Relative Importance of Various Inflammatory Markers and Their Critical Thresholds for COVID-19 Mortality (preprint)

BackgroundVarious inflammatory markers are commonly assessed in many patients to help in the management of COVID-19 patients. It is not clear, though, how much risk of mortality their different levels of elevations entail, and which marker signifies more risk than others and how much. This study was undertaken to describe their levels and to answer these questions regarding eight inflammatory markers, namely, CRP, D-dimer, ferritin, IL-6, LDH, CPK, troponin-I. MethodsThe data were retrieved from the electronic records of 19852 CoViD-19 patients admitted to a chain of hospitals in north India from March 2020 to July 2021. Levels for most markers were available for more than 10,000 patients. In view of widely different ranges of values of different markers, we divided their values into quintiles (Qs) and studied the pattern of mortality and for running the logistic regression. In addition, logarithm transformation was also tried. The statistical distribution of the values was compared by Mann-Whitney test. Relative importance was judged by the mortality rates, area under the ROC curves (AUROCs), and the odds ratios. ResultsAlthough the mortality increased with decreasing ALC and increasing level of all the other markers, more than 70% survived even with levels in the extreme quintile. The adjusted odds ratio was the highest (7.62) for the Q5 levels of IL-6, closely followed by D-dimer (OR = 6.04). The AUROC was the highest (0.817) for LDH and the least (0.612) for CPK. However, the optimal cut-off for any marker could correctly classify not more than 80% deaths and the multivariable logistic regression could correctly classify patients with mortality in less than 24% cases. ConclusionAlthough elevated levels of all the markers and low values of ALC were significant risk factor but no firm evidence was available for any of the eight markers to be a major indicator of the mortality in COVID-19 unless they reach to a critical threshold. Among those studied, D-Dimer (>192 ng/mL) followed by IL-6 (>4.5 pg/mL) had stronger association with mortality even with moderate and higher end of the normal levels and LDH (>433 U/L) and troponin-I (>0.002ng/mL) with only steeply increased levels. Ferritin had modest association, and CPK, CRP and ALC were a relatively poor risk of mortality.

Survival and outcomes of tocilizumab use in severe and critically ill Covid-19 patients not responding to steroids (preprint)

BackgroundMortality and morbidity are highest in severe and critically ill patients with COVID -19 pneumonia. Recently corticosteroids have shown a definite mortality benefit in these patients. In this study we used interleukin -6 inhibitor, tocilizumab in patients who failed to show any clinical improvement after initial treatment with steroids. Patients and methodsThis is a retrospective observational study conducted at a tertiary care referral hospital in India. Severe and critical COVID 19 patients, who got admitted to intensive care unit and subsequently received tocilizumab were included. Patients who worsened clinically or had no change in oxygen requirement even after 24hrs of receiving Intravenous methylprednisolone at a dose of 1-2mg/kg/day received a maximum total dose of 800mg of intravenous tocilizumab. The day 28 all cause mortality and progression to mechanical ventilation were the primary outcome measures. Clinical improvement and oxygen requirements after tocilizumab administration along with trends in inflammatory markers were secondary outcome. Secondary infections rates and other drug related side effects were also noted. ResultsA total of 51 patients who did not show clinical improvement even after 24 hours of intravenous steroids and received tocilizumab were included. In these patients, there was a significant decrease in oxygen requirement by day 3 and clinical improvement by day 7 of tocilizumab administration. Among the inflammatory markers, we observed elevated median baseline values of CRP (114.2 mg/L), IL-6 (55.4 pg/ml) and Neutrophil to Lymphocyte Ratio (12.4). Out of these only CRP showed a significant decrease after the drug administration. 13 (26.5%) of the 49 patients who were on non-invasive or conventional oxygen support progressed to mechanical ventilation. The day 28 all-cause mortality rate was 10/51(19.6%). 10(19.6%) of the 51 patients had life threatening infections, 5/51 had thrombocytopenia, 3/51 had pneumo-mediastenum/pneumothorax, 1 patient had colonic perforation and 1 patient had transaminitis following tocilizumab administration. ConclusionEarly and timely administration of tocilizumab only in selected severe and critical covid patients not responding to initial steroids appears to increase the survival. Further randomized controlled trials are required to confirm this finding.

Secondary infections modify the overall course of hospitalized COVID-19 patients: A retrospective study from a network of hospitals across North India (preprint)

IntroductionSARS-CoV-2 infection increases the risk of secondary bacterial and fungal infections and contributes to adverse outcomes. The present study was undertaken to get better insights into the extent of secondary bacterial and fungal infections in Indian hospitalized patients and to assess how these alter the course of COVID-19 so that the control measures can be suggested. MethodsThis is a retrospective, multicentre study where data of all RT-PCR positive COVID-19 patients was accessed from Electronic Health Records (EHR) of a network of 10 hospitals across 5 North Indian states, admitted during the period from March 2020 to July 2021.The data included demographic profile of patients, clinical characteristics, laboratory parameters, treatment modalities, and outcome in those with secondary infections (SIs) and those without SIs. Spectrum of SIS was also studied in detail. ResultsOf 19852 RT-PCR positive SARS-CO2 patients admitted during the study period, 1940 (9.8%) patients developed SIs. Patients with SIs were 8 years older on average (median age 62.6 years versus 54.3 years; P<0.001) than those without SIs. The risk of SIs was significantly (p < 0.001) associated with age, severity of disease at admission, diabetes, ICU admission, and ventilator use. The most common site of infection was urinary tract infection (UTI) (41.7%), followed by blood stream infection (BSI) (30.8%), sputum/BAL/ET fluid (24.8%), and the least was pus/wound discharge (2.6%). As many as 13.4% had infections with more than organism and 34.1% patients had positive cultures from more than one site. Gram negative bacilli (GNB) were the commonest organisms (63.2%), followed by Gram positive cocci (GPC) (19.6%) and fungus (17.3%). Most of the patients with SIs were on multiple antimicrobials - the most commonly used were the BL-BLI for GNBs (76.9%) followed by carbapenems (57.7%), cephalosporins (53.9%) and antibiotics carbapenem resistant entreobacteriace (47.1%). The usage of emperical antibiotics for GPCs was in 58.9% and of antifungals in 56.9% of cases, and substantially more than the results obtained by culture. The average stay in hospital for patients with SIs was twice than those without SIs (median 13 days versus 7 days). The overall mortality in the group with SIs (40.3%) was more than 8 times of that in those without SIs (4.6%). Only 1.2% of SI patients with mild COVID-19 at presentation died, while 17.5% of those with moderate disease and 58.5% of those with severe COVID-19 died (P< 0.001). The mortality was highest in those with BSI (49.8%), closely followed by those with HAP (47.9%), and then UTI and SSTI (29.4% each). The mortality rate where only one microorganism was identified was 37.8% and rose to 56.3% in those with more than one microorganism. The mortality in cases with only one site of infection was 28.8%, which steeply rose to 62.5% in cases with multiple sites of infection. The mortality in diabetic patients with SIs was 45.2% while in non-diabetics it was 34.3% (p < 0.001). ConclusionsSecondary bacterial and fungal infections can complicate the course of almost 10% of COVID-19 hospitalised patients. These patients tend to not only have a much longer stay in hospital, but also a higher requirement for oxygen and ICU care. The mortality in this group rises steeply by as much as 8 times. The group most vulnerable to this complication are those with more severe COVID-19 illness, elderly, and diabetic patients. Varying results in different studies suggest that a region or country specific guideline be developed for appropriate use of antibiotics and antifungals to prevent their overuse in such cases. Judicious empiric use of combination antimicrobials in this set of vulnerable COVID-19 patients can save lives.

Profile of Mucormycosis Cases from a Network of Hospitals in North India Amidst COVID-19 Pandemic (preprint)

Incidence of mucormycosis suddenly surged in India after the second wave of COVID-19. This is a crippling disease and needs to be studied in detail to understand the disease, its course, and the outcomes. Between 1st March and 15th July 2021, our network of hospitals in North India received a total of 155 cases of COVID-associated mucormycosis cases as all of them reported affliction by COVID-19 earlier or concurrent. Their records were retrieved from the Electronic Health Records system of the hospitals and their demographics, clinical features, treatments, and outcomes were studied. More than 80% (125 cases) had proven disease and the remaining 30 were categorized as possible mucormycosis as per the EORTC criteria. More than two-thirds (69.0%) of the cases were males and the mean age was 53 years for either sex. Nearly two-thirds (64.5%) had symptoms of nose and jaws and 42.6% had eye involvement. Some had multiple symptoms. As many as 78.7% had diabetes and 91.6% gave history of use of steroids during COVID-19 treatment. The primary surgery was functional endoscopic sinus surgery (FESS) (83.9%). Overall mortality was 16.8%, which is one-and-a-half times the mortality in hospitalized COVID-19 patients in the corresponding population. Occurrence of mucormycosis was associated with diabetes and use of steroids, but mortality was not associated with either of them. Cases undergoing surgery and on antifungal had steeply lower mortality (11.9% vs. 50.0%, P < 0.001) than those who were exclusively on antifungal drugs. Treatment by different drugs did not make much of a difference in mortality.

Differentials in the characteristics of COVID-19 cases in Wave-1 and Wave-2 admitted to a network of hospitals in North India (preprint)

Second wave of COVID 19 pandemic in India came with unexpected quick speed and intensity, creating an acute shortage of beds, ventilators, and oxygen at the peak of occurrence. This may have been partly caused by emergence of new variant delta. Clinical experience with the cases admitted to hospitals suggested that it is not merely a steep rise in cases but also possibly the case profile is different. This study was taken up to investigate the differentials in the characteristics of the cases admitted in the second wave versus those admitted in the first wave. Records of a total of 14398 cases admitted in the first wave (2020) to our network of hospitals in north India and 5454 cases admitted in the second wave (2021) were retrieved, making it the largest study of this kind in India. Their demographic profile, clinical features, management, and outcome was studied. Age sex distribution of the cases in the second wave was not much different from those admitted in the first wave but the patients with comorbidities and those with greater severity had larger share. Level of inflammatory markers was more adverse. More patients needed oxygen and invasive ventilation. ICU admission rate remained nearly the same. On the positive side, readmissions were lower, and the duration of hospitalization was slightly less. Usage of drugs like remdesivir and IVIG was higher while that of favipiravir and tocilizumab was lower. Steroid and anticoagulant use remained high and almost same during the two waves. More patients had secondary bacterial and fungal infections in Wave 2. Mortality increased by almost 40% in Wave 2, particularly in the younger patients of age less than 45 years. Higher mortality was observed in those admitted in wards, ICU, with or without ventilator support and those who received convalescent plasma. No significant demographic differences in the cases in these two waves, indicates the role of other factors such as delta variant and late admissions in higher severity and more deaths. Comorbidity and higher secondary bacterial and fungal infections may have contributed to increased mortality.