnea and dry cough for one week. He endorsed fatigue and chills, but denied subjective fever, weight loss, edema, or congestion. Vitals were notable for a temperature of 100.3 F, respiratory rate of 25, and SpO2 of 82% on room air, which increased to 95% on 10 L of oxygen. Physical exam revealed clear lung sounds bilaterally without accessory muscle use. Labs showed a leukocytosis of 15.6, hemoglobin of 11.6, and pro-BNP of 631.2. ABG revealed compensated respiratory alkalosis. BMP, troponin, EKG, and COVID-19 PCR tests were all unremarkable. Of note, the patient had been on prednisone 10 mg daily for the past four years for sarcoidosis which was increased to 20 mg daily one month prior. After admission, further work-up revealed elevations in pro-calcitonin of 0.61, LDH of 396, and 1,3-beta-D-glucan of >500. Chest CT revealed bilateral scattered ground-glass opacities and underlying evidence of chronic interstitial disease. The patient was continued on a higher dose of prednisone 40 mg twice daily and started on atovaquone 750 mg twice daily for empiric Pneumocystis jiroveci pneumonia (PJP) therapy. Unfortunately, he continued to deteriorate and required intubation. His bronchoalveolar lavage fluid returned positive for Pneumocystis jiroveci by DFA. The patient was started on high- dose TMP-SMX. However, he developed DIC, bilateral upper extremity DVTs, and hyperkalemia thought to be secondary to TMP-SMX. The family decided to withdraw care and the patient passed. IMPACT/DISCUSSION: The role of Pneumocystis jiroveci pneumonia (PJP) prophylaxis in non-HIV patients on chronic steroids remains poorly elucidated and lacks evidence in literature. While some experts support prophylaxis for those on daily prednisone equivalents of greater than 20 mg for over 4 weeks, others suggest that daily prednisone equivalents of greater than 30 mg for over 12 weeks should warrant prophylaxis. We describe a patient with sarcoidosis who was on 20 mg of daily prednisone for over 4 weeks without PJP prophylaxis and subsequently died while battling PJP. Nearly 53% of PJP infections occur in nonHIV patients. Studies in patients with leukemia or organ transplant have shown that PJP prophylaxis with TMP-SMX decreases PJP occurrence by 85% and PJP-related mortality by 83%. The scarcity of literature on the use of PJP prophylaxis, particularly in those with chronic lung diseases such as sarcoidosis that require prolonged steroids, impedes timely consideration of PJP prophylaxis and poses a significant risk to these patients. CONCLUSION: We describe a patient with sarcoidosis on chronic steroids who subsequently developed a fatal case of PJP. Our case highlights the need to consider PJP as a differential diagnosis in non-HIV patients on steroids, and more importantly, to consider PJP prophylaxis in these individuals.

In silico Drug Repurposing for the Identification of Antimalarial Drugs as Candidate Inhibitors of SARS-CoV-2

Background: Coronavirus disease (COVID-19) is a severe acute respiratory condition that has affected millions of people worldwide, indicating a global health emergency. Despite the deteriorating trends of COVID-19, no drugs are validated to have substantial efficacy in the potential treatment of COVID-19 patients in large-scale trials. Methods: This study aimed at identifying potential antimalarial candidate molecules for the treatment of COVID and evaluating the possible mechanism of action by in silico screening method. In silico screening studies on various antimalarial compounds, like amodiaquine, chloroquine, hydroxychloroquine, mefloquine, primaquine, and atovaquone, were conducted using PyRx and AutoDoc 1.5.6 tools against ACE 2 receptor, 3CL protease, hemagglutinin esterase, spike protein of SARS HR1 motif, and papain-like protease virus proteins. Results: Based on PyRx results, mefloquine and atovaquone were found to have higher docking affinity scores against virus proteins compared to other antimalarial compounds. Screening report of atovaquone exhibited affirmative inhibition constant for spike protein of SARS HR1 motif, 3CL protease, and papain-like protease. Conclusion: In silico analysis reported atovaquone as a promising candidate for COVID 19 therapy.

Atovaquone for Treatment of COVID-19 (Ataq COVID-19) Trial

Background. Our group performed an in-silico screen to identify FDA approved drugs that inhibit SARS-C0V-2 main protease (Mpro), followed by in vitro viral replication assays, and in vivo pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. Methods. Enrolled patients were randomized in a 2:1 fashion to atovaquone 1500 mg twice daily versus matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Patients agreed to allow collection of saliva at baseline and twice a day while hospitalized or up to 10 days. Saliva was collected and RNA extracted for viral load (VL) measurement by Real-time PCR. Our primary outcome was to examine the between group differences in log transformed VL(copies/mL) using generalized linear mixed-effect models of repeated measures from all samples. Additional analysis of Atovquone plasma concentrations were examined and correlated with viral load and body mass index (BMI). Results. Of the 61 patients enrolled;41 were received atovaquone and 19 placebo. Overall the population was predominately male Hispanic with a mean age of 51 years. The two groups were balanced (Table 1) with regard to age, gender, race, co-morbidities, days from onset of symptoms, baseline oxygen requirements, and receipt of COVID-19 specific standard of care treatment. A higher proportion with diabetes was noted in the Atovaquone arm. The log10 VL was 5.25 copies/mL vs. 4.79 copies/mL at baseline in the atovaquone vs. placebo group. Although there was a decrease in VL over time, there was no differences between the atovaquone plus standard of care arm versus the standard of care arm (Figure 1). Additional analysis of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, inverse association between atovaquone levels and BMI (rho -0.44, p=0.03), and Day 5 concentrations and VL (rho -0.54, p=0.005). Conclusion. Although atovaquone showed promising in vitro antiviral properties for COVID-19, in this pilot study we did not detect a change in VL in patients who received atovaquone compared to placebo, possibly due to failure of patients achieve adequate drug levels.

Infectious Complications Following Chimeric Antigen Receptor (CAR) T-cell Therapy

Background. Chimeric antigen receptor (CAR-T) T-cell therapy is a novel immunotherapy for cancer treatment in which patients are treated with targeted, genetically-modified T-cells. Common side effects include cytokine release syndrome, neurotoxicity, hypogammaglobulinemia, and increased susceptibility to infections. Long-term infectious outcomes are poorly characterized. Methods. We retrospectively examined patients who received CAR-T therapy at BIDMC & MGH from July 2016 to March 2020 and evaluated bacterial, fungal, viral, and parasitic infections at 3 months intervals to 1 year following cell infusion. The incidence, timing, and outcomes of the infectious complications were evaluated. Results. In total, there were 47 patients;averaging 61.4 years of age (±12 years). Primary indications for CAR-T therapy included diffuse large b-cell lymphoma (65%) and multiple myeloma (25%), chronic lymphocytic leukemia (2%) and mantle cell lymphoma (2%). Patients had received an average 4 ± 2.9 lines of chemotherapy prior to CAR-T infusion;19 subjects (40%) had a history of prior autologous stem cell transplant. All patients received acyclovir for antiviral prophylaxis and most received either trimethoprim-sulfamethoxazole (24/47;51%) or atovaquone (16/47;34%) for pneumocystis prophylaxis. In the first year, 35/47 (74.5%) of subjects experienced at least one infection with an infection rate of 84.4/10,000 person days. Median time to first infection was 59 days (range 1-338 patient days). 31/47 (66.0%) subjects had at least one bacterial infection, with pulmonary (42/113;37.2%) sources being the most common site of infection. 13/47 (27.7%) of patients had a viral infection (predominantly respiratory viral infections) and 6/47 (12.8%) had a proven or probable fungal infection. Death attributed to infection was noted in 2 subjects (4.3%), both related to COVID-19. Baseline IgG levels were significantly lower in the group with infections (p=0.028), while white blood cell count and absolute neutrophil counts were comparable. Conclusion. Infectious complications, particularly of bacterial etiology, are common in the first year following CAR-T therapy. These data may inform future prophylactic strategies in this patient population.

Nocardiosis in Renal Transplant Recipients Linked to Decreased Utilization of Trimethoprim/Sulfamethoxazole during COVID-19

Background. The renal transplant population is at increased risk of Nocardiosis due to impaired T-cell mediated immunity with immunosuppression. Pneumocystis jirovecii (PJP) prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX) provides coverage against Nocardia spp. unlike alternative agents such as atovaquone (ATQ), aerosolized pentamidine (AP), and dapsone. During the COVID-19 pandemic, patients receiving AP were transitioned to ATQ to avoid the use of nebulized medication. This, in turn, led to decreased use of TMP/SMX as patients on oral ATQ were not reassessed for the use of TMP/SMX as would have occurred while on AP. Additionally, an increased incidence of Nocardia infections was observed during this time. The objective of this study was to determine the association between the incidence of Nocardia infections and number of TMP/SMX prophylaxis-days in preversus COVID-19 cohorts. Methods. This was a single center retrospective chart review of all renal transplant recipients between September 2018 - August 2019 (pre-COVID-19 cohort) and April 2020 - March 2021 (COVID-19 cohort). Patients were included if they were at least 18 years of age and a recipient of a cadaveric or living donor kidney transplant. Exclusion criteria included multi-organ transplant, pediatric patients, and repeat transplants. The primary outcome was incidence of Nocardiosis within the first 6 months post-transplant in the pre- and COVID-19 cohorts. Results. A total of 218 patients were included (Table 1). Induction therapy and initial immunosuppression did not differ significantly between groups, nor did rates of rejection within 180 days of transplant (Table 2). Although the pre-COVID-19 cohort had a higher rate of neutropenia, there was no difference in median absolute lymphocyte count between the two groups. The COVID-19 cohort had a decreased percentage of TMP/SMX prophylaxis-days (59.2% vs. 72.5%, p < 0.0001) and an increased incidence of Nocardia infections in the first 6 months post-transplant (4% vs. 0%, p=0.0292). All 4 cases of Nocardia infections occurred in patients receiving ATQ. Conclusion. The increased incidence of Nocardiosis was associated with a decreased use of TMP/SMX for PJP prophylaxis which may have been an unintended consequence of increased use of ATQ in lieu of AP during COVID-19.

TOXIC EPIDERMAL NECROLYSIS FOLLOWING MACROPHAGE ACTIVATION SYNDROME

Introduction: The risk of toxic epidermal necrosis (TEN) depends on both drug and host factors, such as autoimmune disease. We present a case of TEN in a patient with recently diagnosed macrophage activation syndrome (MAS). Case Description: A 23-year-old previously healthy woman was admitted multiple times over 4 weeks for spiking fevers, cervical lymphadenopathy, and macular rash. Her symptoms began one week after her second SARS-CoV-2 mRNA vaccine and did not respond to outpatient treatment with azithromycin and steroids for presumed upper respiratory infection. Extensive infectious evaluation was unrevealing. She had elevated liver enzymes, cytopenias, lymphadenopathy, and splenomegaly. Lymph node and bone marrow biopsies were unrevealing. Further evaluation demonstrated elevated triglycerides, ferritin, and soluble IL-2 receptor. Natural killer cell function was normal. IL-18 was markedly elevated (181,803 pg/mL) supporting the diagnosis of adult-onset Still’s disease with MAS. Dexamethasone and anakinra were initiated on day 29 of illness with prophylactic atovaquone and pantoprazole. Her symptoms and labs improved until day 57 of illness when she developed a diffuse, painful, blistering maculopapular rash consistent with TEN. Potential culprit drugs were held (pantoprazole, atovaquone, and cephalosporins) and she received a short course of IVIG and cyclosporine in addition to anakinra and steroids. She required prolonged hospitalization for wound care and rehabilitation. She has recovered well and remains on prednisone and canakinumab. Discussion: The widespread innate immune activation from MAS, possibly triggered by preceding vaccination, may have augmented her risk of developing TEN. Treatment was therefore directed towards ongoing MAS in addition to TEN. [Formula presented]

A case of warm autoimmune hemolytic anemia

Introduction Warm autoimmune hemolytic anemia (AIHA) is a rare clinical disease which usually arises during or after concomitant clinical pathologies. Autoantibodies are formed against the red blood cell membrane, destroying them and causing extravascular hemolysis. Case A 68-year-old woman with medical history of anemia requiring transfusions, CAD s/p stents in 2007 and 2021, type 2 diabetes mellitus, hypertension, and COVID-19 infection nine months ago presented with chest pain and shortness of breath on exertion for two months. She described the pain as central, non-radiating chest tightness associated with dyspnea on exertion, which resolved with a few minutes of rest. She originally attributed this chest pain to her recent cardiac stent. Three weeks prior , She was treated for anemia (hemoglobin 5.4 gm/dL) with four units of packed red blood cells. Her hemoglobin increased to 7.9 gm/dL after transfusion with temporary improvement of her symptoms until this presentation. Her admit vitals were BP 154/65, HR 99, RR 20, O2 99% on room air, T 97.9°F. Physical exam was notable for generalized jaundice and scleral icterus. Laboratory results included hemoglobin of 6.5 gm/dL, MCV 106 fL, reticulocyte count 17.3%, peripheral blood smear with polychromatophils, total bilirubin 6.5 mg/dL, lactate dehydrogenase 321 U/L, and haptoglobin <30 mg/dL. Her EKG and troponin were normal. She was found to have hepatosplenomegaly on abdominal ultrasound. Further workup showed a direct antiglobulin test was positive with anti-IgG and complement C3 antibodies. This result confirmed the diagnosis of warm autoimmune hemolytic anemia. She received one unit of packed red blood cells with a subsequent hemoglobin of 6.1 gm/dL. She was then started on rituximab and prednisone with an increase in her hemoglobin to 6.9 gm/dL prior to discharge. The patient was discharged on high dose prednisone, scheduled for further rituximab infusions and given close follow-up with hematology and PCP. Atovaquone was added for pneumocystis jirovecii pneumonia prophylaxis during rituximab and prednisone treatment. Discussion Warm autoimmune hemolytic anemia is the most common type of AIHA, and its prevalence is approximately 170 per million. It can present with symptoms of chest pain, shortness of breath, and dyspnea on exertion which may at first seem to be cardiac in nature. However, further investigation with laboratory workup can reveal underlying hematologic abnormalities which can present similarly with more severe cases of AIHA. Approximately 50-60 percent of warm AIHA are associated with underlying conditions including EBV, HIV, HCV, lymphoproliferative disorders, and immunodeficiency states. It is important to consider AIHA in anemic patients with immunocompromised conditions. Cases have also been reported of new onset AIHA in association with COVID-19 infection, although there is no evidence yet of AIHA occurring several months after resolving COVID-19 infection.

Atovaquone and Berberine Chloride Reduce SARS-CoV-2 Replication In Vitro.

Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is still missing is effective antivirals that can be used at the onset of infections and therefore prevent pandemics. Here, we screened FDA-approved compounds against SARS-CoV-2. We found that atovaquone, a pyrimidine biosynthesis inhibitor, is able to reduce SARS-CoV-2 infection in human lung cells. In addition, we found that berberine chloride, a plant-based compound used in holistic medicine, was able to inhibit SARS-CoV-2 infection in cells through direct interaction with the virion. Taken together, these studies highlight potential avenues of antiviral development to block emerging viruses. Such proactive approaches, conducted well before the next pandemic, will be essential to have drugs ready for when the next emerging virus hits.

Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern.

The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone/atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARS-CoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.

Covid Media Misguidance: A Case Report Highlighting the Influence of Media on Patient Medication Decision Making.

PURPOSE: This case report details the influence of media on patients and the responsibility of health care providers to educate their patients on proper use of medications, and to be aware of potential misadventures based on messages in popular media. SUMMARY: The sudden rise of the COVID19 pandemic has led to media outlets reporting science without necessary peer review and has resulted in preliminary data presented as factual evidence. It is difficult for patients without an extensive medical background in science to fully understand the uncertainty of information shared in popular media. This was demonstrated when preliminary data showed potential promise of hydroxychloroquine for the treatment/prevention of COVID19. This led to patients requesting hydroxychloroquine prescriptions from their providers, as well as stockpiling medication, which led to a shortage. In addition, patients began taking chloroquine containing substances not intended for human consumption. Popular media created a belief in the general public that all antimalarial drugs may work to prevent COVID19. This case report presents an elderly patient that presented to clinic with shortness of breath and lightheadedness. Upon interviewing the patient, it was discovered that he had been taking an old supply of atovaquone and proguanil hydrochloride. Physical exam, and laboratory examination were evaluated to rule out any other etiology with all tests and exams being unremarkable. Two weeks after stopping atovaquone and proguanil hydrochloride, the patient's symptoms completely resolved. CONCLUSION: The media provides a significant portion of the information that patients receive regarding rapidly changing treatment information in a pandemic. It is crucial for health care providers to know what information patients are exposed to, and to educate patients with evidence-based information. Pharmacists are the most accessible health care providers and have a key role in medication review and management. Educating patients on evidence-based use of medications may help avoid harm caused by misinformation from unreliable media sources.