Efficacy of Bacillus Calmette-Guérin (BCG) Vaccination in Reducing the Incidence and Severity of COVID-19 in High-Risk Population (BRIC): a Phase III, Multi-centre, Quadruple-Blind Randomised Control Trial.

INTRODUCTION: Universal coverage of vaccines alone cannot be relied upon to protect at-risk populations in lower- and middle-income countries against the impact of the coronavirus disease 2019 (COVID-19) pandemic and newer variants. Live vaccines, including Bacillus Calmette-Guérin (BCG), are being studied for their effectiveness in reducing the incidence and severity of COVID-19 infection. METHODS: In this multi-centre quadruple-blind, parallel assignment randomised control trial, 495 high-risk group adults (aged 18-60 years) were randomised into BCG and placebo arms and followed up for 9 months from the date of vaccination. The primary outcome was the difference in the incidence of COVID-19 infection at the end of 9 months. Secondary outcomes included the difference in the incidence of severe COVID-19 infections, hospitalisation rates, intensive care unit stay, oxygen requirement and mortality at the end of 9 months. The primary analysis was done on an intention-to-treat basis, while safety analysis was done per protocol. RESULTS: There was no significant difference in the incidence rates of cartridge-based nucleic acid amplification test (CB-NAAT) positive COVID-19 infection [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.54-2.14] in the two groups, but the BCG arm showed a statistically significant decrease in clinically diagnosed (symptomatic) probable COVID-19 infections (OR 0.38, 95% CI 0.20-0.72). Compared with the BCG arm, significantly more patients developed severe COVID-19 pneumonia (CB-NAAT positive) and required hospitalisation and oxygen in the placebo arm (six versus none; p = 0.03). One patient belonging to the placebo arm required intensive care unit (ICU) stay and died. BCG had a protective efficacy of 62% (95% CI 28-80%) for likely symptomatic COVID-19 infection. CONCLUSIONS: BCG is protective in reducing the incidence of acute respiratory illness (probable symptomatic COVID-19 infection) and severity of the disease, including hospitalisation, in patients belonging to the high-risk group of COVID-19 infection, and the antibody response persists for quite a long time. A multi-centre study with a larger sample size will help to confirm the findings in this study. CLINICAL TRIALS REGISTRY: Clinical Trials Registry India (CTRI/2020/07/026668).

The Bacillus Calmette­Guérin (BCG) vaccine has been studied previously in several settings, including reducing childhood mortalities due to viral infections and induction of trained immunity and reducing upper respiratory tract infections and pneumonia in older adults. This multi-centre trial has tried to evaluate the efficacy of BCG revaccination in reducing the incidence and severity of COVID-19 infections in adults between 18 and 60 years of age belonging to the high-risk group owing to the presence of comorbidities including diabetes, chronic kidney disease, chronic liver disease and chronic lung diseases. A single dose of BCG vaccine produced significantly high titres of BCG antibodies lasting for six months. While there was no significant reduction in the incidence of COVID-19 infection, there was an 8.4% reduction in the incidence of symptomatic COVID-19 disease at the end of 9 months of follow-up. In addition, there were significantly fewer severe COVID-19 infections requiring hospital stay and oxygen support. However, the overall numbers of severe COVID-19 infections were low. Thus, the study shows that BCG can protect against symptomatic and severe COVID-19 disease. However, it might not reduce the incidence of new infections. The study results are significant for low- and middle-income countries without adequate coverage of primary doses of COVID-19 vaccination, let alone the booster doses. Future studies should evaluate the BCG vaccine's efficacy as a booster compared with routine COVID-19 vaccine boosters.

Routine hematology parameters in COVID-19: A predictor of disease severity and mortality.

Background: Our understanding of the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still evolving and is limited for prognostication. The study was performed to predict severity and mortality based on hematology parameters in coronavirus disease (COVID-19). Material and Methods: The study was a single-center retrospective analysis of 240 patients with COVID-19. The hematological parameters were compared between different grades of severity. The receiver operating characteristics (ROC) curve along with the Classification and Regression Trees (CART) methods were used for the analysis. Result: The total leukocyte count, absolute neutrophil count, neutrophil-lymphocyte ratio (NLR), and neutrophil-monocyte ratio (NMR) were increasing along with an increase in severity; while the absolute lymphocyte count and lymphocyte-monocyte ratio (LMR) were decreasing (P < 0.001). For prediction of severity and mortality on admission, the NLR, NMR, and LMR were significant (P < 0.001). The NLR, NMR, and LMR had an area under the receiver operating characteristics curve (AUROC) of 0.86 (95% CI of 0.80-0.91), 0.822 (95% CI of 0.76-0.88), and 0.69 (95% CI of 0.60-0.79), respectively, for severity. While the NLR, NMR, and LMR had an AUROC value of 0.85 (95% CI of 0.79-0.92), 0.83 (95% CI of 0.77-0.89), and 0.67 (95% CI of 0.57-0.78), respectively, for mortality. Conclusion: With the increase in severity there was an increase in the total leukocyte count and absolute neutrophil count while the absolute lymphocyte count decreased. On admission, the cut-off value of NLR >5.2, NMR >12.1, while LMR <2.4 may predict severity and mortality in COVID-19.

Association of hyperglycaemia at-admission & diabetes mellitus with 28 day mortality in patients admitted with moderate-severe SARS-CoV-2 infection: A retrospective study.

Background & objectives: The association between hyperglycaemia at admission, diabetes mellitus (DM) status and mortality in hospitalized SARS-CoV-2 infected patients is not clear. The purpose of this study was to determine the relationship between DM, at-admission hyperglycaemia and 28 day mortality in patients admitted with moderate-severe SARS-CoV-2 infection requiring intensive care. Methods: All consecutive moderate-to-severe patients with SARS-CoV-2 infection admitted to the intensive care units (ICUs) over six months were enrolled in this single-centre, retrospective study. The predicators for 28 day mortality were analysed from the independent variables including DM status and hyperglycaemia at-admission. Results: Four hundred and fifty two patients with SARS-CoV-2 were admitted to the ICU, with a mean age of 58.5±13.4 yr, 78.5 per cent being male, HbA1c of 7.2 per cent (6.3-8.8) and 63.7 per cent having DM. Overall, 28 day mortality was 48.9 per cent. In univariate analysis, mortality in diabetes patients was comparable with non-diabetes (47.9 vs. 50.6%, P=0.58), while it was significantly higher in hyperglycaemic group (60.4 vs. 35.8%, P<0.001). In multivariate Cox regression analysis, after adjusting for age, sex and comorbidities, hyperglycaemia at-admission was an independent risk factor of mortality [hazard ratio (HR) 1.45, 95% confidence interval (CI) (1.06-1.99), P<0.05]. Interpretation & conclusions: This study showed that the presence of hyperglycaemia at-admission in critically ill SARS-CoV-2 patients was an independent predictor of 28 day mortality. However, the findings may be susceptible to unmeasured confounding, and more research from prospective studies is required.

Pattern of Conventional Coagulation and Thromboelastographic Parameters in Patients with COVID-19 Diseases and Association of COVID-Associated Coagulopathy with Mortality in Intensive Care Unit

Background: Knowledge of underlying pathophysiology of coagulopathy is evolving and the pattern of coagulation parameters in coronavirus disease 2019 (COVID-19)–associated diseases is still not very clear. Aims: In the present study, we aimed to find out the pattern and distribution of conventional coagulation parameters and thromboelastographic (TEG) parameters in COVID-19–associated coagulopathy (CAC) in survivors and nonsurvivors at 28 days. Setting and Design: The present prospective observational study was conducted at a tertiary care COVID-19 intensive care unit (ICU) facility from March 21, 2020, to July 15, 2021. Materials and Methods: Admission clinical and laboratory data (conventional coagulation, inflammatory and TEG parameters, and disease severity parameters) of 64 COVID-19 patients admitted to the ICU were collected. Patients were divided into two groups, i.e., survivors and nonsurvivors. Statistical Analysis: Data were compared between two groups, i.e., survivors versus no survivors on 28 days using Student's t-test/Mann–Whitney U-test or Chi-square test/Fisher's exact test. Results: Admission mean plasma fibrinogen levels (474.82 ± 167.41 mg.dL−1) and D-dimer were elevated (1.78 [0.66, 3.62] mg.mL−1) in the COVID-19 ICU patients. Overall, COVID-19 patients had mean lower normal platelet count (150 ± 50 × 103 cells.mm−3), with marginally elevated prothrombin time (16.25 ± 3.76 s) and activated partial thromboplastin time (38.22 ± 16.72 s). A 65.6% (42/64) TEG profile analysis showed a normal coagulation profile, and the rest 21.9% (14/64) and 12.5% (8/64) had hypercoagulable and hypocoagulable states, respectively. Plasma D-dimer level was markedly elevated in nonsurvivors compared to survivors (P < 0.05), while no other conventional coagulation parameters and TEG profile demonstrated statistically significant between the two groups. Conclusion: Markedly elevated plasma D-dimer level was observed in nonsurvivors of COVID-19 ICU patients. A large portion of COVID-19 ICU patients had a normal TEG profile. Conventional coagulation parameters and TEG profile were similar between survivors and nonsurvivors.

A Delphi consensus statement for the management of post-COVID interstitial lung disease.

INTRODUCTION: As millions of people worldwide recover from COVID-19, a substantial proportion continue to have persistent symptoms, pulmonary function abnormalities, and radiological findings suggestive of post-COVID interstitial lung disease (ILD). To date, there is limited scientific evidence on the management of post-COVID ILD, necessitating a consensus-based approach. AREAS COVERED: A panel of experts in pulmonology and thoracic radiology was constituted. Key questions regarding the management of post-COVID ILD were identified. A search was performed on PubMed and EMBASE and updated till 1 March 2022. The relevant literature regarding the epidemiology, pathophysiology, diagnosis and treatment of post-COVID ILD was summarized. Subsequently, suggestions regarding the management of these patients were framed, and a consensus was obtained using the Delphi approach. Those suggestions which were approved by over 80% of the panelists were accepted. The final document was approved by all panel members. EXPERT OPINION: Dedicated facilities should be established for the care of patients with post-COVID ILD. Symptom screening, pulmonary function testing, and thoracic imaging have a role in the diagnosis. The pharmacologic and non-pharmacologic options for the management of post-COVID ILD are discussed. Further research into the pathophysiology and management of post-COVID ILD will improve our understanding of this condition.

Thrombosis leading to acute abdomen in corona virus disease- 19:A case series.

Involvement of the gastrointestinal (GI) system in corona virus disease-19 (COVID-19) in form of diarrhea, loss of taste, nausea, and anorexia is common and associated with poor prognosis. COVID-19 is also associated with a hypercoagulable state that mainly involves the pulmonary vasculature. However, GI complications involving thrombosis are observed infrequently. We report two COVID-19 patients who had two different causes of acute abdomen. The first patient was a 49-year-old male diagnosed with an aortic thrombus along with a splenic infarct. He was diagnosed early and successfully managed with anticoagulants. The second patient was a 30-year-old male who developed pain in the abdomen and was found to have features suggestive of peritonitis. A contrast-enhanced computerized tomography (CECT) scan of the abdomen revealed dilated bowel loops. Immediate exploratory laparotomy was performed; he was found to have jejunal perforation with gangrene. Histopathological examination of the resected specimen showed inflammatory cells with edema and thrombotic vessels. However, he succumbed to sepsis and multiorgan failure. Therefore, it is important to investigate cases of acute abdomen in COVID-19 thoroughly and whenever indicated CT angiogram should be obtained.

New insights into development and mortality of COVID-19-associated pulmonary aspergillosis in a homogenous cohort of 1161 intensive care patients.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) has been widely reported but homogenous large cohort studies are needed to gain real-world insights about the disease. METHODS: We collected clinical and laboratory data of 1161 patients hospitalised at our Institute from March 2020 to August 2021, defined their CAPA pathology, and analysed the data of CAPA/non-CAPA and deceased/survived CAPA patients using univariable and multivariable models. RESULTS: The overall prevalence and mortality of CAPA in our homogenous cohort of 1161 patients were 6.4% and 47.3%, respectively. The mortality of CAPA was higher than that of non-CAPA patients (hazard ratio: 1.8 [95% confidence interval: 1.1-2.8]). Diabetes (odds ratio [OR] 1.92 [1.15-3.21]); persistent fever (2.54 [1.17-5.53]); hemoptysis (7.91 [4.45-14.06]); and lung lesions of cavitation (8.78 [2.27-34.03]), consolidation (9.06 [2.03-40.39]), and nodules (8.26 [2.39-28.58]) were associated with development of CAPA by multivariable analysis. Acute respiratory distress syndrome (ARDS) (2.68 [1.09-6.55]), a high computed tomography score index (OR 1.18 [1.08-1.29]; p < .001), and pulse glucocorticoid treatment (HR 4.0 [1.3-9.2]) were associated with mortality of the disease. Whereas neutrophilic leukocytosis (development: 1.09 [1.03-1.15] and mortality: 1.17 [1.08-1.28]) and lymphopenia (development: 0.68 [0.51-0.91] and mortality: 0.40 [0.20-0.83]) were associated with the development as well as mortality of CAPA. CONCLUSION: We observed a low but likely underestimated prevalence of CAPA in our study. CAPA is a disease with high mortality and diabetes is a significant factor for its development while ARDS and pulse glucocorticoid treatment are significant factors for its mortality. Cellular immune dysregulation may have a central role in CAPA from its development to mortality.

Role of low-dose tissue plasminogen activator in patients with refractory hypoxia due to presumed microthrombi in pulmonary vasculature in coronavirus disease 2019: A case series and review of the literature.

Severe hypoxia due to coronavirus disease 2019 (COVID-19) is challenging in the intensive care unit (ICU). It is often unresponsive to mechanical ventilation at high positive end-expiratory pressure and the fraction of inspired oxygen combination. The cause of such worsening hypoxia may be microvascular thrombosis in the pulmonary vascular system because of the procoagulant nature of COVID-19 infection. Confirming the diagnosis with computed tomographic pulmonary angiography is not always possible, as the patients are too sick to be shifted. Tissue plasminogen activator (tPA) is recommended for pulmonary thromboembolism with hypotension and worsening hypoxia, as confirmed by computed tomography pulmonary angiography. However, its role in worsening hypoxia because of presumed microthrombi in the pulmonary vasculature in COVID-19 is unclear. We present six cases from our ICU where we used low-dose tPA in COVID-19 refractory hypoxia with presumed microthrombi in the pulmonary vasculature (oligemic lung field, refractory hypoxia, increased D dimer, electrocardiographic features of pulmonary embolism, and right ventricular strain on echocardiography). Oxygenation improved within 6 h and was maintained for up to 48 h in all patients. Therefore, there is a possible role of microthrombi in the mechanism of hypoxia in this setting. An early decision to start low-dose tPA may improve the outcome. However, all patients finally succumbed to sepsis and multiorgan failure later in their course. A systematic review of the literature has also been performed on the mechanism of thrombosis and the use of tPA in hypoxia due to COVID-19.

Definition, diagnosis, and management of COVID-19-associated pulmonary mucormycosis: Delphi consensus statement from the Fungal Infection Study Forum and Academy of Pulmonary Sciences, India.

COVID-19-associated pulmonary mucormycosis (CAPM) remains an underdiagnosed entity. Using a modified Delphi method, we have formulated a consensus statement for the diagnosis and management of CAPM. We selected 26 experts from various disciplines who are involved in managing CAPM. Three rounds of the Delphi process were held to reach consensus (≥70% agreement or disagreement) or dissensus. A consensus was achieved for 84 of the 89 statements. Pulmonary mucormycosis occurring within 3 months of COVID-19 diagnosis was labelled CAPM and classified further as proven, probable, and possible. We recommend flexible bronchoscopy to enable early diagnosis. The experts proposed definitions to categorise dual infections with aspergillosis and mucormycosis in patients with COVID-19. We recommend liposomal amphotericin B (5 mg/kg per day) and early surgery as central to the management of mucormycosis in patients with COVID-19. We recommend response assessment at 4-6 weeks using clinical and imaging parameters. Posaconazole or isavuconazole was recommended as maintenance therapy following initial response, but no consensus was reached for the duration of treatment. In patients with stable or progressive disease, the experts recommended salvage therapy with posaconazole or isavuconazole. CAPM is a rare but under-reported complication of COVID-19. Although we have proposed recommendations for defining, diagnosing, and managing CAPM, more extensive research is required.

Practice Guidelines for the Diagnosis of COVID-19-Associated Pulmonary Aspergillosis in an Intensive Care Setting.

Coronavirus disease-2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is a new disease characterized by secondary Aspergillus mold infection in patients with COVID-19. It primarily affects patients with COVID-19 in critical state with acute respiratory distress syndrome, requiring intensive care and mechanical ventilation. CAPA has a higher mortality rate than COVID-19, posing a serious threat to affected individuals. COVID-19 is a potential risk factor for CAPA and has already claimed a massive death toll worldwide since its outbreak in December 2019. Its second wave is currently progressing towards a peak, while the third wave of this devastating pandemic is expected to follow. Therefore, an early and accurate diagnosis of CAPA is of utmost importance for effective clinical management of this highly fatal disease. However, there are no uniform criteria for diagnosing CAPA in an intensive care setting. Therefore, based on a review of existing information and our own experience, we have proposed new criteria in the form of practice guidelines for diagnosing CAPA, focusing on the points relevant for intensivists and pulmonary and critical care physicians. The main highlights of these guidelines include the role of CAPA-appropriate test specimens, clinical risk factors, computed tomography of the thorax, and non-culture-based indirect and direct mycological evidence for diagnosing CAPA in the intensive care unit. These guidelines classify the diagnosis of CAPA into suspected, possible, and probable categories to facilitate clinical decision-making. We hope that these practice guidelines will adequately address the diagnostic challenges of CAPA, providing an easy-to-use and practical algorithm to clinicians for rapid diagnosis and clinical management of the disease.

A questionnaire-based study on quality and adequacy of clinical communication between physician and family members of admitted Covid-19 patients.

OBJECTIVE: To assess adequacy of present means of clinical communication between physicians and (Covid-19) patients' family members, to analyse their perspectives and recommend felicitous practices for virtual conversation during ongoing pandemic. METHODS: Cross-sectional questionnaire-based (20 questions) anonymous online survey was conducted including patient's relatives (Group-1) and treating physicians (Group-2), through Google Forms. RESULTS: Response Rate was 82.5%. Group-1 and Group-2 included 155 and 204 respondents respectively. Group-1 preferred update by resident doctors (39%), twice a day (41.9%), daily case-summaries (80%) and hand-written document/electronic messages (53%,31%) as consent. Whereas Group-2 favored update by senior consultants (63%), daily one appraisal (55.9%) and scanned copies of hand written consent (81%) before high-risk procedures. The groups broadly agreed on the desired duration for a fruitful discussion (5-10 min) and designating one responsible person from the family for daily appraisal. CONCLUSION: Use of modern techniques/technologies of communication (voice/video calls, texts) during the ongoing pandemic is acceptable to majority. PRACTICE IMPLICATIONS: Study proposes a senior physician should communicate to a designated responsible family member at-least once a day for stable and twice a day for critical covid patients (more if patient's health condition changes), either by voice or video calls for 5-10 min.

A novel epidemiological scoring system for the prediction of mortality in COVID-19 patients.

BACKGROUND: Most of the reported risk score models for coronavirus disease 2019 (COVID-19) mortality are based on the levels of inflammatory markers, comorbidities or various treatment modalities, and there is a paucity of risk score models based on clinical symptoms and comorbidities. METHODS: To address this need, age, clinical symptoms and comorbidities were used to develop a COVID-19 scoring system (CSS) for early prediction of mortality in severe COVID-19 patients. The CSS was developed with scores ranging from 0 to 9. A higher score indicates higher risk with good discrimination quality presented by Mann Whitney U test and area under receiver operating characteristic curve (AUROC). RESULTS: Patient age of ≥60 y, cough, breathlessness, diabetes and any other comorbidity (with or without diabetes) are significant and independent risk factors for non-survival among COVID-19 patients. The CSS showed good sensitivity and specificity (i.e. 74.1% and 78.5% at CSS≥5, respectively), with an overall diagnostic accuracy of 82.8%, which was close to the diagnostic accuracy detected in the validation cohort (81.9%). In the validation cohort, high (8-9), medium (5-7) and low (0-4) CSS groups had 54.80%, 28.60% and 6.5% observed mortality, respectively, which was very close to the predicted mortality (62.40%, 27.60% and 5.2%, respectively, by scoring cohort). CONCLUSIONS: The CSS shows a positive relationship between a higher score and proportion of mortality and, as its validation showed, it is useful for the prediction of risk of mortality in COVID-19 patients at an early stage, so that referral for triage and admission can be predetermined even before admission to hospital.

The Spectrum of Gastrointestinal Symptoms in Patients With Coronavirus Disease-19: Predictors, Relationship With Disease Severity, and Outcome.

INTRODUCTION: We prospectively studied the frequency, spectrum, and predictors of gastrointestinal (GI) symptoms among patients with coronavirus disease-19 (COVID-19) and the relationship between GI symptoms and the severity and outcome. METHODS: Consecutive patients with COVID-19, diagnosed in a university hospital referral laboratory in northern India, were evaluated for clinical manifestations including GI symptoms, their predictors, and the relationship between the presence of these symptoms, disease severity, and outcome on univariate and multivariate analyses. RESULTS: Of 16,317 subjects tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in their oropharyngeal and nasopharyngeal swabs during April-May 2020, 252 (1.5%) were positive. Of them, 208 (82.5%) were asymptomatic; of the 44 symptomatic patients, 18 (40.9%) had non-GI symptoms, 15 (34.1%) had a combination of GI and non-GI symptoms, and 11 (25.0%) had GI symptoms only. Thirty-three had mild-to-moderate disease, 8 severe, and 5 critical. Five patients (1.98%) died. On multivariate analysis, the factors associated with the presence of GI symptoms included the absence of contact history and presence of non-GI symptoms and comorbid illnesses. Patients with GI synptoms more often had severe, critical illness and fatal outcome than those without GI symptoms. DISCUSSION: Eighty-two percent of patients with COVID-19 were asymptomatic, and 10.3% had GI symptoms; severe and fatal disease occurred only in 5% and 2%, respectively. The presence of GI symptoms was associated with a severe illness and fatal outcome on multivariate analysis. Independent predictors of GI symptoms included the absence of contact history, presence of non-GI symptoms, and comorbid illnesses.(Equation is included in full-text article.).