Spectrum of Serious Neurological and Psychiatric Adverse Events in Indian COVID-19 Vaccine Recipients: A Systematic Review of Case Reports and Case Series.

Indian data regarding serious neurological and psychiatric adverse events, following coronavirus disease 2019 (COVID-19) vaccination, are lacking. We, therefore, systematically evaluated cases of post-vaccinal serious neurological and psychiatric adverse reactions published from India. A systematic review of cases published from India, which were archived in PubMed, Scopus, and Google Scholar databases, was performed; pre-print databases along with ahead-of-print contents were searched in addition. Retrieved articles, as on June 27, 2022, were evaluated following PRISMA guidelines. EndNote 20 web tool was used to make a PRISMA flow chart. Individual patients' data were compiled in a tabular form. The protocol of the systematic review was registered with PROSPERO (CRD42022324183). A total of 64 records describing 136 instances of serious neurological and psychiatric adverse events were identified. More than 50% (36/64) reports were from the following four states, namely, Kerala, Uttar Pradesh, New Delhi, and West Bengal. The mean age of persons developing these complications was 44.89 ± 15.77 years. In the majority, adverse events occurred within 2 weeks of administration of the first dose of COVISHIELD vaccine. Immune-mediated central nervous system (CNS) disorders were identified in 54 instances. Guillain-Barre syndrome and other immune-mediated peripheral neuropathies were reported in 21 cases. Post-vaccinal herpes zoster was recorded in 31 vaccine recipients. Psychiatric adverse events were recorded in six patients. In Indian recipients of COVID-19 vaccine, a variety of serious neurological complications were reported. The overall risk appears minuscule. Immune-mediated central and peripheral neuronal demyelinations were the most frequently reported post-vaccinal adverse events. A large number of cases of herpes zoster have also been reported. Immune-mediated disorders responded well to immunotherapy.

Utility of itraconazole and terbinafine in mucormycosis: a proof-of-concept analysis.

An epidemic of mucormycosis followed the second wave of COVID 19 in the state of Uttar Pradesh, India in May 2021. This epidemic, however, had additional challenges to offer in the form of acute shortage of all forms of amphotericin B, posaconazole and isavuconazole. It was, therefore, planned to assess the trends in minimum inhibitory concentration (MIC) of antifungal agents, viz itraconazole and terbinafine, and provide a template for personalized therapy to see whether the results could be translated clinically. This is an observational, single-center study. Samples comprising nasal swab, nasal and paranasal sinus tissue, brain tissue, brain abscess and orbital content, derived from 322 patients from northern India with mucormycosis, of whom 215 were male and 107 were female, were used for analysis. Cultures were identified both by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and conventional methods of identification. Antifungal susceptibility was done for amphotericin B, posaconazole, isavuconazole, itraconazole and terbinafine as per Clinical Laboratory Standard Institute M38-A2. The outcome was identification of the species of mucormycosis and susceptibility to itraconazole and terbinafine besides other primary antifungal agents. Patients or the public were not involved in the design, or conduct, or reporting or in the dissemination plans of our research. Of 322 patients, 203 were culture-positive, of whom 173 were positive by both MALDI-TOF and conventional methods of identification. Final antifungal susceptibility testing was available for 150 patients. The most common Mucorales found to cause this epidemic was Rhizopus oryzae, followed by R. microsporus Amphotericin B, posaconazole and isavuconazole had low MIC values in 98.8% of all Mucorales identified. The MIC of itraconazole was species-dependent. 97.7% of Roryzae had MIC ≤2 µg/mL. However, only 36.5% of Rmicrosporus had MIC ≤2 µg/mL. For terbinafine, 85.2% of R. microsporus had MIC ≤2 µg/mL. We conclude that identification at the species level is required as antifungal susceptibilities seem to be species-dependent. Assessment of the efficacy of itraconazole and terbinafine warrants further studies with clinical assessment and therapeutic drug monitoring as they seem to be potential candidates especially when the primary agents are not available.

T-cell dysfunction as a potential contributing factor in post-COVID-19 mucormycosis.

BACKGROUND: The second wave of COVID-19 in India was followed by large number of mucormycosis cases. Indiscriminate use of immunosuppressive drugs, underlying diseases such as diabetes, cancers, or autoimmune diseases was thought to be the cause. However, the mortality was not as high as that seen in non-COVID mucormycosis. OBJECTIVE: To study the detailed characteristics of T-cells for evaluating the underlying differences in the T-cell immune dysfunction in post-COVID and non-COVID mucor patients. MATERIAL AND METHOD: The study included histopathologically confirmed cases of mucor (13 post-COVID, 13 non-COVID) and 15 healthy individuals (HI). Expression of T-cell activation (CD44, HLADR, CD69, CD38) and exhaustion (CTLA, PD-1, LAG-3 and TIM-3) markers was evaluated by flow cytometry. RESULTS: All cases showed significant depletion of T-cells compared to HI. Both post-COVID and non-COVID groups showed increased activation and exhaustion as compared to HI. Non-COVID mucor group showed significant activation of CD4+ T cells for HLADR and CD38 (p = .025, p = .054) and marked T-cell exhaustion in form of expression of LAG-3 on both CD4+ T and CD8+ T cells in comparison with post-COVID patients (p = .011, p = .036). Additionally, co-expression of PD-1 & LAG-3 and LAG-3 & TIM-3 on CD8+ T cells was statistically significant in non-COVID mucor patients (p = .016, p = .027). CONCLUSION: Immunosuppression in non-COVID mucor showed pronounced exhaustion of T-cells in comparison to post-COVID mucor cases implicating T-cell immune dysfunction is much more severe in non-COVID mucor which are in a state of continuous activation followed by extreme exhaustion leading to poorer outcome.

Determinants of stroke in patients with rhino cerebral mucormycosis seen during the second wave of COVID-19 pandemic: A prospective cohort study.

BACKGROUND: Rhino cerebral mucormycosis is an uncommon opportunistic infection of the nasal sinuses and brain, and a group of saprophytic fungi causes it. During the second wave of COVID-19, India witnessed an unprecedented number of patients with rhino cerebral mucormycosis. Invasion of the cavernous sinus and occlusion of the internal carotid artery in many cases resulted in a stroke. The study aimed to assess the clinical and neuroimaging predictors of stroke in patients with rhino cerebral mucormycosis. We also evaluated the predictors of death in these patients at 90 days. METHODS: A prospective study was performed at a tertiary care centre in India between July 2021 and September 2021. We enrolled consecutive microbiologically confirmed patients of rhino cerebral mucormycosis. All patients underwent neuroimaging of the brain. Treatment comprised of anti-fungal drugs and endoscopic nasal/sinus debridement. We followed the patients for 90 days and assessed the predictors of stroke and mortality RESULTS: Forty-four patients with rhino cerebral mucormycosis were enrolled. At inclusion, in 24 patients, the RT-PCR test for SARS-COV-2 was negative. Diabetes mellitus was the most frequent (72.7 %) underlying risk factor; in most, diabetes mellitus was recently discovered. At inclusion or subsequent follow-up, stroke was seen in 11 (25 %) patients. Only seven patients had hemiparesis. Imaging revealed internal carotid artery occlusion in 17 (38.6 %) patients. Hypertension, corticosteroid use, and cavernous sinus thrombosis were independent predictors of stroke. Nine (20.5 %) died during follow-up, and stroke was an independent predictor of death. CONCLUSION: Stroke indicated poor prognosis among rhino cerebral mucormycosis patients encountered during the second wave of the COVID-19 epidemic.

Acute hemorrhagic leukoencephalitis after administration of the first dose of ChAdOx1 nCoV-19 SARS-CoV-2 (COVISHIELD™) vaccine

Background Many central and peripheral nervous system complications, following COVID-19 vaccination, have been described. We report an unusual case of central demyelinating disorder, following the administration of the ChAdOx1 nCoV-19 SARS-CoV-2 (COVISHIELD™) vaccine. Case-report The 28-year female developed sudden onset headache followed by weakness of the left upper and lower limbs, and gait ataxia. Neurological symptoms developed two weeks after administration of the first dose of the ChAdOx1 nCoV-19 SARS-CoV-2 (COVISHIELD™) vaccine. Magnetic resonance imaging brain revealed T2/FLAIR hyperintense lesions involving bilateral subcortical white matter, splenium of the corpus callosum, and both cerebellar hemispheres. Few lesions showed blooming on gradient echo sequence suggestive of a hemorrhagic component. Post-contrast T1 images showed mild enhancement of demyelinating lesions. The patient was treated intravenously with methylprednisolone. After 12 weeks of follow-up, there was a substantial improvement in her symptoms. She became independent in all her activities of daily living. Conclusion In conclusion, this is an unusual case of acute hemorrhagic leukoencephalitis following ChAdOx1 nCoV-19 SARS-CoV-2 (COVISHIELD™) vaccination.

COVID-19 cases and their outcome among patients with uncommon co-existing illnesses: A lesson from Northern India

Introduction Newer coexisting conditions should be identified in order to modify newer risk factors. Aim was to identify patients with non-classical or less common coexisting conditions in patients infected of COVID 19. Method Single centred study from June 2020 to May 2021 at a tertiary centre in North India. A preformed questionnaire was used to record clinical and laboratory parameters and to identify cases which are in addition to CDC list and Indian data. Results 0.67% (46) cases out of 6832 patients were identified to have non-classical coexisting illness. It was divided into 2 groups-infections A (60.1%) and non-infections B (39.9%). Group A included-tuberculosis- pulmonary (14.3%) & extra pulmonary (32.9%), bacterial (25.0%) viral infections [dengue, hepatitis B & C] (14.3%), HIV disease (10.7%) and malaria (3.6%). Group B included- organ transplant (27.8%), autoimmune [myasthenia gravis, polymyositis, psoriasis] (22.6%), haematologic [Haemophilia, ITP, Aplastic anaemia, APML, CML] (27.8%), uncommon malignancies [disseminated sacral chordoma and GTN] (11.1%) and snakebite (11.1%). Serum Procalcitonin was not helpful for diagnosis of bacterial infection in COVID-19 disease. Group A had significantly longer duration of illness, hepatitis and elevated CRP. The mortality in group A & B were 32.1% and 43.8% respectively. Death in non-severe COVID cases was in tetanus and snakebite. 30.7% death among tuberculosis patients. More than 70% of deaths were attributable to COVID 19 in both the groups. Conclusion In Indian settings, comorbidities like tuberculosis and bacterial infections can precipitate severe COVID 19 unlike other parts of the world where tuberculosis is relatively uncommon.

COVID-19 associated mucormycosis: Staging and management recommendations (Report of a multi-disciplinary expert committee).

Even before the onslaught of COVID-19 pandemic could settle, the unprecedented rise in cases with COVID-19 associated mucormycosis pushed the medical health to the fringe. Hyperglycaemia and corticosteroids appear to be the most consistent associations leading to the commonest manifestation of mucormycosis, Rhino-Orbito-Cerebral Mucormycosis. To address challenges right from categorisation and staging of the disease to the management of relentless progression, a multi-disciplinary expert committee was formed to handle the task in an evidence-based format to enforce best practices. The report of the committee on one hand attempts to succinctly present the currently available evidence while at the other also attempts to bridge the evidence-deficient gaps with the specialty-specific virtuosity of experts.

Hemophagocytic histiocytosis in severe SARS-CoV-2 infection: A bone marrow study.

INTRODUCTION: The clinical and laboratory features of severe COVID-19 infection overlap with those of hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder often associated with several viral infections. The clinical syndrome of HLH encompasses fever, organomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, raised transaminases, hypofibrinogenemia, absent natural killer (NK) cell activity, increased soluble CD25 and hemophagocytic lymphohistiocytosis in bone marrow, spleen, and lymph nodes. METHODS: We analyzed clinicopathological and laboratory features of thirteen patients with severe COVID-19 infection suspected to have HLH and found to have hemophagocytic histiocytosis on bone marrow examination (BME). RESULTS: Five of thirteen (38.46%) patients fulfilled five of eight HLH 2004 criteria and/or had a H-score ≥169. Three (23.08%) satisfied four of eight and remainder five (38.46%) satisfied three of eight HLH 2004 criteria. Fever, raised serum ferritin (13/13, 100%), transaminases (9/13, 69.23%), triglycerides (4/13, 30.76%), cytopenias (5/13, 38.46%), hypofibrinogenemia (2/13, 15.38%), and organomegaly (1/13, 7.69%) were observed in our patients. BME showed hemophagocytic histiocytosis without lymphocytosis in all. Contrary to HLH, lymphocytopenia (11/13, 84.61%), leukocytosis (7/13, 53.84%), neutrophilia (7/13, 53.84%), and hyperfibrinogenemia (7/13, 53.84%) were observed. Serum CRP, LDH, and plasma D-dimer were elevated in all, while serum albumin was decreased in 12 of 13 (92.3%) patients. Five patients recovered with high-dose pulsed corticosteroid therapy. CONCLUSION: The immune response associated with severe COVID-19 infection is similar to HLH with few differences. HLH should be suspected in severe COVID-19 infection although all patients may not fulfill required HLH diagnostic criteria. BME should be done in suspected cases so that appropriate therapy may be initiated early.

A deep learning-based COVID-19 automatic diagnostic framework using chest X-ray images.

The lethal novel coronavirus disease 2019 (COVID-19) pandemic is affecting the health of the global population severely, and a huge number of people may have to be screened in the future. There is a need for effective and reliable systems that perform automatic detection and mass screening of COVID-19 as a quick alternative diagnostic option to control its spread. A robust deep learning-based system is proposed to detect the COVID-19 using chest X-ray images. Infected patient's chest X-ray images reveal numerous opacities (denser, confluent, and more profuse) in comparison to healthy lungs images which are used by a deep learning algorithm to generate a model to facilitate an accurate diagnostics for multi-class classification (COVID vs. normal vs. bacterial pneumonia vs. viral pneumonia) and binary classification (COVID-19 vs. non-COVID). COVID-19 positive images have been used for training and model performance assessment from several hospitals of India and also from countries like Australia, Belgium, Canada, China, Egypt, Germany, Iran, Israel, Italy, Korea, Spain, Taiwan, USA, and Vietnam. The data were divided into training, validation and test sets. The average test accuracy of 97.11 ± 2.71% was achieved for multi-class (COVID vs. normal vs. pneumonia) and 99.81% for binary classification (COVID-19 vs. non-COVID). The proposed model performs rapid disease detection in 0.137 s per image in a system equipped with a GPU and can reduce the workload of radiologists by classifying thousands of images on a single click to generate a probabilistic report in real-time.