Factors associated with mortality among moderate and severe patients with COVID-19 in India: a secondary analysis of a randomised controlled trial.

OBJECTIVE: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma. DESIGN: Secondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease. SETTING: 39 public and private hospitals across India during the study period from 22 April to 14 July 2020. PARTICIPANTS: Of the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed. PRIMARY OUTCOME MEASURE: Factors associated with all-cause mortality at 28 days after enrolment. RESULTS: The mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3-7) and non-survivors (4 days; IQR 3-6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO2/FiO2 ratio <100 (3.47, 1.64-7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65-27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14-5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44-4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60-5.45, p=0.001) were significantly associated with death. CONCLUSION: In this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death. TRIAL REGISTRATION NUMBER: CTRI/2020/04/024775.

Plasma exchange with immunosuppression in pulmonary alveolar haemorrhage due to leptospirosis.

BACKGROUND & OBJECTIVES: Pulmonary involvement due to leptospirosis carries high case fatality rate and is the commonest cause of death due to leptospirosis. Immune mechanisms play a key role in the pathogenesis of leptospiral pulmonary haemorrhage. As other immune pulmonary haemorrhages due to non leptospiral causes are treated with plasma exchange and cyclophosphamide we evaluated their efficacy in patient with leptospiral pulmonary haemorrhage. METHODS: Of the 602 confirmed patients of leptospirosis, 236 (39.2%) had pulmonary haemorrhage. Of these,144 had mild haemorrhage (acute lung injury score < 2.5) and were included in the study. One hundred and fourteen patients were given two cycles of plasma exchange, 24 h apart, 25 ml/kg body weight of plasma was removed in each cycle. Cyclophosphamide (20 mg/kg body weight) was given after the first plasma exchange cycle. The remaining 30 patients were not given this treatment, and used as control. RESULTS: In the control group only 5 (16.6%) patients survived while in the treatment group 70 (61.40%) patients survived. Thrombocytopenia was observed in 111 (77.08%) patients. Renal and hepatic involvement was seen but did not account for mortality. Minor complications were seen in group I patients after plasma exchange and cyclophosphamide treatment, but none were serious. INTERPRETATION & CONCLUSIONS: Our findings showed that plasma exchange with immunosuppression improved survival in patients of pulmonary alveolar haemorrhage due to leptospirosis, suggesting that immune mechanisms play a key role in the pathogenesis of the disease.

Cyclophosphamide in pulmonary alveolar hemorrhage due to leptospirosis.

BACKGROUND AND AIMS: Severe pulmonary involvement in leptospirosis carries high mortality rates. It is the most common cause of death due to leptospirosis in many parts of India and the world. Exacerbated immune response of the host plays an important role in its pathogenesis. Hence, immunosuppressive drugs could be useful in its treatment. Glucocorticosteroids have been found to be useful in several studies. Cyclophosphamide, an immunosuppressive agent, has been found to be useful in a majority of pulmonary alveolar hemorrhages due to non leptospiral causes. This study was carried out to study the effects of cyclophosphamide in patients with leptospiral pulmonary alveolar hemorrhage. METHOD: A total of 65 patients with confirmed leptospirosis with severe pulmonary involvement admitted to a tertiary care center in south Gujarat were included in the study. All of the patients were treated with injection crystalline penicillin, methyl prednisolone pulse therapy, and non invasive mechanical ventilation. A total of 33 patients were given parenteral cyclophosphamide 60 mg/kg body weight stat on diagnosis. Their outcomes were compared with the remaining 32 patients who had not been given this drug. Survival was considered the main outcome indicator. RESULTS: Out of the 33 patients treated with cyclophosphamide, 22 (66.7%) survived, while in the control group out of 32 patients, three (9.4%) survived. On statistical analysis, the odds ratio was 19.33 (4.22-102.13) and the P-value was < 0.001. Leucopenia (78.78%) and alopecia (18.75%) were the main side effects noted. No mortality was noted due to these side effects. CONCLUSION: Cyclophosphamide improves survival in cases of severe pulmonary alveolar hemorrhage due to leptospirosis. Statistically, the improvement is highly significant.