Genetic overlap study between idiopathic pulmonary fibrosis and COVID-19

Background/Objectives: Genetic factors influence COVID-19 susceptibility and outcomes, including the development of pulmonary fibrosis (i.e. lung scarring). Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease and the most common cause of pulmonary fibrosis in the general population. Genome-wide association studies (GWAS) of COVID-19 and IPF revealed genes associated with both diseases, suggesting these share genetic risk factors. Here we performed a genetic overlap study between COVID-19 and IPF. Method(s): Summary statistics from an IPF 5-way meta-GWAS and from the COVID-19 Host Genetics initiative GWAS metaanalysis (v6) were used. We performed genetic correlation analyses and assessed individual genetic signals to identify those variants shared between both traits. We conducted colocalisation analyses to determine whether the same causal variant was driving both traits. Finally, the association of overlapping variants with gene expression was assessed and a phenome-wide association study was performed. Result(s): There was a positive genetic correlation between severe COVID-19 and IPF. We found four genetic loci with likely shared causal variants between both traits, including one novel risk locus at 7q22.1 that colocalised with decreased ZKSCAN1 and TRIM4 expression in blood. The other three loci colocalised with MUC5B, ATP11A and DPP9 expression. The locus associated with increased ATP11A expression was also associated with higher Hb1AC levels, a biomarker used in diabetes. Conclusion(s): Results suggest there are shared biological processes driving IPF and severe COVID-19 phenotypes.

Patients with interstitial lung disease are high-risk of COVID-19 morbidity with implications on access to early oral anti-viral treatments

Introduction/Aim: Patients with interstitial lung disease (ILD) are at higher risk of COVID-19 infection associated morbidity and mortality, and hence may benefit from early anti-viral therapy. The access criteria for early oral anti-viral therapies for COVID-19 varied in early 2022 due to limited supplies nationally. We created a live clinical database of ILD patients in a tertiary hospital setting, stratifying them by measurable risk factors and therefore accessibility by state or national criteria to anti-viral therapy. Method(s): A list of active ILD clinic patients was generated from the WEBPAS clinic database. Data on patient demographics, co-morbidities and immunosuppressive medications relevant to access to anti-viral medications via the PBS criteria and state-based criteria was gathered by medical records review. Demographic information included age, BMI, ethnicity, residential care living and rurality. Co-morbidity risk factors included congestive cardiac failure, neurological disease, diabetes mellitus, chronic kidney disease, liver cirrhosis, chronic lung disease and immunodeficiencies. Medications of relevance included glucocorticoids, steroid-sparing immunomodulators and chemotherapy. Combinations of the above risk factors equate to eligibility to treatment. Result(s): Between the data capture dates of 1 February 2021 and 31 January 2022, 526 patients were identified. Of these 457 fit the inclusion criteria. Median age was 71.4 years (range 20-92), ratio of F:M was 1.09. 11% of patients were on long term oxygen therapy. Commonest conditions were idiopathic pulmonary fibrosis (26.3%), connective-tissue disease ILD (18%) and sarcoidosis (13.4%). 92 (20%) of patients fit into 'moderate or severely immunocompromised' criteria. 346 (75%) of patients fit criteria for early anti-virals by the first iteration of PBS criteria. Using the second iteration of PBS criteria, 374 (82%) of the ILD patients fit criteria for early anti-viral treatment. Notably, some patients qualify for anti-virals on multiple eligibility PBS criteria. Conclusion(s): A large proportion of our ILD cohort is deemed 'high risk' for COVID-19 morbidity and would qualify for early anti-viral therapies (regardless of vaccination status).

Pulmonary sarcoidosis

The lung is the most common organ affected by sarcoidosis. Multiple tools are available to assist clinicians in assessing lung disease activity and in excluding alternative causes of respiratory symptoms. Improving outcomes in pulmonary sarcoidosis should focus on preventing disease progression and disability, and preserving quality of life, in addition to timely identification and management of complications like fibrotic pulmonary sarcoidosis. While steroids continue to be first-line therapy, other therapies with fewer long-term side-effects are available and should be considered in certain circumstances. Knowledge of common clinical features of pulmonary sarcoidosis and specific pulmonary sarcoidosis phenotypes is important for identifying patients who are more likely to benefit from treatment.Copyright © ERS 2022.

Humoral Response among patients with Interstitial Lung Disease Vaccinated with the BNT162b2 SARS-Cov-2 vaccine - a prospective cohort study

Background: Patients with interstitial lung disease (ILD) are at high risk of severe COVID-19 infection. Method(s): We conducted an observational prospective cohort study to evaluate the rate of anti-spike (S-IgG) antibodies after two doses of the BNT162b2 vaccine in patients with ILD. The cohort included 40 patients with idiopathic pulmonary fibrosis (IPF) treated with anti-fibrotic therapy and 29 patients with non-IPF ILD treated with anti-inflammatory therapy. An age and sex matched control groups was created from a healthy control cohort of 107 patients. Result(s): All patients in the anti-fibrotic arm were seropositive (40/40), corresponding to the matched control group (P=1.0). The antifibrotic arm had a significantly lower median antibody titer in comparison to the matched control group (361.10 [ IQR, 207-811] AU/ml vs 820.75 [IQR, 459-1313] AU/ml;P<0.001). Only 48.3% (14/29) of patients in the anti-inflammatory arm were seropositive in comparison to 100% (29/29) in the healthy control group (P<0.001). The anti-inflammatory arm had a significantly lower median antibody titer in comparison to the healthy control group (39.6 [ IQR, 4.25-165] AU/ml vs 970.1 [IQR, 505-1926] AU/ml;P<0.001). Conclusion(s): IPF patients treated with antifibrotic therapy mount an adequate immune response after 2 doses of the BNT162b2 vaccine, maintain a 100% seropositivity rate, 4-6 months after vaccination. Among patients with non-IPF ILD, treated with anti-inflammatory therapy, 48% were seronegative 4-6 months after the second vaccine dose.

Covid-19 in lung allograft recipients - better outcomes after vaccination?

Vaccination remains a main weapon against Coronavirus Disease 2019 (Covid-19). Although its efficacy is reduced in the immunocompromised population, we felt empirically that outcomes of Covid-19 in lung transplant recipients (LTRs) were better after widespread vaccination than in earlier phases of the pandemic. We aimed to compare outcomes of unvaccinated and vaccinated LTRs infected with SARS-CoV-2. All LTRs followed in our hospital were reviewed and those with a positive polymerase chain reaction test were included. We analysed disease severity (using World Health Organization criteria) and mortality rates in unvaccinated and fully vaccinated patients (pts). Twenty-four pts were included, two-thirds of which were male, with a mean age of 51 years. Main diagnoses were hypersensitivity pneumonitis (25%), chronic obstructive pulmonary disease (16,7%), idiopathic pulmonary fibrosis (12,5%) and cystic fibrosis (12,5%). Lung transplant was bilateral in 79,2% of pts, unilateral in 16,7% and lobar in one pt (4,1%). The most common immunosuppression regimen was tacrolimus, mycophenolate-mofetil and prednisolone. Thirteen pts were unvaccinated and 11 were vaccinated at time of infection, with a mean time since transplant of 746 and 1641 days, respectively. In the unvaccinated group 69,2% had mild disease, 30,8% had severe disease and mortality was 25%. No deaths occurred among fully vaccinated pts;disease was mild in 72,7%, moderate in 18,2% and severe in 9,1%. Neither the difference in severity (p=0,156) or mortality (p=0,089) reached statistical significance, presumably due to the small sample size. Nevertheless, we confirmed that, in our centre, vaccinated LTRs had better overall outcomes than unvaccinated pts.

GALACTIC-1: Galectin-3 inhibition in idiopathic pulmonary fibrosis (IPF) - rationale, objectives and design of a 52-week, Phase IIb study of GB0139

Availability of well-tolerated novel agents that can slow or stop disease progression and improve quality of life remain an unmet medical need in IPF management. GB0139, a novel inhaled galectin-3 inhibitor, has shown good tolerability and antifibrotic potential via changes in biomarkers associated with IPF progression in an animal model (Delaine, T. et al. Chembiochem 2016;17:1759-70) and a Phase I study (Hirani, N. et al. Eur Respir J 2021;57(5):2002559) in healthy participants and IPF patients. We report the design of a Phase IIb study of GB0139 in IPF. This randomised, double-blind, placebo-controlled, parallel-group, multicentre study (NCT03832946) was initiated in April 2019. The primary endpoint is rate of decline in forced vital capacity (FVC) over 52 weeks. Key secondary endpoints are proportion of participants with an absolute decline from baseline in FVC % predicted of <=10%, change from baseline in St. George's Respiratory Questionnaire total score, time to first respiratory-related hospitalisation, and time to death (all-causes). Systemic GB0139 pharmacokinetics are included as an exploratory endpoint. Despite the COVID-19 pandemic, study recruitment has continued in ~100 centres across 15 countries, with over 400 participants randomised as of February 2022. Initially, participants treated with or without standard of care (SOC) were included. Following a protocol amendment in 2021, the current target is to randomise 141 participants who are not treated with SOC, with study completion in mid-2023.

Machine Learning analysis of human pulmonary extracellular matrix architecture identifies disease-specific remodeling patterns

Background: Normal organ function is critically dependent on an intact three-dimensional architecture. Structural abnormalities induced by pathological situations instruct cells to behave abnormally and promoting disease progression oftentimes leading to organ failure. Current approaches do not allow for high-resolution (HR) threedimensional (3D) visualisation and analysis of human organ structure. Method(s): Here, we develop a method to perfuse human tissue segments to remove cells and study the 3D structural scaffold, which could be applied to any organ. Our approach enables HR-3D imaging of organ architecture, which we apply to study healthy and diseased human lung, specifically emphysema, usual interstitial pneumonia, pulmonary sarcoidosis, and COVID-19. Result(s): Our imaging reveals major structural abnormalities previously unseen by existing methodologies. Furthermore, we identify disease-specific patterns of structural remodelling using machine learning, including the altered spatial relationship between extracellular matrix (ECM) proteins collagen type IV, elastin and fibrillar collagen present across all diseases. Conclusion(s): Given the importance of organ structure on function, our approach opens the possibility to understand human physiology in a new way, which may assist in future disease diagnosis and explain the detrimental pulmonary effects of the diseases studied here.

Reduced immunogenicity of the mRNA vaccine BNT162b2 in patients with IPF

Introduction: Immunocompromised individuals including solid organ transplants recipients present with blunted immune responses to two doses of SARS-CoV-2 mRNA vaccine. Studies have shown that patients with Idiopathic Pulmonary Fibrosis (IPF) present with disrupted cellular and humoral immune response. Aim and objectives: To investigate immune response following SARS-CoV-2 mRNA vaccine in patients with IPF. Method(s): We compared anti-SARS-CoV-2 antibodies three months after the second dose of the mRNA vaccine BNT162b2 in: 1) patients with IPF receiving antifibrotics, 2) patients with IPF under no treatment, 3) aged-matched controls. Result(s): Sixty-seven (n=67) subjects were included in the analysis (patients with IPF receiving antifibrotics: 32, patients with IPF under no treatment: 10, controls: 25). Groups were age and gender balanced. Both groups of patients with IPF whether receiving or not antifibrotic compounds exhibited similarly reduced levels of anti-SARSCoV- 2 antibodies after two doses of the mRNA vaccine BNT162b2 compared to general population [IPF/treatment: 666.1, (95%: 540.1 to 900.0) vs IPF/no treatment: 579.5 (95% CI: 232.4 to 4054.2) vs controls: 2118.6 (95% CI: 1248.3 to 4035.5), p=0.002]. The prevalence of anti-SARS-CoV-2 antibodies above the suggested cut-off threshold of 1000 AU/ml was 21.9%, 40% and 72% in the IPF/treatment, IPF/no treatment and control groups, respectively. Conclusion(s): Patients with IPF did not mount appreciable antispike antibody responses to two doses of the mRNA vaccine BNT162b2 compared to general population. National authorities should prioritize patients with IPF for booster doses.

The lived experiences of people with idiopathic pulmonary fibrosis (IPF)to inform Home Based Pulmonary Rehabilitation (HBPR)in Delhi,India: A Qualitative Study

Background: Pulmonary Rehabilitation is a high-impact intervention for IPF but access is limited in India, a problem exacerbated by the pandemic which has seen HBPR become a necessity. Aim(s): To explore the lived experiences of people living with IPF to inform HBPR in Delhi, India. Method(s): Ten semi-structured interviews with Adults with IPF. Data were analysed using thematic analysis. Result(s): Five key themes were developed (Figure): (1) Diagnosis Journey: Experiences before and during diagnosis, including misdiagnosis, and how family, friends and colleagues reacted to diagnosis. (2) Impact of IPF: The physical and psychological impacts on their life. (3) Non-IPF Impact: The impact of COVID-19 infection and restrictions and previous/existing comorbidities. (4) Management of IPF: Strategies to manage symptoms, including exercise and relaxed breathing. (5) HBPR: Perspectives of HBPR, including its advantages and challenges, their goals if they were to participate, and suggestions to the development of a paper HBPR manual. Conclusion(s): Patients living with IPF were positive about HBPR and the development of a paper-based manual to facilitate HBPR. The content of HBPR should be sensitive to the previous negative experiences of diagnosis, the additional impact of non-IPF health issues and challenges of reduced interactions with healthcare professionals.

Airway remodeling in COVID-19 lungs

Besides parenchymal changes that have been described extensively in COVID-19, bronchiectasis is also reported but detailed characterization of airway changes is lacking. Hence, we aimed to quantify the number of visible airways and their diameters in end-stage COVID-19 lungs. Explanted right lungs, obtained after lung transplantation (n=2) or autopsy (n=1) (65.3+/-26.7 days after symptom onset), were inflated to total lung capacity, frozen and scanned with whole lung microCT (155 mum). Airways were segmented using Mimics Innovation Suite (Materialise, Belgium) and airway count and diameter were assessed using Neuronstudio. Three discarded donor lungs were used as controls. Number of visible airways increased in COVID-19 lungs compared to controls (fig.1a) potentially caused by airway remodeling and bronchiectasis (fig.1b, red arrows) due to fibrotic rearrangement (fig. 1b). Small airway count (diameter 0-2 mm) in generation (G) 1-11 was lower in COVID-19 patients compared to controls, with a shift of small airways from lower generations (G1-11) to higher generations (G12-27) in COVID-19 patients. Simultaneously, airways with a diameter > 2 mm were increased in all generations in COVID-19 (present until G21 compared to G13 in controls). This study shows that COVID-19 causes a remodeling of the (small) airways, leading to an increase of visible airways and diameter of large and small airways, similar to that seen in idiopathic pulmonary fibrosis due to traction bronchiectasis. (Figure Presented).

Is daily home spirometry feasible in remote monitoring of interstitial lung disease?

Introduction: Access to in-clinic spirometry for patients with interstitial lung disease (ILD) has been restricted by the COVID19 pandemic. Remote monitoring of patient-recorded at-home spirometry & pulse oximetry offers an alternative approach to traditional hospital-based monitoring. Objective(s): To assess the feasibility of a remote monitoring programme (with spirometry & pulse oximetry) delivered within ILD clinical care settings for a 3-month period through assessment of adherence to study measurements. Method(s): In this prospective, single-arm, observational study (NCT04850521), patients were asked to record 1 spirometry and pulse oximetry measurement per day for 91 days, using a digital health application (patientMpowerTM) & Bluetooth-linked devices. Patient-recorded data could be viewed in real time by their clinical teams via a secure, password-restricted web-based portal. Health-related quality of life and patient experience were also assessed. Result(s): 51 ILD patients enrolled and provided >=1 spirometry reading. Baseline demographics: 35M/16F;29 idiopathic pulmonary fibrosis (IPF)/22 non-IPF ILD;age: 67+/-12Y;in-clinic FVC: 84+/-20% predicted;TLCO 54+/-19% predicted (mean+/-SD);median modified ILD GAP score: 3. Patients recorded spirometry on median 92% of days & pulse oximetry on median 93% of days. To date, 30 patients have completed follow-up. 26/30 patients recorded spirometry and pulse oximetry >=3 days/week & >=70% of days. Conclusion(s): In this study, daily recording of home spirometry & pulse oximetry over 3 months appeared feasible. Further research is needed to understand how remote monitoring is best used within ILD clinical services. .

Characterization of Mesenchymal Cell from BAL of post COVID-19 patient whit fibrosis

Increasing number of severe COVID 19 patients develop pulmonary Fibrosis, but the management of this complication is still unclear due to a lack of clinical trials. Aim of this study was to characterize mesenchymal cells (MC) isolated from 10 broncho-alveolar lavage (BAL, at 2 months after discharge) from patients with COVID19 fibrosis (COVID19-f) and to compare them with those isolated from 8 patients with collagen tissue diseaseassociated interstitial fibrosis(CTD-ILD). BAL fluid (BALf) levels of TGFbeta, VEGF, TIMP2, RANTES, IL6, IL8, and PAI1 were assessed by ELISA. Primary MC foci were cultured and expanded in D-MEM +10% FBS, characterized by flow cytometry and osteogenic and adipogenic differentiation. Collagen 1 production (+/-TGF-beta) was tested by WB and mRNA expression. BALf cytokine and GF levels were comparable in the two groups. Efficiency of MC isolation from BAL was 100% in COVID-f compared to 65% in CTD-ILD. MC antigen surface expression of CD105, CD73, CD90 (>90%, respectively), CD45, CD34, CD19 and HLA-DR (<5%, respectively) was comparable. None of MC samples differentiated in adipocytes, while COVID19-f were positive for calcium deposition. COVID19-f MC showed at WB, higher Collagen 1 production with respect to CTD-ILD with TGF-beta stimulation. Our preliminary data suggest MC from COVID19-f share several features with CTD-ILD but might have a higher response to fibrogenic and differentiation signals.

Acute kidney injury (AKI) post-mRNA SARS-CoV-2 vaccine in patients with cancer, treated with immune check point inhibitor (ICPi): An immune double whammy!

Background: Immune check point inhibitors (ICPi) have become the first line treatment for most of the cancers and have shown promising results. However, they can provoke reactions, the most feared being immune related adverse events (irAE). Case presentation: We present a series of three cases, of patients recieving ICPi. All three patients developed AKI after administration of SARS-CoV-2 mRNA vaccine. Two patients had kidney-biopsy-proven acute interstitial nephritis (AIN) which responded to ICPi discontinuation and treatment with steroids. One had presumed AIN based on the high levels of CRP and urine retinol binding protein to creatinine ratio and responded to cessation of ICPi alone. Conclusion(s): These three cases demonstrate that a strong immune response from the SARS-CoV-2 mRNA vaccine combined with an uninhibited immune system under influence of ICPi led to an amplification of autoimmunity leading to AKI presenting as AIN.Copyright © The Author(s) 2022.

Insights into the lung microenvironment after severe COVID-19

The SARS-CoV-2 is the betacoronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Severe COVID-19 affects approximately 10-15% of patients and results in prolonged morbidity and mortality. Little is known about the immunophenotypic changes of the lung parenchyma driven by the viral infection in patients who die of severe COVID-19. Ultrasound-guided lung biopsies (LB) were collected (IRB approval#1561/21) within few hours from death in 15 severe COVID-19 patients between November 2020 and January 2021, in two patients who underwent lung transplantation after COVID-19 and in one patient who had surgery for bacterial superinfection during COVID-19 disease. All samples underwent histologic and immunohistochemistry evaluation and molecular profiling using the nCounter Host Response and Coronavirus Panel plus. As controls, lungs from end-stage usual interstitial pneumonia (UIP;n=9) and from lobectomy for lung cancer (Norm;n=5) were used. Eleven lungs (61%) were positive for SARS-CoV-2 RNA. Signs of diffuse alveolar damage (DAD) were observed in 6 patients (30%). COVID-19 lungs showed a marked macrophage infiltration with M2 polarization compared with controls. Globally, COVID-19 lungs showed distinct molecular profiles from UIP or Norm lungs. Specifically, a marked upregulation of interferon-genes that was directly correlated with SARS-CoV-2 genes was seen in COVID-19 lungs. COVID-19-specific genes signatures (Log2FC >1.5;adj p<0.05) obtained using VENN diagram showed impairment of the STAT3-pathway accompanied by the upregulation of the NFkB signaling. Results herein provide new insights into lung alterations induced by severe COVID-19 and suggest novel potential targets for therapeutic intervention.

SARS-CoV2 vaccination in Hungarian IPF patients

Introduction: SARS-CoV2 infection is associated with significant risk of coronavirus disease (COVID-19) and represents a significant risk factor for functional deterioration in idiopathic pulmonary fibrosis (IPF) patients. Method(s): We retrospectively reviewed all IPF patients treated at our university center for their SARS-CoV2 vaccination status starting from January 2021 in Hungary. Result(s): Total of 68 (out of treated 70 IPF patients) received minimum 2 doses of SARS-CoV2 vaccines (male 52.85%, age: 72.24 +/- 9.65 years), 20 of them were vaccinated with non-mRNA vaccines (BBIBP-CorV-Sinopharm, ChAdOx1-AstraZeneca, Gam-Covid-Vac-Sputnik and Ad26. COV2.S-Janssen), while 48 with mRNA vaccines. Majority (N=57) of patients also took a third dose: most patients received BNT162b2-mRNA-Pfizer/Biontech (58.82%), followed by BBIBP-CorV and mRNA-1273-Moderna (both 11.76 %). There were no hospitalizations for COVID-19 in the vaccinated group, regardless of the type of the vaccine received and no significant adverse event was detected. One of the non-vaccinated patients (2 women, age 70 and 73 years) died in COVID-19 pneumonia. IPF patients were mainly in a good functional state (FVC = 2.52 +/- 1.03 L;78.81 +/- 22.72%) with reduced diffusion capacity (TLCO = 5.28 +/- 2.11 mmol/kPa/min;66.28 +/- 21.58%). Conclusion(s): SARS-CoV2 vaccination is utmost important in IPF patients, and independent of vaccine type used it resulted in significantly decreased risk of COVID-19 hospitalization.

Histopathologic changes in lung tissue after Covid-19 pneumonia

Current knowledge of histopathological changes in Covid-19 pneumonia is mainly based on autopsy findings. There are few data on dynamics of lung lesions in vivo after acute phase of disease. The aim of this study was to determine histopathologic changes during the long/post-Covid stage in patients who had suffered from moderate to severe Covid-19 pneumonia. Bronchoscopy with transbronchial lung biopsy was performed in patients with HRCT lesions involving >40% of lung parenchyma, at least 4 weeks after discharge. Additional criteria were restrictive pattern in lung function tests and signed informed consent. Histopathologic analyses were performed using H&E, MSB, MOVAT, TTF1, CD34 and CD68 staining. Research was approved by the Hospital Ethical Committee. Among 26 patients that met inclusion criteria, adequate biopsy samples were obtained from 24. The mean time from the onset of disease to biopsy was 13 weeks. We found 4 histopathologic patterns: diffuse alveolar damage-DAD with vascular abnormalities, nonspecific interstitial inflammation, organizing pneumonia and interstitial fibrosis in 11, 9, 2 and 2 patients, respectively. Vascular abnormalities included capillary thrombi, dilated venules and dissection of small pulmonary arteries. Given the duration of disease, DAD and vascular abnormalities were detected up to the 12 week from the onset of symptoms. All patients biopsied after 12th weeks had some degree of tissue inflammation without vascular changes. Our findings show rather slow recovery of lung tissue after Covid-19 pneumonia. Long lasting DAD with vascular abnormalities may explain prolonged dyspnea and exercise intolerance and should be taken into consideration when planning further rehabilitation.

Tuberculosis while on Lung transplant wait list & on ECMO as bridge to transplant- An ethical and clinical challenge

Introduction: The incidence of Tuberculosis(TB) is 4 times more in patients with Interstitial lung diseases(ILD). Active TB is considered as contraindication for lung transplant. We report a case of a patient with Idiopathic Pulmonary Fibrosis(IPF) with COVID 19 exacerbation who, while being bridged to transplant on ECMO, tested positive for Tuberculosis and underwent a bilateral lung transplantation. Case: 40 year old male, known case of IPF, admitted with severe COVID ARDS was evaluated and listed for Bilateral Lung transplantation. In view of acute deterioration, he was initiated on ECMO as a bridge to transplant. His Broncho Alveolar Lavage(BAL) showed AFB and CBNAAT confirmed Mycobacterium tuberculosis which was rifampicin sensitive. He was initiated on antitubercular drugs and subsequently underwent bilateral lung transplant. He was weaned off ECMO and his further BAL samples did not show evidence of M. Tb. He had a series of postoperative complications including Acute kidney injury, weaning failure and Acute coronary syndrome with LV dysfunction and eventually succumbed. Discussion(s): This case poses a unique ethical challenge of whether or not to proceed for transplant in patients who test positive for pulmonary tuberculosis while on waitlist and on ECMO as bridge to transplant. However, the unfavorable outcome of the transplant reinforces the available data that active tuberculosis is associated with high mortality in lung transplant. Further guidance is required to manage such patients to improve lung transplant survival rates, especially in TB endemic regions such as India.