key: cord-0774945-bqat2q88 authors: Singh, S.; John, T.; Kumar, P.; Quadery, S. R. title: The impact of high dose oral cotrimoxazole in patients with COVID-19 with hypoxic respiratory failure requiring non-invasive ventilation: A Case Control Study date: 2021-01-15 journal: nan DOI: 10.1101/2021.01.14.21249803 sha: fda86a43b2ae77fe291165ead2a5e2b9bc7cb15d doc_id: 774945 cord_uid: bqat2q88 Background COVID-19 can be fatal in a significant proportion of people who develop critical illness, resulting in hypoxic respiratory failure secondary to Acute Respiratory Distress Syndrome (ARDS) which is thought to be mediated by a cytokine storm syndrome. Steroids have been shown to be of some benefit, but the mainstay of treatment remains supportive. Methods The data was collected retrospectively from consecutive, newly diagnosed patients presenting to the critical care facility of I Q City Medical College Hospital, Durgapur, India between June and November 2020 with critical COVID-19 on non-invasive ventilation treated with high dose oral cotrimoxazole (CTX) in addition to standard therapy (ST) and compared with patients with critical COVID-19 receiving standard therapy alone. Results 201 patients were identified. Of which 151 patients received CTX in addition to ST (mean age +/- SD 59 +/- 13 years, 81% male and mean BMI +/- SD 28 +/- 2) and 50 patients received ST alone (mean age +/- SD 63 +/- 12, 64% male and mean BMI +/- SD 27 +/- 2). We observed that the patients with critical COVID-19 receiving CTX in addition to ST had significantly better outcomes including reduced in-patient mortality (13% versus 40%, p <0.001), length of hospital and critical care unit stay (mean, 11 versus 15 days (p <0.001) and 6 versus 11 days (p <0.001) respectively), and the need for mechanical ventilation (16% versus 42%, p <0.001) with improved CRP at day 7 (mean, 38mg/L versus 62mg/L, p = 0.001). Conclusion These results may be due to the antibiotic and anti-cytokine effects of CTX. Clinical trials are currently underway to test our observations. Over 10 million people in India have had confirmed Coronavirus Disease 19 , resulting in >150,000 deaths. The disease is self-limiting for the majority of those infected, but for those with critical disease steroids and supportive measures remains the mainstay of treatment. 1 Severity of the disease is related to various factors including male sex, obesity, ethnicity, diabetes and prior cardiac or respiratory diseases. Cotrimoxazole also has effects upon the immune system, although not widely recognised. 10 The cytokine storm may occur as a result of neutrophil recruitment to the lung due to the stimulation of the formyl peptide receptors (FPRs) by formyl peptides also known as Damage associated Molecular patterns which are released upon the mitochondrial injury of the host cells. FPRs are situated on the outside of the neutrophils and monocytes, and when stimulated cause the release of intracellular and extracellular reactive oxygen series (ROS) which can drive the cytokine activation. In addition it stimulates the formation of Neutrophil Extracellular Traps (NETs) which block the alveolar capillary bed leading to significant hypoxaemia. Co-trimoxazole blocks the FPRs and can reduce the movement of neutrophils to the lung and NETosis. In addition sulphamethaxazole inhibits neutrophil activation by inhibiting Phorbol 12-myristate 13-acetate (PMA) stimulation thereby preventing Protein Kinase C activation and reducing inflammation. 11, 12 This offers a possible explanation for the observed clinical benefit by reducing neutrophil, monocyte and lymphocyte activation leading to a reduction in the risk of ARDS. [12] [13] [14] [15] [16] [17] Case reports describing clinical recovery from acute respiratory distress sydrome after the addition of cotrimoxazole are seen in medical literature. 18 Recently more data has been published on the benefits of CTX in severe COVID-19. [19] [20] [21] [22] We have treated nearly 700 patients with severe to critical COVID-19 with co-trimoxazole. Here we report our preliminary findings with the use of cotrimoxazole in the treatment of critical COVID-19, compared with a group of concurrent controls. We retrospectively analysed data obtained from electronic case records and case notes of patients admitted to the critical care facility of the IQ City Medical College Hospital, Durgapur, West Bengal, India from 15 th June 2020 to 15 th November 2020 and followed up until discharge, death or the census date of 30 th November 2020. Data was collected, anonymized and stored in a highly secure, password protected database. Patients admitted with clinically suspected or confirmed COVID -19 were commenced on standard therapy including antibiotics (piperacillin/tazobactam and clarithromycin or azithromycin), dexamethasone, low molecular weight heparin, paracetamol, supplemental . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 15, 2021. ; oxygen therapy, intravenous fluids, antiviral drugs and other investigational therapies based on ICMR guidelines. 23 All the patients had Chest X rays and CT chest scan done on admission which confirmed lung infiltrates in a pattern consistent with a radiological diagnosis of COVID-19. All patients fitted the WHO criteria for critical Cotrimoxazole is licensed for the treatment of respiratory infections and pneumonia. Patients Mortality, progression to mechanical ventilation, length of stay, improvements in CRP and Neutrophil-Lymphocyte Ratio (NLR) at Day 7 were the outcomes analysed. 25, 26 Day 0 in the cases and controls was the day of admission to hospital. Data on comorbidities previously suggested to be linked to higher risk of mortality in COVID- 19 were also compared between the two groups. Continuous data are presented using mean and standard deviation. Comparisons between two groups of continuous data was made using the t-test for parametric and Mann Whitney Utest/Wilcoxon signed rank test for non-parametric data. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101/2021.01.14.21249803 doi: medRxiv preprint Categorical data was presented as number or percentage of patients. For categorical variables comparison between two groups was done using Chi-squared test or Fishers exact test (for small numbers). Prognostic variables were assessed using univariate and multivariate Cox regression analysis for survival. 27 variables in the whole cohort, case and control group were identified based on previous literature and entered into univariate Cox regression analysis. 2 Variables with a p-value of <0.20 at univariate analysis and < 10% missing data were included in the multivariate analysis using forward logistic regression method. A p-value of < 0.05 was considered to be significant. The statistical software SPSS was used for the analysis. Ethical approval was obtained from the IQ City Medical College Hospital Institutional Ethics Committee. Baseline characteristics from anonymized record reviews are shown in table 1 for standard therapy patients and those treated with the addition of CTX to standard therapy. Prior to 'Day 0' these patients had symptoms for a mean duration of 4 days in the CTX and control group. The groups were comparable for age, ethnic group, BMI, chronic lung disease, ischemic heart disease and Hypertension. Diabetes and chronic kidney disease were lower in the CTX added group at 39% and 2.7% respectively, compared with standard therapy alone at 60% and 18% respectively. Male sex was higher in the cotrimoxazole group at 81% compared to 64% in the standard therapy only group. Baseline observations were similar for duration of symptoms, respiratory rate, body temperature, C-reactive protein and NLR (table 1). All patients required either CPAP or HFNC fulfilling the criteria for critical COVID- 19. 24 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101/2021.01.14.21249803 doi: medRxiv preprint Outcome: 87% of patients with added CTX were discharged well without oxygen after a mean length of hospital and critical care unit stay of 11 and 6 days respectively, 15% required mechanical ventilation, while 13% succumbed to the illness (table 2) . Data from the patients receiving standard therapy alone, showed that 60% of patients were discharged with a mean length of hospital and critical care unit stay of 15 and 11 days respectively, 42% required mechanical ventilation, while 40% died. At day 7 patients in both groups showed a significant reduction in C-reactive protein levels compared to day 0, however the reduction was more pronounced in the CTX+ST group compared to the ST only group. In addition, patients with added CTX showed a significant improvement in NLR that was not seen in the group on standard therapy alone. (table 2) . None of the patients in the cotrimoxazole group experienced any side effects warranting stopping of the medication. Univariate and multivariate analysis of the whole cohort, cotrimoxazole with ST and standard therapy only groups identified a number of predictors of outcome (supplementary table S1). In the ST only group male sex (p = 0.191), DM (p=1.00) and CKD (p = 0.299) did not predict survival at univariate analysis. To the best of our knowledge, this is the first study primarily focussing on pharmacological interventions in patients with COVID-19 on non-invasive ventilation. We have compared the baseline characteristics and clinical outcomes in patients who received high dose CTX in addition to ST with patients who received standard only, in a critical care setting. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; In this study we have shown a significant reduction in mortality, intubation rate, length of hospital and critical care stay and inflammatory markers in the CTX+ST group compared to the ST only group in keeping with the study by Quadery and co-workers. 19 The mortality and the rate of intubation in the ST only group was similar to that of current literature where patients with COVID 19 on non-invasive ventilation who were for further escalation was 47% and 57% respectively. 27 The higher dose cotrimoxazole used in our study is indicated in patients with nocardiasis with excellent safety profile. 28 Given that this is a case control study, there may be a potential of selection bias. Despite being a retrospective observational study there was excellent data completeness particularly because the patients were closely monitored in a critical care setting. Use of other investigational drugs . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101/2021.01.14.21249803 doi: medRxiv preprint as part of ST could have been confounding factors, but due to the significantly large difference in the outcomes and no other investigational drug found to be effective in COVID-19 it is obvious that despite the subtle differences in treatment the impact of co-trimoxazole cannot be overlooked. If our observation is confirmed by other large scale studies, then hundreds of thousands of lives could be potentially saved worldwide by the use of this inexpensive, widely avalable and safe drug. In addition reducing hospital stay and use of ventilators could potentialy reduce the overwhelming pressure upon the healthcare resources of developing nations. Furthermore this will improve public confidence in the healthcare system and improve and maintain global economy. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 15, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 15, 2021. ; https://doi.org/10.1101/2021.01.14.21249803 doi: medRxiv preprint The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19A Meta-analysis Clinical predictors of mortality due to 150 COVID-19 based on analysis of 150 patients from Wuhan, China COVID-19 consider cytokine storm syndromes and Immunosuppression CAR T cellinduced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade Management of respiratory failure due to covid-19 Increase in methicillin-resistant Staphylococcus aureus acquisition rate and change in pathogen pattern associated with an outbreak of severe acute respiratory syndrome Severe Pneumonia Caused by Coinfection with Influenza Virus Followed by Methicillin-Resistant Staphylococcus aureus induces Higher Mortality in Mice Sulfonamides as antiinflammatory agents in the treatment of wegener's granulomatosis P49 The effects of oral cotrimoxazole upon neutrophil and monocyte activation in patients with pulmonary fibrosis and healthy controls; does this relate to its action in idiopathic pulmonary fibrosis New Development in Studies of Formyl-Peptide Receptors: Critical Roles in Host Defense Concentration-dependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells The Immunomodulatory Effect of Antibiotics on the Secretion of Tumour Necrosis Factor Alpha by Peripheral Blood Mononuclear Cells in Response to Stenotrophomonas Maltophilia Stimulation Tumor necrosis factor-induced degranulation in adherent human neutrophils is dependent on CD11b/CD18-integrin-triggered oscillations of cytosolic free Ca2+ Cotrimoxazole Reduces Systemic Inflammation in HIV Infection by Altering the Gut Microbiome and Immune Activation Targeting Potential Drivers of COVID-19: Neutrophil Extracellular Traps Health Care Associated Middle East Respiratory Syndrome (MERS): A Case from Iran Improved Recovery and Survival with Trimethoprim or Cotrimoxazole in Patients with Severe COVID-19: A Retrospective Analysis Cotrimoxazole as adjuvant therapy in critical ill COVID-19 patients Cotrimoxazole and teicoplanin in the management of Covid-19: Pleiotropic effects, shadows and lights Cotrimoxazole in the domiciliary management of patients with severe COVID-19: A case series Government of India Ministry of Health and Family Welfare Directorate General of Health Services (EMR Division) Clinical management of COVID-19: interim guidance The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients Association Between Peripheral Blood Oxygen Saturation (SpO2)/Fraction of Inspired Oxygen (FiO2) Ratio Time at Risk and Hospital Mortality in Mechanically Ventilated Patients Clinical characteristics and respiratory support of 310 COVID-19 patients, diagnosed at the emergency room: a single-centre retrospective study Treatment Guidelines for Antimicrobial Use in Common Syndromes World Health Organization Model List of Essential Medicines. 21st List Cotrimoxazole in hospitalised patients with moderate to early-severe COVID-19 infection the author/funder, who has granted medRxiv a license to display the preprint in perpetuity