Drug utilization study in patients affected with COVID-19 in a dedicated COVID hospital

Background: There exists a treatment dilemma regarding the optimal and effective use of therapeutic drugs (hydroxychloroquine/chloroquine/azithromycin) for COVID-19. Furthermore, with changing guidelines, the data on drug utilization patterns across India are limited. Hence, this study was conducted to assess the prescription pattern and drug utilization trends in COVID-19 patients with the aim to study the drug utilization pattern in patients affected with COVID-19 in a dedicated COVID-19 hospital. Aims and Objectives: The objectives of the study are as follows: (1) To study drug utilization patterns according to the severity of the disease. (2) To study the prevalence of adverse drug reactions (ADRs). Materials and Methods: Data were collected retrospectively from 100 medical records of patients 18 years irrespective of sex admitted in the COVID ward and ICU of a dedicated COVID hospital from May to August 2020. Pregnant and lactating women were excluded from the study. ADRs reported were also analyzed. Results: About 71% were mild in this study, 18% were moderate, and 11% were severe COVID-19 patients. Overall, the most common drugs prescribed were multivitamins, followed by pantoprazole, paracetamol, and azithromycin. Hydroxychloroquine was prescribed in 22%, favipiravir in 7%, and remdesivir in 3% of cases. The majority of moderate COVID patients received injectables piperacillin-tazobactam, methylprednisolone, and enoxaparin. The mean number of medications, duration of admission, and number of days on oxygen were higher and significant in moderate compared to mild and severe COVID patients. Overall, ADRs were encountered in 9% of cases. Conclusion: The prescribed pattern of drugs was by the national standard guidelines. Multivitamins, followed by pantoprazole, paracetamol, and azithromycin dominated the prescription pattern. Polypharmacy was encountered, which needs to be addressed for the rational use of drugs.

Management of Acquired von Willebrand Syndrome During Prolonged VV-ECMO

Acquired von Willebrand syndrome (AVWS) contributes to bleeding during extracorporeal membrane oxygenation (ECMO) support. Although it is recognized that AVWS rapidly resolves after ECMO decannulation, this approach may often be clinically unsuitable. In such cases, optimal AVWS management during ECMO support is not well established. We report our approach to managing AVWS in a patient on veno-venous (VV) ECMO for 59 days. A 19-year-old male developed hypoxemic respiratory failure from SARS-CoV-2 pneumonia. Following intubation, he progressed to VV-ECMO support for refractory hypoxemia and was started on bivalirudin for systemic anticoagulation. Two days later, he developed refractory gastrointestinal and oro-nasopharyngeal bleeding despite blood product transfusions and discontinuing bivalirudin. He was started on pantoprazole along with infusions of octreotide and aminocaproic acid. Upper endoscopy on ECMO day 5 revealed an ulcerative bleeding vessel in the duodenum that was clipped. Recurrent mucosal bleeding precluded resumption of systemic anticoagulation. On ECMO day 23, AVWS was diagnosed based on elevated von Willebrand factor (VWF) activity (207%, normal 55-189%) and antigen (234%, normal 50-210%) levels with abnormally low VWF high-molecular-weight multimers. Factor VIII complex was administered twice over the following week. Between doses, the ECMO circuit was exchanged to empirically mitigate suspected shear-related VWF consumption from the fibrin burden, and a repeat endoscopy controlled additional intestinal bleeding with local hemostatic agents. He received 36 units of red blood cells, 2 units of platelets, 2 units of plasma, and 7 pooled units of cryoprecipitate over 31 days leading into these combined interventions. In the 28 days afterwards, he received 3 units of red blood cells, 3.5 pooled units of cryoprecipitate, and no additional platelets or plasma. Our patient was maintained off systemic anticoagulation for 54 of 59 days of VV-ECMO support without any thrombotic complications occurring. With no subsequent clinical evidence of bleeding, repeat VWF testing was done two months post-decannulation and showed near-normal VWF activity (54%) and normal multimer distribution. Our patient rehabilitated well without any neurologic deficits and on discharge was requiring supplemental oxygen with sleep and strenuous activity. Avoiding systemic anticoagulation, repleting VWF, maintaining circuit integrity, and providing local hemostasis, when possible, may be a safe and effective management strategy of AVWS on ECMO support when decannulation is not a viable option.

Esophageal Mucosal Calcinosis: A Rare Site of Calcium Deposition in End-Stage Renal Disease

Introduction: Calciphylaxis, otherwise known as calcium uremic arteriolopathy, is defined as calcium deposition around blood vessels in skin and fat tissue which occurs in 1-4% of patients with end-stage renal disease (ESRD). Calcium deposition in the esophagus is extremely rare;to date, there have been only 4 cases reported worldwide. We report the fifth case of esophageal mucosal calcinosis occurring in a young male with ESRD. Case Description/Methods: A 37-year-old Thai man with ESRD on peritoneal dialysis since 2005 presented with generalized weakness and odynophagia due to oral ulcers, resulting in poor PO intake. He denied drinking alcohol, illicit drug use, or smoking. On exam his abdomen was soft, non-distended, non-tender, without any guarding. Past medical history included hypertension and COVID-19 in January 2022. Laboratory tests revealed neutropenia and pancytopenia, hyperphosphatemia, and hypocalcemia. EGD revealed distal esophageal esophagitis and hemorrhagic erosive gastropathy. Biopsy showed ulcerative esophagitis with dystrophic calcification, consistent with esophageal mucosal calcinosis .No intestinal metaplasia was noted. Immunohistochemistry was negative for CMV, HSV1, and HSV2. The patient was treated with pantoprazole 40mg IV every 12 hours, Magic Mouthwash 5ml qid, and Carafate 10mg qid. He was transferred to a cancer center where he had a bone marrow biopsy formed which was negative. His symptoms resolved and the patient was discharged to home (Figure). Discussion(s): Esophageal mucosal calcinosis is extremely rare. It is due to a combination of factors involving acidosis and the phenotypic differentiation (and apoptosis) of vascular smooth muscle cells (VSMC) into chondrocytes or osteoblast-like cells. These changes, along with the passive accumulation of calcium and phosphate, induce calcification. Acidosis is well-known to promote inflammation of the arterial walls, releasing cytokines that induce vascular calcification. The benefits of treatment with sodium thiosulfate remain unclear. An ample collection of cases should help devise standardized treatment options and establish management guidelines for this condition.

A Case of Primary Biliary Cirrhosis With New Onset Hyperthyroidism and Supratherapeutic INR

Introduction: Hyperthyroidism is known to increase catabolism of vitamin-K-dependent clotting factors (II, VII, IX, X) and increase the response of vitamin K antagonists, usually warfarin. Primary biliary cirrhosis (PBC) has been associated with thyroid dysfunction (TD), especially with autoimmune thyroid disease. In the below case, a patient with known PBC on warfarin is found to have severely elevated INR related to new-onset hyperthyroidism with clinical consequences of hemorrhage including upper GI bleed. Case Description/Methods: A 64-year-old female with PBC and antiphospholipid antibody syndrome on warfarin was admitted for hemorrhagic epiglottitis requiring emergency intubation and supratherapeutic INR. Her PBC was diagnosed as stage II on biopsy 23 years ago and has remained clinically stable on ursodiol therapy. On presentation, the patient was tachycardic, tachypneic, and had O2 saturations <90% on HFNC prior to intubation. Physical exam significant for larger goiter with diffuse upper airway swelling. She was admitted and found to have COVID-19 infection, INR .16.0 and PT>200.0 (limit of lab), WBC of 22.8, and lactate of 2.5. LFTs WNL aside from albumin of 2.0. TSH was <0.0017 (limit of lab) and free T4 of 3.4, free T3 of 5.3. TSH receptor antibody (TRAB) and thyroid stimulating immunoglobulin (TSI) levels were normal. Her last TSH was normal a year ago. CTA chest found a 5.7cm heterogeneous, partially calcified superior mediastinal mass consistent with multinodular thyroid goiter. Patient was initially given prothrombin complex concentrate and vitamin K with correction of INR over the following few days. She was extubated and started on methimazole. During the hospital course, she was found to have coffee ground emesis for which an EGD was done with findings of non-bleeding gastric ulcer (Forrest Class IIc) and LA Grade D esophagitis with adherent clot and bleeding for which hemostatic spray was applied. Patient was discharged a few days later following resumption of warfarin and on pantoprazole and methimazole. Discussion(s): The above case demonstrates a rare case of PBC and new-onset hyperthyroidism due to multinodular thyroid goiter causing significantly elevated INR in the setting of warfarin use with hospital course complicated by GI bleed. PBC is associated with TD - hyperthyroidism, hypothyroidism, and thyroid cancer. Hyperthyroidism is less commonly associated with PBC compared to other TDs but should be considered especially with a finding of elevated INR.

Acute Pancreatitis as a Rare and Unusual Manifestation of COVID-19 in a Child with Acute Lymphoblastic Leukemia

Introduction: The coronavirus disease 2019 (COVID-19) mainly causes pulmonary disease. However, extrapulmonary manifesta-tions, which affect the gastrointestinal tract and hepatobiliary system, have been reported. Case Presentation: Here we reported a 4-year-old boy with acute lymphoblastic leukemia and abdominal pain who had acute necrotic pancreatitis secondary to COVID-19. Conclusion(s): According to the COVID-19 epidemic, if drug-induced pancreatitis is ruled out, viral causes, especially COVID-19, should be considered.Copyright © 2023, Author(s).

Idiopathic anomalous congenital band causing small intestinal obstruction in a 5-month-old dog

A 5-month-old, intact male, yellow Labrador retriever was presented with a 24-hour history of anorexia and vomiting. Abdominal imaging revealed the presence of a mechanical obstruction in the jejunum and peritoneal effusion. Cytologic evaluation and culture of the effusion prior to surgery identified a suppurative exudate with bacteria consistent with septic peritonitis and suspected to be related to the intestinal lesion. An exploratory laparotomy was performed, and a segment of jejunum was circumferentially severely constricted by an off-white, fibrous band of tissue. Resection and anastomosis of the strangulated segment of jejunum and excision of the constricting band provided resolution of the clinical signs. The dog made a complete recovery. Histologic evaluation revealed the band to be composed of fibrovascular and smooth muscle tissue, consistent with an idiopathic anomalous congenital band. No other gastrointestinal lesions were observed, either grossly at surgery or histologically in the resected segment of intestine. To our knowledge, a similar structure has not been reported in the veterinary literature.Copyright © 2022 Canadian Veterinary Medical Association. All rights reserved.

Safety profile of CoviShield (ChAdOx1nCoV-19) vaccine among healthcare workers in a tertiary care hospital

Background: Coronavirus 2019 was declared as a pandemic by the World Health Organization in March 2020. Bereft of specific treatment for the disease, vaccinations and COVID appropriate behavior have come to be the main approaches to combat the pandemic. A number of vaccines have been approved after clearing clinical trials. Hence, it is essential to evaluate the safety profile of each vaccine for ensuring optimum health of the general population. This study was conducted to evaluate the adverse events following CoviShield vaccination in a tertiary care center. Aims and Objectives: The aim of the study was to describe the pattern of adverse effects, treatment given, and comorbidities seen in healthcare workers (HCW) who reported to the adverse drug reaction (ADR) monitoring center in the department of pharmacology Government T.D. Medical College, Alappuzha, following CoviShield vaccination from January 2021 to October 2021. Material(s) and Method(s): A retrospective and descriptive study was carried out at Department of Pharmacology, GTDMCA involving all HCW who reported side effects following CoviShield vaccination in the ADR monitoring centre (AMC) in the Department of Pharmacology, GTDMCA from January 2021 to Oct 2021. Result(s): Out of 620 HCWs who reported adverse event following vaccination, majority (45%) were from the age group 21-30 years. About 83% of HCWs who reported adverse effect were women. Majority of the respondents (96%) experienced the adverse effects within 24 h. About 88% of respondents experienced these adverse effects after the initial dose alone. Commonly encountered adverse effects were fever (57%), headache (43%), myalgia (38%) etc. Hypertension (7%) was the most common comorbidity seen. Majority of the beneficiaries (70%) took paracetamol for the treatment of the adverse effect. Conclusion(s): Majority of the vaccinated HCWs experienced minor and self-limiting adverse event following immunization (AEFI) with Chimpanzee Adenovirus Oxford novel CoronaVirus-19. No serious AEFI were reported to the AMC. Despite the record speed at which the vaccine has been developed, it has shown to have a good safety profile considering the millions of doses that have been administered.Copyright © 2023 Sai Nathan R, et al.

Sars-Cov-2 and Mrna Vaccine-Associated Recurrent Pericarditis Treated with Rilonacept

Background While rare, pericarditis is associated with both acute infection by SARS-CoV-2 as well as the Moderna mRNA-1273 vaccine. The interleukin-1 (IL-1) blocking drugs show promise in cases unresponsive to traditional therapy. Rilonacept is a fusion protein IL-1 alpha and beta cytokine trap which binds and inactivates circulating IL-1. The FDA approved it for the treatment of recurrent pericarditis in 2021. Case A 35-year-old man presented complaining of progressively worsening sharp chest pain aggravated by supine positioning, fatigue, and intermittent low-grade fever two weeks after a booster dose of the mRNA-1273 vaccine. His only past medical history was persistent tachycardia following SARS-CoV-2 infection in early 2020, now well controlled with a metoprolol tartrate. Acute pericarditis was diagnosed by history and echocardiography which showed a small pericardial effusion and enhancement of the pericardium. He was treated successfully with high-dose ibuprofen. Four months later, the patient presented with similar symptoms and echocardiography results following SARS-CoV-2 infection. He was prescribed indomethacin, colchicine, and pantoprazole. The patient returned after two weeks and reported his symptoms were unchanged. Decision-making In this setting of recurrent pericarditis, the standard treatment was ineffective despite a good previous response. Rilonacept was instead initiated. He received a 320 mg dose and reported resolution of symptoms after four days. The patient continued taking rilonacept 160 mg subcutaneously once weekly, and three months later he was again diagnosed with PCR-confirmed acute symptomatic SARS-CoV-2 infection. He continued to take rilonacept weekly and at a follow-up eight weeks after recovering, he reported no recurrence of pericarditis symptoms. Conclusion This case shows that rilonacept is an effective treatment for SARS-CoV-2 and mRNA vaccine-associated pericarditis, and implies that cytokine dysregulation is a significant contributor to its pathogenesis. Furthermore, the case suggests that rilonacept may prevent recurrence of pericarditis in a susceptible individual acutely diagnosed with SARS-CoV-2Copyright © 2023 American College of Cardiology Foundation

Ouch!My Chest. Pfizer-biontech COVID-19 Vaccination Induced Acute Myopericarditis: A Case Report

Introduction: During the pediatric trials for Coronavirus disease 2019 (COVID-19) vaccine the patient population was limited, likely leading to an inappreciable amount of adverse events. As more of the healthy adolescent male population began receiving the COVID-19 vaccination, cases of myocarditis shortly after became more frequently seen. Case Description: A previously well 15-year-old obese male presented to a pediatric ER with 3 days of left arm pain and 1 day of acute left-sided chest pain three days after receiving his second Pfizer-BioNTech COVID-19 vaccine in his left anterior deltoid area. The patient felt unwell afterwards with myalgias, headache, numbness, tingling, emesis, and 1-day history of fever of 38.8°C. He denied feelings of dizziness, syncope, palpitations, change in pain with position or deep breaths. Motrin and Tums did not seem to provide any relief. He had no history of recent viral illness and no known COVID-19 exposure. Initial evaluation included a normal chest Xray and normal sinus rhythm on EKG. Laboratory work revealed elevated troponin-I at 3.18 ng/mL, elevated Total CK at 399 units/L, CK-MB at 19 ng/mL, and BNP <10 pg/mL. Cardiology was consulted and following a normal echocardiogram, the patient was sent for a stat cardiac MRI. The imaging revealed acute myopericarditis with a small pericardial effusion. Mild patchy delayed subepicardial enhancement was also noted in the mid cavity and basal posterolateral wall (suggestive of postinflammatory scarring related to localized myocarditis.) During this time, CK-MB and Troponin-I continued to trend upwards. The patient was then started on standard treatment with Ibuprofen 800 mg Q6H and pantoprazole for gastric protection. His CK-MB peaked at 174 and Troponin-I at 26 which both subsequently trended downwards and normalized prior to discharge. Discussion: Patients who present with chest pain require a broad differential to encompass other possible etiologies including Coxsackie virus, Echovirus, Mycoplasma, EBV, and even Syphilis. Infectious diseases also followed along with the patient throughout his hospital course. All work-up for other potential causes remained negative. 1 week after presentation, his cardiac markers returned to baseline normal values. Conclusion: The study included close to 3,000 adolescents with only 754 ranging in the 16-17 age group further emphasizing the limited power of the study. Myocarditis and pericarditis are known, however rare, side effect of vaccinations and is seen more commonly in males. As the time period between receiving the COVID-19 vaccination and presenting with cardiac symptoms is short it is crucial to provide rapid care and adequate treatment.

A Young Heart Broken: A Case of COVID-19 Associated Multisystem Inflammatory Syndrome Resulting in New Onset Heart Failure in an Adult

Introduction: COVID-19-related Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare complication seen 2 to 6 weeks after the resolution of an acute COVID-19 infection. There has been only one described case of COVID-19 related hyperinflammatory syndrome in adults. Here we present a case of COVID-19 associated MIS causing myocarditis and new onset heart failure with reduced ejection fraction in an adult. Case Description: A 23 year-old male presented with fever, fatigue, exercise intolerance, myalgias, headaches, and a positive COVID-19 PCR test approximately 5 weeks earlier. On admission, the patient was noted to be febrile to 102.2, tachycardic, and hypotensive. Physical exam notable for bilateral conjunctival irritation and trace lower extremity edema. Labs on admit were significant for creatine of 1.67, mild transaminitis, BNP 262, Troponin 0.67, and WBC 12.8. Bedside echo performed in the ED was significant for a decreased LVEF 40-45%, global hypokinesis, and collapsible IVC. The patient was empirically treated with vancomycin and zosyn for possible sepsis however blood cultures remained clear and no source of infection was ever identified. Inflammatory markers were elevated with a LDH 252, D-Dimer 588, Ferritin 1,500, CPK 108, and CRP of 28. Angiogram of chest showed no evidence of acute cardiopulmonary/airspace disease, no pulmonary embolism. Troponins peaked at 1.64 and CRP peaked at 37. Discussion: The patient continued to worsen with no obvious source of infection with a pattern of inflammatory markers consistent with MIS in the setting of recent COVID-19 infection. The severity of his presentation prompted treating the patient according to MIS-C guidelines developed for children which included IVIG, IV steroids, and high dose aspirin which resulted in a quick resolution of his fever and improvement in his cardiac function and end-organ labs and markers. Patient was discharged home on aspirin and pantoprazole. Follow up echocardiogram one month later demonstrated a return of normal cardiac function. Conclusion: Our understanding of acute COVID-19 infection, its sequelae, and long term complications is rapidly evolving. A MIS-C-like illness should be considered in adults presenting with atypical clinical findings and a recent COVID-19 infection. Pediatric conditions have the potential to present later in life, as physicians we must remain vigilant in our assessment, especially in the setting of an evolving global pandemic.

TRANSVERSE MYELITIS: A RARE BUT SERIOUS COMPLICATION OF COVID-19 VACCINATION

CASE: The patient is a 66-year-old male presenting with progressive ambulatory dysfunction and lower extremity weakness that began ten days ago. Notably, the patient was admitted to the hospital two months prior with similar complaints. At that time, he was diagnosed with transverse myelitis after MRI showed a spinal cord lesion concerning for demyelination at T3-T4. The patient was treated with IV steroids and discharged. Neurology impression at time of discharge was transverse myelitis possibly related to Covid vaccination two weeks prior to admission. The patient states he was doing fine after initial discharge before recurrence of his progressive weakness and difficulty walking that led to the current admission. He denies fever, chest pain, abdominal pain, and bladder/ bowel incontinence. The patient is a former smoker and denies current alcohol or drug use. Past medical history includes WPW status post ablation, stable thoracic aortic aneurysm, peripheral neuropathy secondary to past alcohol abuse, osteoarthritis, GERD, and anxiety. Family history is remarkable for cancer, coronary artery disease, and diabetes in his father. Medications include metoprolol, tamsulosin, pantoprazole, olanzapine, and venlafaxine. Neurological exam is positive for atrophy and decreased vibratory sensation in bilateral lower extremities. His gait is not assessed due to safety concerns, but the patient notes he has begun using a cane to assist with ambulation. Otherwise, physical exam is unremarkable. Imaging studies include MRI showing T3-T4 hyperintensity, as seen during previous admission two months prior. Labs including ANA, rheumatoid factor, SPEP, CSF studies, and AQP-4 were negative. After an unrevealing workup, the patient experienced symptomatic improvement with IV steroids and was discharged home. IMPACT/DISCUSSION: Our case illustrates a clinical picture of Covid-19 vaccine-related transverse myelitis, a rare but serious complication of the vaccine. The prolonged course of this patient's complications is concerning, although the benefit of receiving the vaccine remains unquestionable. Furthermore, although the timing of symptom onset and vaccination suggests a relation, there are other diagnoses that could explain the presentation and further research is needed regarding vaccine-related side effects. This case emphasizes the importance of maintaining a high index of suspicion for neurological issues of unclear etiology following recent Covid-19 vaccination despite their rare occurrence. CONCLUSION: Teaching points: Diagnostic criteria for transverse myelitis includes sensory, motor, or autonomic dysfunction attributable to spinal cord, no evidence of cord compression, bilateral symptoms with clear sensory level, and inflammation defined by CSF analysis, elevated IgG, or MRI enhancement. Neurological complications of the Covid vaccine include general symptoms such as headache, fever, and fatigue, Bell's palsy, encephalomyelitis, myelitis, and cerebral venous sinus thrombosis.

Dysgeusia and Appetite Loss: Thinking Beyond MDD and COVID-19

Background: Dysgeusia is a distortion of taste sensation. Etiologies can include medications and Covid-19, among others. Dysgeusia may lead to appetite loss which is nonspecific and can have multiple causes, including major depressive disorder (MDD) (Coulter, 1988). Although post-marketing data revealed no association between nifedipine and dysgeusia (Ackerman, 1997), case reports of dysgeusia from nifedipine exist (Ackerman, 1997). We present a case of nifedipine-induced dysgeusia mistaken for depression. Case Report: A 42-year-old man with hypertension and diabetes was admitted to the hospital following right thalamocapsular and intraventricular hemorrhages. Hypertension was managed with metoprolol, lisinopril, nifedipine, and chlorthalidone. Levetiracetam was started for seizure prophylaxis. Medications included pantoprazole, simethicone, transdermal lidocaine, insulin, metformin, docusate, senna, and subcutaneous heparin. Psychiatric consultation was requested out of concern that appetite loss indicated depression. The day before psychiatric evaluation, mirtazapine 15 mg at bedtime for mood and appetite was started. Nifedipine 90 mg daily had been started 9 days prior to his first complaint of decreased appetite. The patient reported feeling disconnected from his family and “sad" for ∼10 years, complaining that family members “talk behind his back.” He was otherwise without paranoia. He denied insomnia, anhedonia, hopelessness, poor concentration, suicidal ideation, homicidal ideation, guilt, mania, or hallucinations. He reported poor appetite due to epigastric discomfort and bad taste to foods. Covid-19 testing was not yet widely available. No other signs or symptoms suggestive of Covid-19 were present. Although alert and fully oriented, concentration was impaired with sometimes tangential thought processes. Affect was full without depression. A diagnosis of adjustment disorder was made. The psychiatry team suspected nifedipine-induced dysgeusia and advised discontinuing nifedipine. Appetite improved two days later. Discussion: This case highlights the importance of considering alternative causes of nonspecific symptoms of depression, including decreased appetite, that may have non-psychiatric causes. Dysgeusia is widely recognized as a symptom of Covid-19. Other causes, including medications may be underrecognized and amenable to intervention. Conclusion: It would be helpful to consider medication side-effects as potential causes for taste distortion alongside psychiatric diagnoses, and COVID-19. References: 1. Coulter DM: Eye pain with nifedipine and disturbance of taste with captopril: a mutually controlled study showing a method of post marketing surveillance BMJ 1988;296: 1086–8. 2. Ackerman BH, Kasbekar N: Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997;17(3):482-96.

A CASE REPORT ON COVID- 19: REVIEW OF MEDICATIONS

Rationale: COVID-19 is also known as Novel coronavirus 2019 or acute respiratory syndrome caused due to coronavirus or SARS-CoV-2 is an RNA virus belongs to β- Coronaviridae family.COVID also causes severe pneumonia and acute respiratory distress syndrome (ARDS), which can result in difficulty breathing and necessitate mechanical ventilation and intensive care unit management. Patient concerns: A 47-yearmale with a history of hypertension who was presented to hospital with worsening fevers, cough, and respiratory distress. Diagnosis: CT scan of the chest showed multiple subsegmental patchy ill, defined broncho centric and sub-pleural areas of ground glass opacities with septal thickening are seen in both the lungs and test of COVID also turned positive. Interventions: He was being treated aggressively in the intensive care unit with intravenous Prednisolone, Felbinac, Piperacillin/tazobactam.He also received a loading dose of remdesivir however was unable to complete the course due to sudden droppage of SP02. Outcomes: He remained critically ill and eventually passed away. Lessons: COVID-19 has become a global pandemic and a major hit to our healthcare systems, with a rapidly rising death rate. There is currently no approved treatment regimen for COVID-19 infections. The alarming increase in cases per day keeps researchers busy to find a cure and to reduce the global mortality rate.

Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial.

BACKGROUND: Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. METHODS: The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. DISCUSSION: The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. TRIAL REGISTRATION: EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). CLINICALTRIALS: gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).

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]

Impact of pantoprazole on absorption and disposition of hydroxychloroquine, a drug used in Corona Virus Disease-19 (Covid-19): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Primary objective: Evaluation of the effect of the proton pump inhibitor (PPI) pantoprazole on the absorption of hydroxychloroquine (HCQ). Secondary objectives: • Evaluation of the relationship between HCQ concentrations in whole blood, plasma and intracellular concentrations in target cells - peripheral blood mononuclear cells (PBMCs). • Evaluation of HCQ as a potential perpetrator in drug-drug interactions at the level of cytochrome P450 (CYP) 3A4 and CYP2D6 (major drug metabolizing enzymes). TRIAL DESIGN: Single centre, open-label, parallel group, two-arm, phase I drug-drug interaction trial. PARTICIPANTS: Healthy volunteers (18-60 years old) are treated in the Clinical Pharmacological Trial Center of Heidelberg University Hospital, Germany. INTERVENTION AND COMPARATOR: • Participants are randomized in a group to either receive a nine-day course of pantoprazole, or to a control group without pantoprazole. All participants receive a single dose of HCQ 400 mg. • Additionally, CYP3A4 and CYP2D6 phenotyping with microdosed probe drugs is performed using midazolam and yohimbine as enzyme activity markers, respectively. MAIN OUTCOMES: Primary endpoint: Area under the curve (AUC)0-72 h and maximum concentration (Cmax) of a single oral dose of 400 mg HCQ with and without pantoprazole (changes in these two values describe relevant aspects of exposure to HCQ with and without administration of pantoprazole). Secondary endpoints: • AUC2-4 h, AUC0-6 h and Cmax of midazolam and yohimbine. • Correlation of HCQ concentrations in whole blood with concentrations in plasma and peripheral blood mononuclear cells (PBMC). RANDOMISATION: Participants are assigned to treatment groups by using a randomisation list (1:1, block size = 4) and consecutive enrolment. BLINDING (MASKING): The trial is an open-label trial, participants and investigators are not blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total number of 24 participants (12 per group) are planned to be randomised. TRIAL STATUS: Protocol version 2.1 dated 24/04/2020, first patient first visit. April 30th, 2020, recruitment ongoing, anticipated end of study June 30th, 2020. TRIAL REGISTRATION: EudraCT Number: 2020-001470-30 , registered on 31 March 2020 German Clinical trials register number / International Clinical Trials Registry Platform: DRKS00021573, registered on 27 April 2020 FULL PROTOCOL: The full trial protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full trial protocol. The trial protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).