ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause substantial morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. Whereas interferon (IFN)-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced Z-DNA-binding protein 1 (ZBP1)-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with ß-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-ß treatment after ß-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during ß-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.

Post-COVID-19 symptoms are not uncommon among recovered patients-A cross-sectional online survey among the Indian population.

BackgroundCoronavirus disease-2019 (COVID-19) can have a myriad of symptoms. However, it is now known that most patients recovered from COVID-19 have symptoms related to COVID-19. There is a paucity of literature on post-COVID-19 symptoms from India. Hence we aimed to assess the incidence of post-COVID-19 symptoms in patients recovered from COVID-19. Methods: An online Microsoft forms survey was conducted through multiple social media platforms. ResultsOf the 5,347 individuals who received and clicked the link, a total of 2038 infected patients responded (Supplementary figure). Approximately 48% (967/2038) had recovered from COVID-19 within 1-3 months (short-term recovered), 34.2% (375/2038) had recovered from COVID-19 >3 months ago (long recovered), and 18.4% (375) were recovered within the last one month (recently recovered). Nearly 38% (770/2038) had a history of hospitalization for COVID-19. Of them, 34.28% (264/770) required oxygen therapy during the hospital stay. Most patients were discharged within 5-10 days of hospital stay (54%, 415/770). Only 5.58% (43/770) required a stay of more than 20 days. Seventy-five percent (575/770) of the hospitalized patients received steroid therapy. Of those who received steroid therapy, 56.5% (325/575) had not required oxygen therapy. Forty percent (233/575) of patients received steroid therapy for two weeks, 24% (138/575) for one week, 33.73% received steroids only during the hospital stay, and 1.73% were still on steroid therapy during the survey. Most importantly, of the 2038 respondents, 41.8% (851/2038) still had persistent symptoms related to COVID-Most common symptom was fatigue (64.15%), followed by body pain (31%) and gastrointestinal symptoms (25%) (Figure). Six percent (49/851) of them required hospitalization for post-COVID-19 symptoms. Forty-six percent (449/967) in the short term recovered group (1-3 months), 40.1% (279/696) in the long-recovered group, and 32.8% (123/375) in the recently recovered group had persistent symptoms related to COVID-19 (P=0.001). Forty-eight percent (374/770) of the hospitalized patients developed post-COVID-19 symptoms, while only 37.6% (477/1268) developed post-COVID-19 symptoms among the non-hospitalized patients (P<0.001). Fifty-three percent (303/575) of those who received steroids developed post-COVID-19 symptoms, while only 36.41% (71/195) of those who did not receive steroids developed post-COVID-19 symptoms (P<0.001). 49% (159/325) of patients who received steroids despite being not requiring oxygen developed post-COVID-19 symptoms compared to only 37.5% (543/1449) who did not receive steroids and were not on oxygen therapy (P<0.001). Nearly 40% (336/851) of respondents felt that post-COVID-19 symptoms are not being appropriately treated or taken care of seriously. ConclusionsPost-COVID-19 symptoms are common in patients who recovered from COVID-19. These symptoms are more often noted in patients who received steroid therapy. Post-COVID-19 symptomatology is present in a significant number of patients and requires to be addressed seriously.

A Multicenter Study on the Utility of EBUS-TBNA and EUS-B-FNA in the Diagnosis of Mediastinal Lymphoma.

BACKGROUND: There is conflicting data on the utility of endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) for the detection and subtyping of lymphomas. Herein, we present our experience with EBUS-TBNA in suspected lymphoma. METHODS: This was a multicenter retrospective study of subjects with suspected lymphoma who underwent EBUS-TBNA (July 2011 to June 2017). The performance characteristics of EBUS-TBNA were calculated separately for suspected new-onset and recurrent lymphoma as well as for subtyping. We also analyzed the factors predicting the yield of EBUS-TBNA in suspected lymphoma. RESULTS: Among the 4803 EBUS procedures performed, 92 (1.9%) subjects had either suspected or proven lymphoma; 48 were finally diagnosed to have lymphoma. The diagnostic sensitivities of EBUS-TBNA in new-onset and recurrent lymphomas were 72.7% and 73.3%, respectively. Only 24.2% (8/33) subjects with new-onset lymphoma could be appropriately subtyped. This low yield was possibly due to inadequate material for cell block in 10 subjects, and performance of immunophenotyping and flow cytometry in only 5 and 1 subjects, respectively. Among the suspected cases of recurrence, EBUS-TBNA was sufficient for management in 81.8% (18/22). On a multivariate analysis, no factor (rapid onsite evaluation, needle size, number of lymph nodes sampled, passes per node, and size of the largest lymph node sampled) predicted the diagnostic yield. CONCLUSION: EBUS-TBNA is a useful investigation in the diagnostic algorithm of suspected lymphoma as it helps avoid other invasive diagnostic procedures. The sensitivity of EBUS-TBNA in subtyping new-onset mediastinal lymphoma depends on the adequacy of cell aspirate and the judicious utilization of pathologic techniques.

A multicenter study on the utility and safety of EBUS-TBNA and EUS-B-FNA in children.

BACKGROUND AND AIM: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound with an echobronchoscope-guided fine needle aspiration (EUS-B-FNA) are useful modalities in the evaluation of mediastinal lymphadenopathy in adults; however, there is sparse data in children. The aim of this multicenter study is to describe the efficacy and safety of EBUS-TBNA and EUS-B-FNA in children with mediastinal lymphadenopathy of undefined etiology. METHODS: Retrospective analysis of consecutive pediatric (<18 years) subjects who underwent EBUS-TBNA or EUS-B-FNA for the evaluation of mediastinal lymphadenopathy. The demographic characteristics, indications, procedural details, pathological, cytological and microbiological diagnosis, diagnostic yield, and complications are presented. RESULTS: Of the 3,424 EBUS/EUS-B-FNA procedures, 67 (1.9%) were performed in the pediatric (3-17 years) population. Of these, 19 (28.4%) were performed in children ≤12 years of age. Overall, EBUS-TBNA and EUS-B-FNA were performed in 53 and 12 subjects, respectively. In two subjects, no significant lymph node was seen on EBUS. The procedure was performed under moderate sedation in spontaneously breathing subjects in 54 (80.6%) instances. An adequate sample was obtained in 60 (92.3%) subjects while a diagnostic sample was obtained in 37 (56.9%) of the 65 subjects. The diagnostic yield was not significantly different (P = 0.59) between EBUS-TBNA (58.5%) and EUS-B-FNA (50%). The sensitivity of EBUS-TBNA/EUS-B-FNA was 79.1% and led to a change in diagnosis in 28 (41.8%) subjects. Complications, all minor were encountered in six (8.9%) subjects. CONCLUSIONS: EBUS-TBNA and EUS-B-FNA are safe techniques with a good diagnostic yield in the evaluation of children with mediastinal lymphadenopathy. Pediatr Pulmonol. 2016;51:1031-1039. © 2016 Wiley Periodicals, Inc.

Clinical experience on use of oral EGFR-TKIs as first-line treatment of advanced NSCLC from a tertiary care centre in North India and implications of skin rash.

BACKGROUND: Limited data are available from India on treatment outcomes with oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in newly diagnosed non-small cell lung cancer (NSCLC). We studied the demographic profile and treatment outcomes of patients with NSCLC, receiving first-line treatment with oral EGFR-TKIs. METHODS: Retrospective study of newly diagnosed NSCLC patients treated with oral EGFR-TKIs over a 4-year period at a tertiary care institute in North India. RESULTS: Of 76 patients studied, females and non-smokers constituted 32.9% and 48.7%, respectively. Majority of patients had adenocarcinoma (59.2%), stage IV (64.5%) disease and Karnofsky performance status ≤ 70 (74.5%). Gefitinib was the most frequently used EGFR-TKI (92.1%). Most common indication for the use of EGFR-TKIs was poor performance status (65.8%). Among assessable patients, disease control and progressive disease were evident in 66% and 34%, respectively. Most common side effects were skin rash (17%) and diarrhoea (10.6%). Patients with and without skin rash differed significantly in relation to objective response to treatment (100% versus 23.1%) and overall survival (median not reached versus 178 days). On multivariate logistic regression analysis, malignant pleural effusion was associated with occurrence of rash (odds ratio = 0.19; 95% confidence interval = 0.04-0.95; p = 0.04). CONCLUSIONS: Oral EGFR-TKIs appear to be useful for the treatment of clinically selected patients with advanced NSCLC. Occurrence of skin rash was independently associated with treatment response and better survival in the current study.

Rigid bronchoscopy and mechanical debulking in the management of central airway tumors: an Indian experience.

BACKGROUND: Treatment options for central airway tumors include surgery, radiotherapy, and in those with inoperable or emergent airway obstruction, therapeutic bronchoscopy. Herein, we report our experience with the exclusive use of rigid bronchoscope in the management of central airway tumors. METHODS: Retrospective review of charts of patients who underwent rigid bronchoscopy and mechanical coring for the management of central airway (trachea and mainstem bronchi) tumors over a period of 2 years. "Successful" outcome was defined as procedure leading to reduction of luminal obstruction to <50% and improvement of respiratory distress. "Unsuccessful" outcome was defined in cases where the luminal obstruction could not be reduced by ≥50% or there was lack of improvement in the clinical status of the patient. RESULTS: During the study period, 30 patients with symptomatic central airway tumors were encountered. Of these, 23 patients underwent 31 rigid bronchoscopic procedures. Respiratory failure was present in 15 (65.2%) patients. Adenoid cystic carcinoma was the most common primary tracheal tumor, whereas squamous cell carcinoma was the most common secondary tracheobronchial tumor. The procedure was successful in 19 (82.6%) patients. Complications were encountered in 10 of the 31 (32.3%) rigid bronchoscopies. There was no procedural mortality. CONCLUSIONS: Rigid bronchoscopy and mechanical debulking as a sole therapy is an effective and safe procedure for airway obstruction resulting from tracheobronchial tumors.

Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature.

Patients with aspergilloma can be safely managed with supportive therapy in absence of massive haemoptysis. We hypothesised that chronic cavitary pulmonary aspergillosis (CCPA) could also be managed on similar grounds. The aim of this prospective, randomised controlled trial was to evaluate the efficacy and safety of itraconazole in CCPA. Consecutive patients of CCPA with presence of chronic pulmonary/systemic symptoms; and pulmonary cavities; and presence of Aspergillus (immunological or microbiological) were randomised to receive either supportive treatment alone or itraconazole 400 mg daily for 6 months plus supportive therapy. Response was assessed clinically, radiologically and overall after 6 months therapy. A total of 31 patients (mean age, 37 years) were randomised to itraconazole (n = 17) or the control (n = 14) group. The number of patients showing overall response was significantly higher in the itraconazole group (76.5%) vs. the control (35.7%) group (P = 0.02). The numbers of patients demonstrating clinical or radiological response were also significantly higher in the itraconazole group (P = 0.016 and 0.01 respectively). Adverse events were noted in eight patients in the itraconazole group, however, none was serious or led to discontinuation of the study drug. Itraconazole was found to be superior to standard supportive treatment alone in stabilising cases of CCPA. (clinicaltrials.gov; NCT01259336).

In-flight spontaneous pneumothorax: congenital cystic adenomatoid malformation of the lung.

Congenital cystic adenomatoid malformation (CCAM) is a rare congenital abnormality. Symptomatic presentation in adult life is extremely uncommon. The usual radiological appearance of CCAM is a cystic space-occupying lesion. Patients with underlying cystic lung disease can develop in-flight complications because of pressure-volume changes during ascent. We report the first ever case in which spontaneous pneumothorax during flight was the presenting manifestation of CCAM of the lung in a previously healthy and asymptomatic young adult. We also discuss the physiological changes during air travel which contribute to the pathogenesis of respiratory complications during air travel.