Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality

The precise molecular mechanisms behind life-threatening lung abnormalities during severe SARS-CoV-2 infections are still unclear. To address this challenge, we performed whole transcriptome sequencing of lung autopsies from 31 patients suffering from severe COVID-19 related complications and 10 uninfected controls. Using a metatranscriptome analysis of lung tissue samples we identified the existence of two distinct molecular signatures of lethal COVID-19. The dominant "classical" signature (n=23) showed upregulation of unfolded protein response, steroid biosynthesis and complement activation supported by massive metabolic reprogramming leading to characteristic lung damage. The rarer signature (n=8) potentially representing "Cytokine Release Syndrome" (CRS) showed upregulation of cytokines such IL1 and CCL19 but absence of complement activation and muted inflammation. Further, dissecting expression of individual genes within enriched pathways for patient signature suggests heterogeneity in host response to the primary infection. We found that the majority of patients cleared the SARS-CoV-2 infection, but all suffered from acute dysbiosis with characteristic enrichment of opportunistic pathogens such as Staphylococcus cohnii in "classical" patients and Pasteurella multocida in CRS patients. Our results suggest two distinct models of lung pathology in severe COVID-19 patients that can be identified through the status of the complement activation, presence of specific cytokines and characteristic microbiome. This information can be used to design personalized therapy to treat COVID-19 related complications corresponding to patient signature such as using the identified drug molecules or mitigating specific secondary infections.

Clinico-pathological features in fatal Covid-19 Infection: A Preliminary Experience of a Tertiary Care Centre in North India using Post-Mortem Minimally Invasive Tissue Biopsies

BackgroundThe Covid-19 pandemic began in China in December 2019. India is the second most affected country, as of November 2020 with more than 8.5million cases. Covid-19 infection primarily involves the lung with severity of illness varying from influenza-like illness to acute respiratory distress syndrome. Other organs have also found to be variably affected. Studies evaluating the histopathological changes of Covid-19 are critical in providing a better understanding of the disease pathophysiology and guiding treatment. Minimally invasive biopsy techniques (MITS/B) provide an easy and suitable alternative to complete autopsies. In this prospective single center study we present the histopathological examination of 37 patients who died with complications of Covid-19. MethodsThis was an observational study conducted in the Intensive Care Unit of JPN Trauma Centre AIIMS. A total of 37 patients who died of Covid-19 were enrolled in the study. Post-mortem percutaneous biopsies were taken by the help of surface landmarking/ultrasonography guidance from lung, heart, liver, and kidneys; after obtaining ethical consent. The biopsy samples were then stained with haematoxylin and eosin stain. Immunohistochemistry (IHC) was performed using CD61 and CD163 in all lung cores. SARS-CoV-2 virus was detected using IHC with primary antibodies in selected samples. Details regarding demographics, clinical parameters, hospital course, treatment details, and laboratory investigations were also collected for clinical correlation. ResultsA total of 37 patients underwent post-mortem minimally invasive tissue sampling. Mean age of the patients was 48.7years and 59.5% of them were males. Respiratory failure was the most common complication seen in 97.3%. Lung histopathology showed acute lung injury and diffuse alveolar damage in 78% patients. Associated bronchopneumonia was seen in 37.5% patients and scattered microthrombi were visualised in 21% patients. Immunostaining with CD61 and CD163 highlighted megakaryocytes, and increased macrophages in all samples. Immunopositivity for SARS-CoV-2 was observed in Type II pneumocytes. Acute tubular injury with epithelial vacuolization was seen in 46% of the renal biopsies but none of them showed evidence of microvascular thrombosis. 71% of the liver tissue cores showed evidence of Kupfer cell hyperplasia. 27.5% had evidence of submassive hepatic necrosis and 14% had features of acute on chronic liver failure. All the heart biopsies showed non-specific features such as hypertrophy with nucleomegaly with no evidence of myocardial necrosis in any of the samples. ConclusionsThe most common finding in this cohort is the diffuse alveolar damage with demonstration of SARS-CoV-2 protein in the acute phase of DAD. Microvascular thrombi were rarely identified in the lung, liver and kidney. Substantial hepatocyte necrosis, hepatocyte degeneration, Kupffer cell hypertrophy, micro, and macrovesicular steatosis unrelated to microvascular thrombi suggests that liver might be a primary target of Covid-19. This study highlights the importance of MITS/B in better understanding the pathological changes associated with Covid-19.

Simultaneous medullary carcinoma, papillary carcinoma and granulomatous inflammation of the thyroid

Thyroid tumours with both papillary and medullary carcinoma features are rare and represent less than 1% of all thyroid malignancies. These tumours have a different clinical presentation and biological behaviour from tumours that have only papillary or medullary carcinoma features. The phenomenon of mixed thyroid tumours can be observed in two settings--a mixed tumour showing dual differentiation, or a collision tumour. For a precise diagnosis of this rare mixed thyroid carcinoma, fine needle aspiration cytology results should be correlated with serum calcitonin and thyroglobulin levels. The diagnosis should also be confirmed using immunocytochemistry. Surgery is the treatment of choice, and the role of postoperative radioiodine is controversial. We herein report the case of a 35-year-old man with a mixed medullary-papillary carcinoma of the thyroid, which presented with C-cell hyperplasia, granulomatous inflammation and metastasis to the cervical lymph nodes. The patient was treated with total thyroidectomy and nodal clearance. This case highlights the need for awareness of coexistent entities as they warrant separate treatments.

Intra-operative electrocorticography in lesional epilepsy.

Intra-operative electrocorticography (ECoG) is useful in epilepsy surgery to delineate margins of epileptogenic zone, guide resection and evaluate completeness of resection in surgically remediable intractable epilepsies. The study evaluated 157 cases (2000-2008). The preoperative evaluation also included ictal SPECT (122) and PET in 32 cases. All were lesional cases, 51% (81) of patients had >1 seizure/day and another 1/3rd (51) had >1/week. Pre and post resection ECoG was performed in all cases. A total of 372 recordings were performed in 157 cases. Second post-operative recordings (42) and third post-operative recordings (16) were also performed. Site of recordings included lateral temporal (61), frontal (39), parietal (37), hippocampal (16) and occipital (4). 129/157 cases (82%) showing improvement on ECoG, 30/42 cases showed improvement in 2nd post resection, 8/16 showed improvement in the 3rd post-operative ECoG. 116/157 (73%) patients had good outcome (Engel I and II) at follow up (12-94 months, mean 18.2 months). Of these, 104 patients (80%) showed improvement on post-operative ECoG. 12 had good outcome despite no improvement on ECoG. The improvement in ECoG correlated significantly with clinical improvement [Sensitivity: 100% (95% CI; 96-100%); specificity: 68.3% (95% CI; 51.8-81.4%); positive predictive value: 89.9% (95% CI, 83.1-94.3%); negative predictive value: 100% (95% CI, 85-100%)]. The level of agreement was 91.72% (kappa: 0.76). Concluding, pre and post resection ECoG correlated with its grade of severity and clinical outcome.

Recurrence of supratentorial gliomas.

Two hundred patients treated for supratentorial gliomas and for whom a follow up of one to sixteen years was available have been reviewed retrospectively for recurrence of tumor. All patients were initially treated with radical surgical tumour removal followed by radiotherapy. The series consisted of 82 cases of astrocytomas, 46 cases of mixed gliomas (oligoastrocytomas), 8 of oligodendrogliomas, 33 cases of malignant astrocytomas and 31 glioblastomas. However, period of recurrence could not be correlated to histological grade or presence or absence of residual tumour in a postoperative CT scan. Illustrated cases have been described. Problems of diagnosis and therapy have been discussed.

Duchenne muscular dystrophy in a female patient : a case report.

A female patient with Duchenne muscular dystrophy (DMD) with no prior family history of DMD is described. She presented with proximal muscle weakness, enlarged calf muscles and an elevated serum creatine kinase (CK). Histological examination of skeletal muscle revealed myopathic changes and immunoperoxidase examination for dystrophin in muscle biopsy demonstrated a mosaic pattern. Immunostaining of a muscle biopsy with anti-dystrophic serum proved to be valuable in the diagnosis of DMD in a symptomatic female carrier.