Mucormycosis infection associated with global COVID-19 pandemic - an institutional histopathological study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) in the recent times have instilled signs of immunosuppression globally which has further precipitated increasing range of opportunistic infections. Mucormycosis is a distressing opportunistic fungal infection with a high incidence and is the third commonest acute invasive infection following candidiasis and aspergillosis. The aim of the present observational study is to delineate the enigmatic histopathological profile between mucormycosis cases seen prior to pandemic (PPM) and pandemic associated mucormycosis (PAM). MATERIAL AND METHODS: Tissue archives of 105 histopathologically diagnosed cases of mucormycosis were included and analysed for demographical details and histopathological parameters like fungal load and localization, granuloma formation, necrosis, inflammatory infiltrate and tissue invasion. RESULTS: 0ut of 105 included cases, 11/105 (10.48%) were reported PPM and 94/105 (89.52%) PAM. Among 94 cases of PAM, 51/94 (54%) cases also showed COVID-19 positivity, while 43/94 (46%) did not. Of all the histological variables, increased fungal load and necrosis were observed in PAM relative to PPM cases. CONCLUSIONS: The histopathological variables like fungal load, necrosis, granuloma formation and tissue invasion, could help the clinician in assessing the clinical status at the time of tissue diagnosis and improve the treatment accordingly.

Post-intubation Laryngeal Disorders in COVID-19 Patients: A Prospective Study. (preprint)

Objective: To investigate post-intubation laryngeal complications in severe COVID-19 patients. Methods: From September 2020 to April 2021, consecutive patients presenting with laryngological symptoms following severe COVID-19 infection and related intubation were included. Demographic, age, gender, comorbidities, symptoms, intubation duration, tracheostomy features, and laryngeal findings were collected. Videolaryngostroboscopy findings were analyzed by two senior laryngologists in a blind manner. Results: Forty-three patients completed the evaluations. The intubation duration was <14 days in 22 patients (group 1) and >14 days in 21 patients (group 2). The following abnormalities were found on an average post-intubation time of 51.6 days: posterior glottic stenosis (N=14), posterior commissure hypertrophy (N=19) or laryngeal diffuse edema (N=10), granuloma (N=8), laryngeal necrosis (N=2), vocal fold atrophy (N=2), subglottic stenosis (N=1) and glottic flange (N=1). Sixteen patients required surgical treatment (N=17 procedures). The number of intubation days was significantly higher in patients with posterior glottic stenosis (26.1 ± 9.4) compared with those presenting posterior commissure hypertrophy (11.5 ± 2.9) or granuloma (15.1 ± 5.8; p<0.001). Fourteen patients required surgical management. Conclusion: Prolonged intubation used in severe COVID-19 patients is associated with significant laryngeal disorders. Patients with a history of >2-week intubation have a higher risk of posterior glottic stenosis.

Post-intubation Laryngeal Disorders in COVID-19 Patients: A Prospective Study. (preprint)

Objective: To investigate post-intubation laryngeal complications in severe COVID-19 patients. Methods: From September 2020 to April 2021, consecutive patients presenting with laryngological symptoms following severe COVID-19 infection and related intubation were included. Demographic, age, gender, comorbidities, symptoms, intubation duration, tracheostomy features, and laryngeal findings were collected. Videolaryngostroboscopy findings were analyzed by two senior laryngologists in a blind manner. Results: Forty-three patients completed the evaluations. The intubation duration was <14 days in 22 patients (group 1) and >14 days in 21 patients (group 2). The following abnormalities were found on an average post-intubation time of 51.6 days: posterior glottic stenosis (N=14), posterior commissure hypertrophy (N=19) or laryngeal diffuse edema (N=10), granuloma (N=8), laryngeal necrosis (N=2), vocal fold atrophy (N=2), subglottic stenosis (N=1) and glottic flange (N=1). Sixteen patients required surgical treatment (N=17 procedures). The number of intubation days was significantly higher in patients with posterior glottic stenosis (26.1 ± 9.4) compared with those presenting posterior commissure hypertrophy (11.5 ± 2.9) or granuloma (15.1 ± 5.8; p<0.001). Fourteen patients required surgical management. Conclusion: Prolonged intubation used in severe COVID-19 patients is associated with significant laryngeal disorders. Patients with a history of >2-week intubation have a higher risk of posterior glottic stenosis.

Lymphohistiocytic Myocarditis Possibly Due to Moderna mRNA-1273 Vaccine.

OBJECTIVES: Despite the clear benefits of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in mitigating the impact of the coronavirus disease 2019 pandemic, there are emerging reports of postvaccination myocarditis, the majority of which are diagnosed based on the clinical and radiologic findings without biopsy confirmation. We report a case of biopsy-confirmed lymphohistiocytic myocarditis after Moderna mRNA-1273 vaccination. METHODS: We describe a case of a previously healthy 45-year-old woman who had palpitations, exercise intolerance, and syncope 1 week after her first mRNA-1273 vaccine dose. Laboratory tests and cardiac imaging were compatible with myocarditis. Given her unusual clinical presentation, an endomyocardial biopsy was performed to exclude other potential etiologies. RESULTS: The endomyocardial biopsy specimen showed patchy endocardial and intramyocardial lymphohistiocytic infiltrates with scattered eosinophils and focal myocyte injury. CD3 and CD68 immunostains confirmed the lymphocytic and histiocytic nature of the infiltrate, respectively. A focal histiocytic collection suggestive of an ill-defined granuloma was present. The histologic and immunohistochemical findings of a lymphohistiocytic myocarditis were highly suggestive of a postvaccination hypersensitivity reaction. CONCLUSIONS: Myocarditis following SARS-CoV-2 vaccination is a rare adverse event. The findings of a lymphohistiocytic myocarditis with scattered eosinophils and a possible ill-defined granuloma are highly suggestive of a hypersensitivity reaction. The mechanism by which this inflammation occurs remains uncertain. Despite our findings, the benefits of SARS-CoV-2 vaccination far outweigh the risks.

A Rare Case of Granulomatous Interstitial Nephritis in a Patient With COVID-19.

Acute kidney injury (AKI) in patients with coronavirus disease 2019 (COVID-19) is common, especially among severely ill patients. While acute tubular necrosis (ATN) is one of the most common findings in published kidney biopsy series for patients with COVID-19 infections, a number of glomerular pathologies have been described as well. Among glomerular pathologies in COVID-19, COVID-19-Associated Collapsing Glomerulopathy (COVAN) remains the most common pattern of injury. Patients with 2 high-risk APOL1 alleles appear to be at increased risk for COVAN, similar to other forms of collapsing glomerulopathy such as HIV-Associated Nephropathy. Acute interstitial nephritis (AIN) is a less common finding in patients with COVID-19 and reported cases have been mild. Reports of a subtype of AIN, granulomatous interstitial nephritis (GIN), among COVID-19 patients are extremely rare and have not been reported in association with COVAN. Here, we report a case of COVAN associated with severe GIN.

Gastric tuberculosis presenting as a large gastric ulcer.

While gastrointestinal (GI) tuberculosis (TB) accounts for 1%-3% of all TB cases worldwide, TB of the stomach is extremely rare and accounts for 1%-2% of all GI TB. Little is known about this entity, and most data are obtained from case reports. We report a case of a woman in her 60s who presented with a 2-week history of generalised weakness, fatigue and shivering, with severe loss of appetite on background history of dyspepsia and significant weight loss for the preceding 2 years. Upper endoscopy revealed a large gastric ulcer. Biopsy and histopathology revealed caseating granulomas with numerous acid-fast bacilli detected with Ziehl-Neelsen stain. She was diagnosed with gastric TB. Subsequently, she was also diagnosed with pulmonary, adrenal and colonic involvement.

Intramural Ova of Enterobius vermicularis in the Appendix-An Egg-Topic Location!

We report an unusual case of appendicitis in a 9-year-old girl in whom the wall of the appendix contained necrotizing granulomas, as well as eggs of Enterobius vermicularis. Although luminal E vermicularis adult parasites are commonly identified in the appendix and luminal eggs are occasionally seen, intramural worms and eggs are rare. We are unaware of earlier reports of ectopic intramural eggs in the appendix. It is important to and make a correct diagnosis, as both, the patient, as well as the family should be treated for enterobiasis.

Unravelling the transcriptome of the human tuberculosis lesion and its clinical implications (preprint)

ABSTRACT Tuberculosis (TB) disease causes up to 1.5 million deaths every year and represents an important problem of public health at worldwide level. Here, we quantified the gene expression signatures of granuloma biopsies across human TB pulmonary lesions, and validated the best gene candidates using NanoString technology, profiling 157 samples from 40 TB patients who underwent surgery. We characterised the transcriptional profile of the TB granuloma in comparison to healthy tissue, described an 11-gene signature and measured 7 proteins in plasma associated with it. We demonstrated a gradient of immune-related transcript abundance across the granuloma substructure and evidenced metabolically-active Mycobacterium tuberculosis in the lesions. Patients who converted to sputum negative after two months of starting treatment, showed enriched inflammatory pathways in the lesion several months after, supporting use of sputum culture conversion (SCC) as a prognostic biomarker during clinical management and as a factor to prioritise patients when considering lung surgery.

Understanding the tuberculosis granuloma: the matrix revolutions.

Mycobacterium tuberculosis (Mtb) causes the human disease tuberculosis (TB) and remains the top global infectious pandemic after coronavirus disease 2019 (COVID-19). Furthermore, TB has killed many more humans than any other pathogen, after prolonged coevolution to optimise its pathogenic strategies. Full understanding of fundamental disease processes in humans is necessary to successfully combat this highly successful pathogen. While the importance of immunodeficiency has been long recognised, biologic therapies and unbiased approaches are providing unprecedented insights into the intricacy of the host-pathogen interaction. The nature of a protective response is more complex than previously hypothesised. Here, we integrate recent evidence from human studies and unbiased approaches to consider how Mtb causes human TB and highlight the recurring theme of extracellular matrix (ECM) turnover.

A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity.

T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19. Here we conducted a phase I open-label trial, recruiting 36 participants aged 18-80 years, who received a single subcutaneous CoVac-1 vaccination. The primary end point was safety analysed until day 56. Immunogenicity in terms of CoVac-1-induced T cell response was analysed as the main secondary end point until day 28 and in the follow-up until month 3. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study participants, whereas systemic reactogenicity was absent or mild. SARS-CoV-2-specific T cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T helper 1 CD4+ and CD8+ T cells. CoVac-1-induced IFNγ T cell responses persisted in the follow-up analyses and surpassed those detected after SARS-CoV-2 infection as well as after vaccination with approved vaccines. Furthermore, vaccine-induced T cell responses were unaffected by current SARS-CoV-2 variants of concern. Together, CoVac-1 showed a favourable safety profile and induced broad, potent and variant of concern-independent T cell responses, supporting the presently ongoing evaluation in a phase II trial for patients with B cell or antibody deficiency.

COVID-19-associated rhino-orbital- cerebral mixed mycoses with intracranial fungal granuloma - An aggressively managed rare entity.

Rhino-orbital-cerebral mucormycosis (ROCM) with intracranial extension is a fatal disease. A case of extensive ROCM, with rare intracranial fungal granuloma, seen in a COVID-19 positive young male is described. A successful therapy consisting of a multidisciplinary approach for sinuses debridement, orbital exenteration, and intracranial granuloma excision was done. Nonseptate hyphae of Mucor and septate filamentous Aspergillus grew concurrently from exenterated orbital specimen.

Phase I Trial of a Multi-Peptide COVID-19 Vaccine for the Induction of SARS-CoV-2 T-Cell Immunity (preprint)

T-cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS15 emulsified in Montanide TM ISA51 VG, aiming to induce superior SARS-CoV-2 T-cell immunity to combat COVID-19. We conducted a Phase I open-label trial, including 36 participants aged 18 to 80 years, who received one single subcutaneous CoVAC-1 vaccination. The primary endpoint was safety analyzed until day 56. Immunogenicity in terms of CoVac-1-induced T-cell response was analyzed as main secondary endpoint until day 28. No serious adverse events and no grade 4 adverse events were observed. Expected local granuloma formation was observed in all study subjects, while systemic reactogenicity was absent or mild. SARS-CoV-2-specific T-cell responses targeting multiple vaccine peptides were induced in all study participants, mediated by multifunctional T-helper 1 CD4 + and CD8 + T cells. CoVac-1-induced interferon-γ T-cell responses by far surpassed those detected in COVID-19 convalescents and were unaffected by current SARS-CoV-2 variants of concern (VOC). Together, CoVac-1 showed a favorable safety profile and induced broad, potent, and VOC-independent T-cell responses, supporting the presently ongoing evaluation in a Phase II trial for patients with B-cell/antibody deficiency. Funded by the Ministry of Science, Research and the Arts Baden-Württemberg, Germany; ClinicalTrials.gov number, NCT04546841.

Giant nasal granuloma gravidarum.

Nasal granuloma gravidarum usually presents as a small vascular lesion on the septum or turbinates during pregnancy. We present a case of a giant nasal granuloma gravidarum and its management.

Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.

BACKGROUND: Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive. CASE PRESENTATION: The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis. CONCLUSIONS: Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.

Emergency presentation of iatrogenic airway stenosis following intubation in a patient with COVID-19 and its management.

A 59-year-old man presented to the emergency department with recent onset biphasic stridor, dyspnoea and increased work of breathing on the background of prolonged intubation for the novel COVID-19 2 months previously. Flexible laryngoscopy revealed bilateral vocal fold immobility with a soft tissue mass in the interarytenoid region. The patient's symptoms improved with oxygen therapy, nebulised epinephrine (5 mL; 1:10 000) and intravenous dexamethasone (3.3 mg). The following morning, the patient was taken to theatre, underwent suspension microlaryngoscopy and found to have bilateral fixation of the cricoarytenoid joints and a large granuloma in the interarytenoid area. He underwent cold steel resection of the granuloma and balloon dilatation between the arytenoids, with the hope of mobilising the joints. This failed and CO2 laser arytenoidectomy was performed on the left side. The stridor had resolved postoperatively, with normalisation of work of breathing and the patient was discharged home on the first postoperative day.

The Negative Impact of COVID-19 Pandemics on the Diagnosis of Lung Diseases in Brazil. (preprint)

Background: COVID-19 pandemics affects the Health system all around the World. Brazil, since the first case in March, reported more than 4.0 million people infected. The pandemic's magnitude made that Hospitals prioritize the care of the secondary respiratory distress syndrome, and all elective diagnosis and treatment have been postponed. This study aimed to assess changes in patient's profiles submitted to lung or pleural biopsies comparing before and during COVID-19 pandemics.Methods: We retrospectively review the data of patients who underwent lung disease diagnostic approaches across April/May 2019 versus April/May 2020. We collect the data about the total cases, demographics, type of procedure, and disease diagnosis. Histological type, stage of the tumors, and molecular profile were also analyzed in cancer cases.Results: The number of total cases and lung biopsies dropped by more than 90% when the 2019/2020 samples were compared. Benign disease faced a more substantial reduction than cancer cases, with emphasis in granulomatous diseases. We had more advanced cases and more squamous cell carcinomas and small cell neuroendocrine carcinomas in the cancer scenario. Low-grade tumors, as carcinoids, suffered a significant reduction. Also, the molecular profile of the tumors drops in absolute numbers. Still, there was an increase of PD-L1 expression, probably because the sample comprises more squamous cell carcinomas and advanced cases.Conclusions: COVID-19 pandemics have a considerable negative impact on the management and diagnosis of lung diseases in Brazil. The consequences can be significant, and implementing a new policy to patients with lung diseases must be managed.