Adjunctive use of saturated solution of potassium iodide (SSKI) with liposomal amphotericin B (L-AMB) in mucormycosis achieves favorable response, shortened dose and duration of amphotericin: A retrospective study from a COVID-19 tertiary care center.

PURPOSE: Second wave of COVID-19 pandemic was associated with an unprecedented rise in cases of mucormycosis, treatment of which has been challenging owing to the availability and side effects associated with amphotericin. METHODS: All patients presenting with rhino-orbital cerebral mucormycosis (ROCM) following COVID-19 infection between April 2021 to June 2021 were included in this retrospective interventional study. Primary objective was to assess the clinical response with combination of intravenous liposomal amphotericin B (4-5 mg/kg/day) and saturated solution of potassium iodide (SSKI) given orally along with surgical debridement. RESULTS: Twenty-five patients of ROCM were treated with the regimen. Mean age and fasting blood sugar levels were 53.48 years and 239.64 mg/dL respectively. All patients had history of intake of steroids with a mean daily dose of 86.39 mg of prednisolone equivalent. 88% of patients had a "proven" diagnosis of mucormycosis. Cultures were positive in 52% of patients with Rhizopus arrhizus as the predominant species. The mean daily dose of amphotericin received was 268 mg/day with a mean duration of 9.52 days. Mean daily dose of SSKI was 2.57 g. 21 patients (84%) had stabilization of disease at week 8 and achieved cure at the end of treatment whereas the mortality rate was 16%. Factors that significantly affected outcome were eye and central nervous system (CNS) involvement on presentation. CONCLUSION: SSKI, with its remarkably low cost and safety profile, makes it a potential adjuvant drug that may help achieve the twin benefits of shortened duration and dose of LAMB.

COVID-19 Risk Stratification and Mortality Prediction in Hospitalized Indian Patients: Harnessing clinical data for public health benefits.

The variability of clinical course and prognosis of COVID-19 highlights the necessity of patient sub-group risk stratification based on clinical data. In this study, clinical data from a cohort of Indian COVID-19 hospitalized patients is used to develop risk stratification and mortality prediction models. We analyzed a set of 70 clinical parameters including physiological and hematological for developing machine learning models to identify biomarkers. We also compared the Indian and Wuhan cohort, and analyzed the role of steroids. A bootstrap averaged ensemble of Bayesian networks was also learned to construct an explainable model for discovering actionable influences on mortality and days to outcome. We discovered blood parameters, diabetes, co-morbidity and SpO2 levels as important risk stratification features, whereas mortality prediction is dependent only on blood parameters. XGboost and logistic regression model yielded the best performance on risk stratification and mortality prediction, respectively (AUC score 0.83, AUC score 0.92). Blood coagulation parameters (ferritin, D-Dimer and INR), immune and inflammation parameters IL6, LDH and Neutrophil (%) are common features for both risk and mortality prediction. Compared with Wuhan patients, Indian patients with extreme blood parameters indicated higher survival rate. Analyses of medications suggest that a higher proportion of survivors and mild patients who were administered steroids had extreme neutrophil and lymphocyte percentages. The ensemble averaged Bayesian network structure revealed serum ferritin to be the most important predictor for mortality and Vitamin D to influence severity independent of days to outcome. The findings are important for effective triage during strains on healthcare infrastructure.

Secondary infections modify the overall course of hospitalized patients with COVID-19: a retrospective study from a network of hospitals across North India.

Objective: To gain better insight into the extent of secondary bacterial and fungal infections in hospitalized patients in India, and to assess how these alter the course of coronavirus disease 2019 (COVID-19) so that control measures can be suggested. Methods: In this retrospective, multicentre study, the data of all patients who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on reverse transcriptase polymerase chain reaction (RT-PCR), admitted to hospital between March 2020 and July 2021, were accessed from the electronic health records of a network of 10 hospitals across five states in North India. Results: Of 19,852 patients testing positive for SARS-CoV-2 on RT-PCR and admitted to the study hospitals during the study period, 1940 (9.8%) patients developed secondary infections (SIs). Patients with SIs were, on average, 8 years older than patients without SIs (median age 62.6 vs 54.3 years; P<0.001). The risk of SIs was significantly (P<0.001) associated with age, severity of disease at admission, diabetes, admission to the intensive care unit (ICU), and ventilator use. The most common site of infection was urine (41.7%), followed by blood (30.8%) and sputum/bronchoalveolar lavage/endotracheal fluid (24.8%); the least common was pus/wound discharge (2.6%). Gram-negative bacilli (GNB) were the most common organisms (63.2%), followed by Gram-positive cocci (GPC) (19.6%) and fungi (17.3%). Most patients with SIs were on multiple antimicrobials. The most commonly used antibiotics against GNB were beta-lactam/beta-lactamase inhibitors (76.9%), carbapenems (57.7%), cephalosporins (53.9%), and antibiotics against carbapenem-resistant Enterobacteriaceae (47.1%). Empirical use of antibiotics against GPC was seen in 58.9% of patients with SIs, and empirical use of antifungals was observed in 56.9% of patients with SIs. The average length of hospital stay for patients with SIs was almost twice as long as that of patients without SIs (median 13 vs 7 days). Overall mortality among patients with SIs (40.3%) was more than eight times higher than that among patients without SIs (4.6%). Only 1.2% of patients with SIs with mild COVID-19 at admission died, compared with 17.5% of those with moderate COVID-19 at admission and 58.5% of those with severe COVID-19 at admission (P<0.001). The mortality rate was highest in patients with bloodstream infections (49.8%), followed by those with hospital-acquired pneumonia (47.9%), urinary tract infections (29.4%), and skin and soft tissue infections (29.4%). The mortality rate in patients with diabetes with SIs was 45.2%, compared with 34.3% in those without diabetes (P<0.001). Conclusions: SIs complicate the course of patients hospitalized with COVID-19. These patients tend to have a much longer hospital stay, a higher requirement for oxygen and ICU care, and a significantly higher mortality rate compared with those without SIs. The groups most vulnerable to SIs are patients with more severe COVID-19, elderly patients and patients with diabetes. Judicious empirical use of combination antimicrobials in these groups of vulnerable patients can save lives. It is desirable to have region- or country-specific guidelines for appropriate use of antibiotics and antifungals to prevent their overuse.

Efficacy of high-dose intravenous immunoglobulin in severe and critical COVID-19: A retrospective cohort study.

BACKGROUND: Various immunomodulatory therapies have been explored to manage the dysregulated immune response seen in severe COVID-19 infection. The objective of this study was to evaluate the efficacy of intravenous immunoglobulin (IVIG) in severe and critical COVID-19 disease. METHODS: This retrospective study included 535 patients with severe and critical COVID-19 admitted to the intensive care unit (ICU) of a tertiary care hospital, from May 2020 to December 2020. Primary outcome was the percentage of patients requiring mechanical ventilation. Secondary outcomes were a) in-hospital mortality, b) 28-day mortality, c) ICU-length of stay (ICU-LOS), d) days to discontinuation of supplemental oxygen, and e) days to COVID-PCR negativity. Logistic regression and linear regression were performed using the adjusted and unadjusted analyses. RESULTS: We analyzed a total of 535 patients out of which 255 (47.7%) received IVIG along with standard treatment and 280 (52.3%) received only standard treatment. Two groups were similar in terms of COVID-19 severity, APACHE II score, oxygen requirements, and initial management. The requirement of invasive ventilation was significantly less in the IVIG group compared to the Non-IVIG group (32.2% vs 40.4%, p < 0.05). In-hospital mortality, 28-day mortality, and ICU-LOS were also significantly less in the IVIG group (all p < 0.05). Subgroup analysis within the IVIG group showed that early administration of IVIG (≤7 days from ICU admission), old age (≥65 years), and obesity were associated with better outcomes (need for mechanical ventilation and in-hospital mortality) (all p < 0.05). IVIG administration in patients with chronic respiratory disease was associated with a reduced requirement for mechanical ventilation (p < 0.05), but there was an insignificant improvement in mortality. CONCLUSION: High-dose IVIG improves outcomes in severe and critical COVID-19 patients. The study also underscores the importance of timing and patient selection when administering IVIG.

Low FT3 is an independent marker of disease severity in patients hospitalized for COVID-19.

AIM: To study the prevalence of thyroid dysfunction and its association with disease severity in hospitalized patients of coronavirus disease-19 (COVID-19). METHODS: In this retrospective cohort study, thyroid function tests (TFT) of 236 hospitalized patients of COVID-19 along with demographic, comorbid, clinical, biochemical and disease severity records were analysed. Patients were divided into previous euthyroid or hypothyroid status to observe the effect of prior hypothyroidism on the severity of COVID-19. RESULTS: TFT abnormalities were common. Low free T3 (FT3), high thyroid-stimulating hormone (TSH) and low TSH were seen in 56 (23.7%), 15 (6.4%) and 9 (3.8%) patients, respectively. The median levels of TSH (2.06 vs 1.26 mIU/mL, P = 0.001) and FT3 (2.94 vs 2.47 pg/mL, P < 0.001) were significantly lower in severe disease. Previous hypothyroid status (n = 43) was associated with older age, higher frequency of comorbidities, higher FT4 and lower FT3. TFT did not correlate with markers of inflammation (except lactate dehydrogenase); however, FT3 and TSH negatively correlated with outcome severity score and duration of hospital stay. Cox regression analysis showed that low FT3 was associated with severe COVID-19 (P = 0.032, HR 0.302; CI 0.101-0.904), irrespective of prior hypothyroidism. CONCLUSIONS: Functional thyroid abnormalities (low FT3 and low TSH) are frequently seen in hospitalized patients of COVID-19. Although these abnormalities did not correlate with markers of inflammation, this study shows that low FT3 at admission independently predicts the severity of COVID-19.

Respiratory Co-Infections: Modulators of SARS-CoV-2 Patients' Clinical Sub-Phenotype.

Co-infection with ancillary pathogens is a significant modulator of morbidity and mortality in infectious diseases. There have been limited reports of co-infections accompanying SARS-CoV-2 infections, albeit lacking India specific study. The present study has made an effort toward elucidating the prevalence, diversity and characterization of co-infecting respiratory pathogens in the nasopharyngeal tract of SARS-CoV-2 positive patients. Two complementary metagenomics based sequencing approaches, Respiratory Virus Oligo Panel (RVOP) and Holo-seq, were utilized for unbiased detection of co-infecting viruses and bacteria. The limited SARS-CoV-2 clade diversity along with differential clinical phenotype seems to be partially explained by the observed spectrum of co-infections. We found a total of 43 bacteria and 29 viruses amongst the patients, with 18 viruses commonly captured by both the approaches. In addition to SARS-CoV-2, Human Mastadenovirus, known to cause respiratory distress, was present in a majority of the samples. We also found significant differences of bacterial reads based on clinical phenotype. Of all the bacterial species identified, ∼60% have been known to be involved in respiratory distress. Among the co-pathogens present in our sample cohort, anaerobic bacteria accounted for a preponderance of bacterial diversity with possible role in respiratory distress. Clostridium botulinum, Bacillus cereus and Halomonas sp. are anaerobes found abundantly across the samples. Our findings highlight the significance of metagenomics based diagnosis and detection of SARS-CoV-2 and other respiratory co-infections in the current pandemic to enable efficient treatment administration and better clinical management. To our knowledge this is the first study from India with a focus on the role of co-infections in SARS-CoV-2 clinical sub-phenotype.

High Prevalence of Diabetes in Hospitalized Patients With COVID-19 and Its Association With Greater Severity of COVID-19 in Delhi, India

Abstract: India is home to 77 million people with diabetes and has a large number of COVID 19 cases, albeit with a low fatality (&lt;1.5%). Little Indian data is available about the prevalence of diabetes in COVID 19 and its impact on outcomes. This observational prospective study (approved by the Institutional Ethics Committee) was carried out in a designated COVID facility, largely catering to middle and upper socioeconomic classes. A total of 401 (125 F, mean age 54 y, range 19–92 y) consecutive adults hospitalized with COVID-19 infection as proven by positive nasal swab for SARS-CoV2 by RT-PCR were included. Diabetes mellitus was diagnosed either by known history or HbA1c≥6.5%. Severity was assessed using the WHO ordinal scale1. Clinical outcomes and markers of inflammation were compared between diabetes and non-diabetes groups. Out of 401 patients, 210 (52.4%) had either diabetes (189,47.1%) or hyperglycemia requiring insulin treatment (21, 5.2%). 152 (37.9%) reported known diabetes, and 37 (9.2%) had preexisting but undiagnosed diabetes (HbA1c≥ 6.5%). People with diabetes were significantly older (mean age 59.9 vs 47.7 y), and had a higher proportion of men (74.6 vs 63.7 %), hypertension (58.7 vs 25%), CAD (13.8 vs 4.2%), and CKD (5.3 vs 0.9%) and a higher mean baseline severity score (3.4±0.7 vs. 3.2±0.5, p-0.000). The diabetes group had a higher number of severe cases (WHO scale≥5) (20.1% vs 9%, p-0.002) and higher mortality (6.3 vs 1.4%, p-0.015). A higher proportion of the diabetes group required ICU admissions (24.3 vs 12.3%, p-0.002), glucocorticoid therapy (78.3 vs 54.2%, p-0.000), oxygen administration (53.4 vs 28.3%, p-0.000), inotropic support (7.4 vs 2.4%, p-0.019), and renal replacement therapy (3.7% vs 0,p-0.005). The mean duration of hospital stay was higher for the diabetes group (10.4 vs 9.1 days, p-0.016). Of those who died, 12/15 (80%) had diabetes. Baseline Hba1c (n=331) showed a significant correlation with outcome severity scores (r 0.136, p-0.013). Markers of inflammatory response, CRP (41.0±4.4 vs. 19.4±3.8, p-0.000), ferritin (404.8±41.6 vs. 258.8±40.2, p-0.012), IL6 (65.5±11.6 vs. 26.9±4.4, p-0.002), LDH (321.8±10.1 vs. 286.8±8.4, p-0.008) were significantly higher in the diabetes group. Procalcitonin and D Dimer did not differ significantly. In conclusion, we report the highest prevalence of diabetes in a hospitalized COVID-19 population so far. The diabetes group had more severe disease and greater mortality. Baseline HbA1c correlated with poor outcomes. The comorbidities could have contributed to these poorer outcomes in the diabetes group. Strategies to improve outcomes in this pandemic it is imperative to include screening for and better control of diabetes.

Lack of Association Between 25-Hydroxyvitamin D Level and Outcomes in Hospitalized Indian Patients With COVID-19

Vitamin D deficiency (VDD) is thought to play a role in determining the outcomes of COVID-19. India has a high prevalence of VDD. We hypothesized that VDD as measured by serum 25-hydroxyvitamin D (25OHD) &lt;20 ng/mL is associated with severe COVID-19 infection. Outcomes were assessed by the WHO ordinal scale for clinical improvement (OSCI)1, the need for oxygen therapy, admission to an intensive care unit (ICU), and inflammatory markers. The diagnosis of COVID-19 was proven by RT-PCR on the nasopharyngeal swab for SARS-CoV2. Serum 25OHD and PTH were measured in addition to the standard protocol for COVID-19. Clinical and laboratory data were extracted from electronic medical records and analyzed using SPSS v22.0. Patients with OSCI score &lt;5 were classified as mild and ≥5 as severe disease. The study was approved by the Institutional Ethics Committee. A total of 410 patients (127 females, 9 pediatric, 17 asymptomatic) were included with a median age of 54 years (6–92 years) with 272(66.3%) having at least one co-morbid condition, including diabetes (190, 46.3%) and hypertension (164,40%). Patients with VDD (197,48%) were significantly younger (46.7±17.1 vs. 57.8±14.7 years) and had lesser prevalence of diabetes and hypertension (39.1% vs 52.4%, 29.4% vs 49.5%). Proportion of severe cases (26,13.2% vs. 31,14.6%), mortality (4, 2% vs. 11, 5.2%), oxygen requirement (68,34.5% vs.92,43.4), ICU admission (29, 14.7% vs. 42, 19.8%), need for inotropes (7,3.6% vs.12,5.7%) was not significantly different between patients with VDD and those with normal 25OHD level. The proportion of severe cases was similar across all 25OHD categories. There was no significant correlation between 25OHD levels and outcome OSCI, inflammatory markers (CRP, IL-6, D-dimer, ferritin, LDH). PTH levels positively correlated with D-dimer (r 0.117, p- 0.019), ferritin (r 0.132, p-0.010) and LDH (r0.124, p-0.018). Amongst VDD patients, 128(64.9%) were treated with cholecalciferol with a median dose of 60000 IU. The proportion of severe cases, oxygen, or ICU admission was not significantly different in the treated vs. untreated group. In conclusion, baseline levels of 25OHD did not determine the severe clinical outcomes of COVID-19 or levels of inflammatory markers. Treatment with cholecalciferol did not make any difference to the clinical outcomes of those with VDD. Reference:1WHO R&D Blueprint, novel Coronavirus. Retrieved from: https://www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf

Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19.

Vitamin D deficiency (VDD) owing to its immunomodulatory effects is believed to influence outcomes in COVID-19. We conducted a prospective, observational study of patients, hospitalized with COVID-19. Serum 25-OHD level < 20 ng/mL was considered VDD. Patients were classified as having mild and severe disease on basis of the WHO ordinal scale for clinical improvement (OSCI). Of the 410 patients recruited, patients with VDD (197,48.2%) were significantly younger and had lesser comorbidities. The levels of PTH were significantly higher in the VDD group (63.5 ± 54.4 vs. 47.5 ± 42.9 pg/mL). The proportion of severe cases (13.2% vs.14.6%), mortality (2% vs. 5.2%), oxygen requirement (34.5% vs.43.4%), ICU admission (14.7% vs.19.8%) was not significantly different between patients with or without VDD. There was no significant correlation between serum 25-OHD levels and inflammatory markers studied. Serum parathormone levels correlated with D-dimer (r 0.117, p- 0.019), ferritin (r 0.132, p-0.010), and LDH (r 0.124, p-0.018). Amongst VDD patients, 128(64.9%) were treated with oral cholecalciferol (median dose of 60,000 IU). The proportion of severe cases, oxygen, or ICU admission was not significantly different in the treated vs. untreated group. In conclusion, serum 25-OHD levels at admission did not correlate with inflammatory markers, clinical outcomes, or mortality in hospitalized COVID-19 patients. Treatment of VDD with cholecalciferol did not make any difference to the outcomes.

Effectiveness of convalescent plasma in Indian patients with COVID-19.

BACKGROUND: Convalescent plasma (CP) is being used as a treatment option in hospitalized patients with COVID-19. Till date, there is conflicting evidence on efficacy of CP in reducing COVID-19 related mortality. OBJECTIVE: To evaluate the effect of CP on 28-day mortality reduction in patients with COVID-19. METHODS: We did a multi-centre, retrospective case control observational study from 1st May 2020 to 31st August 2020. A total of 1079 adult patients with moderate and severe COVID-19 requiring oxygen, were reviewed. Of these, 694 patients were admitted to ICU. Out of these, 333 were given CP along with best supportive care and remaining 361 received best supportive care only. RESULTS: In the overall group of 1079 patients, mortality in plasma vs no plasma group was statistically not significant (22.4% vs 18.5%; p = 0.125; OR = 1.27, 95% CI: 0.94--1.72). However, in patients with COVID-19 admitted to ICU, mortality was significantly lower in plasma group (25.5% vs 33.2%; p = 0.026; OR = 0.69, 95%CI: 0.50-0.96). This benefit of reduced mortality was most seen in age group 60 to 74 years (26.7% vs 43.0%; p = 0.004; OR = 0.48, 95% CI: 0.29-0.80), driven mostly by females of this age group (23.1% vs 53.5%; p = 0.013; OR = 0.26, 95% CI: 0.09-0.78). Significant difference in mortality was observed in patients with one comorbidity (22.3% vs 36.5%; p = 0.004; OR = 0.50, 95% CI: 0.31-0.80). Moreover, patients on ventilator had significantly lower mortality in the plasma arm (37.2% vs 49.3%; p = 0.009; OR = 0.61, 95% CI: 0.42-0.89); particularly so for patients on invasive mechanical ventilation (63.9% vs 82.9%; p = 0.014; OR = 0.37, 95% CI: 0.16-0.83). CONCLUSION: The use of CP was associated with reduced mortality in COVID-19 elderly patients admitted in ICU, above 60 years of age, particularly females, those with comorbidities and especially those who required some form of ventilation.

High prevalence of diabetes and other comorbidities in hospitalized patients with COVID-19 in Delhi, India, and their association with outcomes.

BACKGROUND AND AIMS: To study the prevalence and impact of diabetes mellitus and other comorbidities among hospitalized patients with COVID-19. METHODS: In a prospective, observational study including consecutive adults hospitalized with COVID-19, clinical outcomes and inflammatory markers were compared in those with and without diabetes. Participants were classified as having mild or severe COVID-19 disease using the WHO ordinal scale. RESULTS: 401 patients (125 females) with median age of 54 years (range 19-92) were evaluated. Of them 189 (47.1%) had pre-existing diabetes and21 (5.2%) had new-onset hyperglycaemia. Overall, 344 (85.8%) and 57 (14.2%) cases had mild and severe COVID-19 disease respectively. The group with diabetes had a higher proportion of severe cases (20.1% vs 9%, p-0.002), mortality (6.3 vs 1.4%, p-0.015), ICU admission (24.3 vs 12.3%, p-0.002), and oxygen requirement (53.4 vs 28.3%, p < 0.001). Baseline Hba1c (n = 331) correlated significantly with outcome severity scores (r 0.136, p-0.013) and 12/15 (80%) of those who succumbed had diabetes. Hypertension, coronary artery disease, and chronic kidney disease were present in 164 (40.9%), 35 (8.7%) and 12 (2.99%) patients respectively. Hypertension was associated with a higher proportion of severe cases, mortality, ICU admission and oxygen administration. CONCLUSIONS: We report a high prevalence of diabetes in a hospitalized COVID-19 population. Patients with diabetes or hypertension had more severe disease and greater mortality.