Inhaled Lipid Nanoparticles Alleviate Established Pulmonary Fibrosis.

Pulmonary fibrosis, a sequela of lung injury resulting from severe infection such as severe acute respiratory syndrome-like coronavirus (SARS-CoV-2) infection, is a kind of life-threatening lung disease with limited therapeutic options. Herein, inhalable liposomes encapsulating metformin, a first-line antidiabetic drug that has been reported to effectively reverse pulmonary fibrosis by modulating multiple metabolic pathways, and nintedanib, a well-known antifibrotic drug that has been widely used in the clinic, are developed for pulmonary fibrosis treatment. The composition of liposomes made of neutral, cationic or anionic lipids, and poly(ethylene glycol) (PEG) is optimized by evaluating their retention in the lung after inhalation. Neutral liposomes with suitable PEG shielding are found to be ideal delivery carriers for metformin and nintedanib with significantly prolonged retention in the lung. Moreover, repeated noninvasive aerosol inhalation delivery of metformin and nintedanib loaded liposomes can effectively diminish the development of fibrosis and improve pulmonary function in bleomycin-induced pulmonary fibrosis by promoting myofibroblast deactivation and apoptosis, inhibiting transforming growth factor 1 (TGFß1) action, suppressing collagen formation, and inducing lipogenic differentiation. Therefore, this work presents a versatile platform with promising clinical translation potential for the noninvasive inhalation delivery of drugs for respiratory disease treatment.

Comparison of two antifibrotic treatments for lung fibrosis in post-COVID-19 syndrome: A randomized, prospective study.

BACKGROUND: Although pulmonary fibrosis secondary to COVID-19 infection is uncommon, it can lead to problems if not treated effectively in the early period. This study aimed to compare the effects of treatment with nintedanib and pirfenidone in patients with COVID-19-related fibrosis. METHODS: Thirty patients who presented to the post-COVID outpatient clinic between May 2021 and April 2022 with a history of COVID-19 pneumonia and exhibited persistent cough, dyspnea, exertional dyspnea, and low oxygen saturation at least 12 weeks after diagnosis were included. The patients were randomized to receive off-label treatment with nintedanib or pirfenidone and were followed up for 12 weeks. RESULTS: After 12 weeks of treatment, all pulmonary function test (PFT) parameters, 6MWT distance, and oxygen saturation were increased compared to baseline in both the pirfenidone group and nintedanib groups, while heart rate and radiological score levels were decreased (p<0.05 for all). The changes in 6MWT distance and oxygen saturation were significantly greater in the nintedanib group than in the pirfenidone group (p=0.02 and 0.005, respectively). Adverse drug effects were more frequent with nintedanib than pirfenidone, with the most common being diarrhea, nausea, and vomiting. CONCLUSION: In patients with interstitial fibrosis after COVID-19 pneumonia, both nintedanib and pirfenidone were observed to be effective in improving radiological score and PFT parameters. Nintedanib was more effective than pirfenidone in increasing exercise capacity and saturation values but caused more adverse drug effects.

Anti-fibrotic agents could be the game-changer for post-COVID-19 pulmonary fibrosis treatment

More than 220 countries and territories are globally affected by the recent pandemic COVID-19 which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is possibility of third wave of this pandemic as per epidemiological and public health experts. Besides that post-COVID-19 complications are alarming matter to look upon. Post-COVID-19 complications include several symptoms like as persistent fever;cough;fatigue;headache;attention disorder;dyspnea;anosmia;ageusia;chest pain discomfort;various respiratory illness;acute respiratory distress syndrome (ARDS) etc., and here the things to worry about is the development of pulmonary fibrosis after COVID-19. In some COVID-19 patients, hyper-inflammation in the form of 'cytokine storm' along with dysregulated immune response, alveolar epithelial tissue injury and wound repair collectively cause this secondary pulmonary fibrosis. Therefore, using anti-fibrotic agents e.g. pirfenidone, nintedanib and other natural compounds could be meaningful in these circumstances although their efficacy in treating COVID-19 is subject to more detailed laboratory research works. In this review article, we have discussed the progression of pulmonary fibrosis development which is triggered by COVID-19;probable solutions with anti-fibrotic agents including anti-fibrotic drugs, some well-known natural compounds, combined anti-fibrotic therapies;and the current challenges of this field.

Incidence of acute exacerbation in patients with interstitial lung disease after COVID-19 vaccination

Acute exacerbations due to COVID-19 vaccination in patients with interstitial lung disease (ILD) have been reported, but their incidence is unknown. We investigated the incidence of exacerbations of ILD and respiratory symptoms due to the mRNA COVID-19 vaccines. A questionnaire survey was conducted on adverse reactions to the mRNA COVID-19 vaccination in 545 patients with ILD attending our hospital and retrospectively examined whether the eligible patients actually developed acute exacerbations of ILD induced by the vaccine. Of the 545 patients, 17 (3.1%) patients were aware of the exacerbation of respiratory symptoms, and four (0.7%) patients developed an acute ILD exacerbation after vaccination. Of the four patients who experienced exacerbations, two had collagen vascular disease-associated ILD, one had nonspecific interstitial pneumonia, another had unclassifiable idiopathic pneumonia, and none had idiopathic pulmonary fibrosis. Four patients were treated using steroid pulse therapy with a steroid taper, and two of the four also received intravenous cyclophosphamide pulse therapy. Tacrolimus was started in one patient with myositis-associated interstitial lung disease. Eventually, all patients exhibited improvement with immunosuppressive treatment and were discharged. COVID-19 vaccination for patients with ILD should be noted for developing acute exacerbations of ILD with low incidence, although manageable with early diagnosis and treatment. © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

Nintedanib: a review of the properties, function, and usefulness to minimize COVID-19-induced lung injury.

INTRODUCTION: In severe COVID-19 patients, acute respiratory distress syndrome (ARDS)-induced lung injury regularly causes a pulmonary fibrotic phase. There is no approved therapy for the COVID-19-induced pulmonary fibrosis. However, administration of an anti-fibrotic agent, in the early acute phase of the severe COVID-19 with ARDS, may improve the infection outcomes. AREAS COVERED: In this review, the main characteristics of nintedanib and its usefulness to treat COVID-19-induced fibrosis were studied. In July 2022, a literature search was performed from PubMed, Google Scholar, and the WHO databases for studies focusing on the properties, function, efficacy, and safety of nintedanib against different lung injuries. EXPERT OPINION: Nintedanib interferes with lung fibrosis and tumor angiogenesis by targeting multiple receptor tyrosine kinases (RTKs). Loss of RTKs activity leads to blocking downstream signaling cascades and inhibiting the proliferation and migration of lung fibroblasts. Targeting RTKs may be useful in the treatment of COVID-19 lung fibrosis. Nintedanib may be a superior agent compared to pirfenidone for the treatment of COVID-19 ARDS-related pulmonary fibrosis. Investigation of the efficacy and safety of nintedanib in the early stages of COVID-19-induced ARDS is critical since it may decrease the oxygen dependency and degree of lung fibrosis after the hospital discharge.

A Study on drug utilization pattern of antifibrotic agents in patients with post-COVID-19 lung fibrosis

Pulmonary fibrosis after COVID-19 is a serious consequence that can result in lifelong lung damage or death. A cytokine storm induced by an abnormal immune mechanism may cause the onset and progression of pulmonary fibrosis. Early detection may assist to avoid or at least slow the progression of the disease. Anti-fibrotic agents are widely used drugs in post-COVID-19 pulmonary fibrosis. There are some well-known clinical agents including Pirfenidone and Nintedanib that can be given to COVID-19 patients to prevent further progression of fibrosis and as prophylaxis as well. This study showed the use of antifibrotic therapy in SARS-CoV-2 infection, which is very officious in minimizing and avoiding fibrotic damage induced by inflammatory immune dysfunction. Evidently, pirfenidone has shown its pleiotropic effectivity to decrease the inflammation and oxidative reactive shock associated with fibrosis. Nintedanib binds to the targeted receptors' intracellular ATP pockets, inhibiting pro-fibrotic signaling and reducing fibroblast proliferation, migration, and differentiation, as well as secretion of extracellular matrix components. Copyright © 2023, Anka Publishers. All rights reserved.

Anti-SARS-CoV-2 activity of targeted kinase inhibitors: Repurposing clinically available drugs for COVID-19 therapy.

Coronavirus disease 2019 (COVID-19) remains a major public health concern, and vaccine unavailability, hesitancy, or failure underscore the need for discovery of efficacious antiviral drug therapies. Numerous approved drugs target protein kinases associated with viral life cycle and symptoms of infection. Repurposing of kinase inhibitors is appealing as they have been vetted for safety and are more accessible for COVID-19 treatment. However, an understanding of drug mechanism is needed to improve our understanding of the factors involved in pathogenesis. We tested the in vitro activity of three kinase inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including inhibitors of AXL kinase, a host cell factor that contributes to successful SARS-CoV-2 infection. Using multiple cell-based assays and approaches, gilteritinib, nintedanib, and imatinib were thoroughly evaluated for activity against SARS-CoV-2 variants. Each drug exhibited antiviral activity, but with stark differences in potency, suggesting differences in host dependency for kinase targets. Importantly, for gilteritinib, the amount of compound needed to achieve 90% infection inhibition, at least in part involving blockade of spike protein-mediated viral entry and at concentrations not inducing phospholipidosis (PLD), approached a clinically achievable concentration. Knockout of AXL, a target of gilteritinib and nintedanib, impaired SARS-CoV-2 variant infectivity, supporting a role for AXL in SARS-CoV-2 infection and supporting further investigation of drug-mediated AXL inhibition as a COVID-19 treatment. This study supports further evaluation of AXL-targeting kinase inhibitors as potential antiviral agents and treatments for COVID-19. Additional mechanistic studies are needed to determine underlying differences in virus response.

Effectiveness and Safety of Pirfenidone and Nintedanib for Pulmonary Fibrosis in COVID-19-Induced Severe Pneumonia: An Interventional Study.

Background After a diagnosis of two to five years, the survival length for pulmonary fibrosis (PF) is considered to be medium. The primary objective of PF treatment is to stabilize or minimize the pace of progression of the illness. The treatment of PF by nintedanib and pirfenidone was a breakthrough. In a group of coronavirus disease 2019 (COVID-19)-induced PF patients, we examined the efficacy of pirfenidone and nintedanib. Methodology From May 2021 to April 2022, 5,000 patients receiving antifibrotic treatment with pirfenidone or nintedanib (mean age of 78.3 ± 23.8) for PF were identified. Their clinical and functional information was retrospectively examined at zero, six, and twelve months of therapy. Results The average age of patients receiving nintedanib was greater than the average age of the pirfenidone group (p < 0.0001). Exertional dyspnea and dry cough, with no distinction between the two groups, were the most prevalent symptoms of the illness (p < 0.05). No significant changes between patients on pirfenidone and nintedanib were seen in forced vital capacity, forced expiratory volume in one second, total lung capacity, and diffusing capacity for carbon monoxide at zero or six months (p > 0.05). After one year, lung function measures were similar to the baseline in individuals treated with pirfenidone and nintedanib. This study highlights the appearance of both antifibrotic medicines as promising treatment options for functional stability in COVID-19-induced PF patients. Conclusions The patients affected by COVID-19 and undergoing fibrinolytic therapy may be well treated by any of the drugs with a significant improvement.

RITUXIMAB USE IN INTERSTITIAL LUNG DISEASE AND COVID-19 PNEUMONIA

SESSION TITLE: COVID-19 Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Much has been learned about the immune dysregulation and release of pro-inflammatory cytokines since the emergence of the COVID-19 pandemic.1 Patients with interstitial lung disease are often on immunosuppressive agents, such as rituximab, which is a B-cell depleting agent. There has been a large retrospective cohort study showing that rituximab therapy was the only immunosuppressive medication with a trend towards in-hospital death.2 We present a case of COVID-19 in a patient on rituximab with ANCA vasculitis. CASE PRESENTATION: A 51-year-old male, never smoker, with ANCA positive vasculitis (positive MPO and PR3) and interstitial lung disease (on 4-5L of oxygen) presented to the hospital with nausea and fever for 2 days and was found to have a positive SARS-CoV-2 PCR. At the time of presentation, he was on rituximab 1000 mg x 2 doses every 6 months with last infusion one month prior to presentation, azathioprine 150 mg daily, prednisone 15 mg daily, nintedanib 100 mg BID, and IVIG monthly. Spirometry showed FVC of 1.60L/37% predicted and an FEV1 1.28L/39% predicted. Patient had 2 COVID vaccinations and one booster (all Pfizer mRNA), the latter 3 months prior to presentation. On admission, he was saturating at 55% on 4L and placed on 15L non-rebreather;he was afebrile, normotensive, and with a pulse of 110 BPM. Exam was notable for a cough, wheezing, and tachypnea. Lab work was notable for positive SARS-COV-2 PCR, a total white blood cell count of 5.3x103 uL, and a normal hemoglobin and platelet count. He had a CO2 of 34, normal creatinine, and no transaminitis. Lactate dehydrogenase (LDH) was elevated at 318 U/L, and lactate was elevated at 3.5 mmol/L. His chest x-ray on admission demonstrated patchy filling opacities and low lung volumes. He received dexamethasone, remdesivir, and the monoclonal antibodies casirivimab and imdevimab (REGEN-COV) on the first day of admission. Patient also received his monthly IVIG dose inpatient. After a week, he was weaned back to his home oxygen and symptomatically back to baseline. Most recent PFTs on the same outpatient immunosuppressive regimen as prior to admission are unchanged. Patient received two doses of preventative monoclonal antibodies (EVUSHELD) 3 months after admission. DISCUSSION: Here we discuss a case of a patient with severe COVID-19 pneumonia requiring inpatient hospitalization despite three COVID mRNA vaccinations, likely secondary to difficulty in mounting an immune response to the vaccinations given his use of immunosuppressive medications. This is also an example of the early use of monoclonal antibodies in an inpatient with long term preservation of his underlying lung function.3 CONCLUSIONS: We recommend counseling and close observation of patients on rituximab due to risk of severe COVID-19 infection as well the use of preventative monoclonal antibodies (EVUSHELD). Reference #1: Jamal M, Bangash HI, Habiba M, Lei Y, Xie T, Sun J, Wei Z, Hong Z, Shao L, Zhang Q. Immune dysregulation and system pathology in COVID-19. Virulence. 2021 Dec;12(1):918-936. doi: 10.1080/21505594.2021.1898790. PMID: 33757410;PMCID: PMC7993139. Reference #2: Andersen, K. M., Bates, B. A., Rashidi, E. S., Olex, A. L., Mannon, R. B., Patel, R. C., Singh, J., Sun, J., Auwaerter, P. G., Ng, D. K., Segal, J. B., Garibaldi, B. T., Mehta, H. B., Alexander, G. C., Haendel, M. A., & Chute, C. G. (2022). Long-term use of immunosuppressive medicines and in-hospital COVID-19 outcomes: A retrospective cohort study using data from the National COVID Cohort Collaborative. The Lancet Rheumatology, 4(1), e33–e41. https://doi.org/10.1016/S2665-9913(21)00325-8 Reference #3: Weinreich, D. M., Sivapalasingam, S., Norton, T., Ali, S., Gao, H., Bhore, R., Xiao, J., Hooper, A. T., Hamilton, J. D., Musser, B. J., Rofail, D., Hussein, M., Im, J., Atmodjo, D. Y., Perry, C., Pan, C., Mahmood, A., Hosain, R., Davis, J. D., Yancopoulos, G. D. (2021). Regen-cov antibody combination and outcomes in outpatients with covid-19. New England Journal of Medicine, 385(23), e81. https://doi.org/10.1056/NEJMoa2108163 DISCLOSURES: Advisory Committee Member relationship with Genentech Please note: 2019-2022 Added 06/06/2022 by Ayodeji Adegunsoye, value=Consulting fee Advisory Committee Member relationship with Boehringer Ingelheim Please note: 2018-2022 Added 06/06/2022 by Ayodeji Adegunsoye, value=Consulting fee Speaker/Speaker's Bureau relationship with Boehringer Ingelheim Please note: 2018-2022 Added 06/06/2022 by Ayodeji Adegunsoye, value=Honoraria Consultant relationship with Genentech Please note: 2018-2020 by Ayodeji Adegunsoye, value=Consulting fee Removed 06/06/2022 by Ayodeji Adegunsoye No relevant relationships by Cathryn Lee No relevant relationships by Kavitha Selvan PI relationship with Boehringer-Ingelheim Please note: >$100000 by Mary Strek, value=Grant/Research Support PI relationship with Galapagos Please note: $70,000-100,00 by Mary Strek, value=Grant/Research Support Endpoint Adjudication Committee Member relationship with Fibrogen Please note: $1-$1000 by Mary Strek, value=Honoraria No relevant relationships by Rachel Strykowski

"BUT I AM TOO YOUNG FOR THIS": EARLY PRESENTATION OF USUAL INTERSTITIAL PNEUMONIA

SESSION TITLE: Diagnosis of Lung Disease through Pathology Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Usual interstitial pneumonia (UIP) is a histological term used to describe a pattern of interstitial fibrosis with alternating areas of the normal lung with temporal fibrosis and architectural alteration due to chronic scarring or honeycomb change. It is a subset of idiopathic interstitial pneumonias (IPF) that usually presents in the sixth and seventh decades of life with progressive dyspnea on exertion and productive cough. CASE PRESENTATION: We present a 46 y/o man with a history of thyroid disease, hypertension and a former smoker of 20 pack-year smoking. Presented to ED complaining of low oxygen saturation with pulse oximetry at home with readings between 60-80%. Accompanied with progressive dyspnea on exertion and unintentional weight loss of 80 pounds in the last year. Also referred productive cough of white sputum that was worse in the morning. Home nebulized Albuterol therapy did not provide improvement. Denied recent viral respiratory infections, night sweats, environmental exposures nor family history of lung disease. DISCUSSION: Physical exam demonstrated bilateral expiratory dry crackles and pulse oximetry oxygen saturation at room air of 78%. RBBB evidenced on EKG. Bloodwork showed polycythemia with hemoglobin of 17.8;ABG's with pH: 7.40, Pco2: 42.2, PO2: 59.8, HCO3: 26, O2 sat: 90.8 and ideal PO2: 85.6 consistent with metabolic alkalosis with BMP CO2 of 30, A/a gradient: 43.0. Mycoplasma IgM, Influenza A & B and COVID-19 antigen test were negative. CXR with increased vascular markings, chest CT demonstrated small pericardial effusion, bilateral coarse interstitial pulmonary markings and bronchiectasis suggestive of chronic interstitial lung disease with no specific pattern. Left heart catheterization revealed right ventricular hypertrophy, normal EF >55%, and no evidence of coronary disease. Alpha-1 antitrypsin: 158, EPO: 6.5, HIV, and hepatitis panel were all negative. Rheumatology work up with only an ANA antibody positive, with titer 1:160. Patient underwent VATS procedure with wedge biopsy of the right upper and middle lobe that revealed usual interstitial pneumonia pattern. Patient improved and was discharged on home oxygen 3L. At follow-up, treatment was started with Nintedanib and Sildenafil Citrate. He had clinical improvement and oxygen requirements decreased to intermittent oxygen. CONCLUSIONS: Patients with interstitial pulmonary fibrosis experience slow progressive decline with typical clinical presentation over 60 years of age. This case remarks the importance of the need for stratification of interstitial lung disease classification, when pattern and history are non specific, with the use of VATS procedure for early start of treatment. Our patient with no environmental exposure or connective tissue disease had an uncommon early presentation of usual interstitial pneumonia. Reference #1: Tibana, R.C.C., Soares, M.R., Storrer, K.M. et al. Clinical diagnosis of patients subjected to surgical lung biopsy with a probable usual interstitial pneumonia pattern on high-resolution computed tomography. BMC Pulm Med 20, 299 (2020). https://doi.org/10.1186/s12890-020-01339-9 DISCLOSURES: No relevant relationships by Jesse Aleman No relevant relationships by Carlos Martinez Crespí no disclosure submitted for Jean Ramos;No relevant relationships by Alexandra Rodriguez Perez No relevant relationships by Paola Vazquez No relevant relationships by Nahomie Veguilla Rivera

INTERSTITIAL LUNG DISEASE IN SERONEGATIVE RHEUMATOID ARTHRITIS

SESSION TITLE: Autoimmune Diffuse Lung Disease Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial lung disease (ILD) associated with connective tissue diseases (CTD) present with varying degrees of severity and functional impairment. Patients with CTD-ILD may often initially present for pulmonary evaluation. Pulmonologists must be familiar with the spectrum of CTD syndromes, the associated serologic testing, and referral criteria to rheumatology. CASE PRESENTATION: A 62-year-old never-smoking female with prior mild COVID-19 infection, previously vaccinated, presented to clinic with a diagnosis of pulmonary fibrosis. She endorsed three years of progressive shortness of breath and dyspnea on exertion walking only eight blocks and with light household chores. The patient had worked as a professional chef in poorly ventilated kitchens. Review of systems was notable for morning stiffness and pain in bilateral hand joints with associated difficulty opening medication bottles secondary to symptoms. Previous computed tomography (CT) of the chest demonstrated peripheral, subpleural, and basal predominant reticulations accompanied by bronchiectasis and bronchioloectasis consistent with probable usual interstitial pneumonia (UIP). Envisia® genomic testing was performed and results were negative for idiopathic pulmonary fibrosis. Extensive serologic testing for CTD was performed, including rheumatoid factor and anti-cyclic citrullinated peptides which were normal. The patient was referred to rheumatology, and hand x-rays demonstrated diffuse MCP joint narrowing. The patient was diagnosed with seronegative rheumatoid arthritis (RA) with RA-ILD and started on treatment. DISCUSSION: Multiple society guidelines recommend serologic testing to rule out CTD-ILD in patients with new ILD. ILD has been reported to occur in 20-60% of patients with RA with multiple patterns. Patients with seronegative RA are more likely to develop extraarticular manifestations of RA including fibrotic lung disease. Patients who are asymptomatic from RA-ILD may be monitored clinically for worsening RA-ILD. The selection of patients for treatment with an immunosuppressive agent or glucocorticoids should be done with a multidisciplinary team. Patients with RA-ILD and a UIP pattern may not respond to immunosuppressive medications but are typically trialed on treatment for worsening lung disease. Randomized controlled trials that included patients with RA-ILD with fibrosis have suggested a role for nintedanib, an anti-fibrotic agent, in slowing the progression of forced vital capacity decline. CONCLUSIONS: CTD-ILD is a common diagnosis in pulmonary clinics, and ILD symptoms may be the chief complaint at presentation. Providers must be familiar with diagnostic criteria for CTD and obtain a detailed review of systems that might suggest the diagnosis of CTD. Early diagnosis of CTD-ILD and monitoring of disease activity is important to prevent progression of CTD-ILD. Reference #1: Yoo H, Hino T, Han J, et al. Connective tissue disease-related interstitial lung disease (CTD-ILD) and interstitial lung abnormality (ILA): Evolving concept of CT findings, pathology and management. Eur J Radiol Open. 2020;8:100311. Published 2020 Dec 16. doi:10.1016/j.ejro.2020.100311 Reference #2: Sahatciu-Meka V, Rexhepi S, Manxhuka-Kerliu S, Rexhepi M. Extra-articular manifestations of seronegative and seropositive rheumatoid arthritis. Bosn J Basic Med Sci. 2010;10(1):26-31. doi:10.17305/bjbms.2010.2729 Reference #3: Cottin V. Pragmatic prognostic approach of rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010 Jun;35(6):1206-8. doi: 10.1183/09031936.00008610. PMID: 20513909. DISCLOSURES: No relevant relationships by Brenda Garcia No relevant relationships by Zein Kattih No relevant relationships by Priyanka Makkar No relevant relationships by Jonathan Moore

Role of Antifibrotic Therapy in Pulmonary Fibrosis Due to COVID-19

Background: It has been more than year of beginning of COVID-19 outbreak, the most serious complication of COVID infection is excessive increase in inflammatory mediators also known as cytokine storm which leads to formation of pneumonia in some patients. After resolution of pneumonia some amount of fibrosis develops which leads to decrease in quality of life and increased mortality. Nevertheless, in elderly patients a small % of fibrosis can be fatal. Therefore, as corona virus has affected several millions of people even though pulmonary fibrosis being a rare complication can cause huge no. of cases of pulmonary fibrosis, Several randomized control trials has been carried out till now for treatment of fibrosis, Perfenidone and nintedanib are approved as a treatment modality of idiopathic pulmonary fibrosis, it has been also useful in non-idiopathic pulmonary fibrotic diseases like interstitial idiopathic fibrosis studies are going out for effectiveness in post COVID pulmonary fibrosis. Several other modalities are also being tested, drugs which help in decreasing the severity of cytokine storm such as steroids. Viral load can be decreased by using antiviral agents. Certain novel drugs are also being researched upon, so in this review article considering the impact of fibrosis on the covid population, cause of pulmonary fibrosis, prevention and treatment modalities has been discussed.

Open questions on the management of targeted therapies for the treatment of systemic sclerosis-interstitial lung disease: results of a EUSTAR survey based on a systemic literature review.

Background: The results of randomized controlled (RCT) and retrospective studies have expanded the armamentarium of drugs for systemic sclerosis (SSc) - interstitial lung disease (ILD) treatment. The correct positioning of these drugs is not yet clarified. Objectives: Systemic literature review (SLR) on rituximab (RTX), tocilizumab (TCZ), nintedanib and abatacept (ABT) for the treatment of SSc-ILD. The results of the SLR were used to create a dedicated survey. Design: The study was performed as a systematic review. Data sources and methods: the SLR was performed using the following terms: "(systemic sclerosis OR scleroderma) AND (interstitial lung disease OR lung fibrosis OR pulmonary fibrosis) AND (rituximab OR tocilizumab OR abatacept OR nintedanib)". The results of the SLR were integrated in a survey including 8 domains. These were sent to all EUSTAR members and to the participants of the 2020 Scleroderma World Congress. Results: 41 studies (34 on RTX, 5 on TCZ, 2 on ABT, and 1 on nintedanib) were identified. RCTs supported the use of TCZ and nintedanib, while retrospective studies supported the use of RTX for SSc-ILD. No clear data were obtained about ABT. The survey showed that RTX is the most available option (96%) whereas the most frequent reason for targeted therapy introduction is lung progression while on csDMARDs (86% RTX, 59% TCZ and 63% nintedanib). Combination therapy was the most frequently mentioned therapeutic scheme for nintedanib (75%) and RTX (63%). Physicians' perception of safety was similar for all drugs, while drug efficacy was the same for RTX and nintedanib, followed by TCZ (4.8 ± 2). The most frequently raised concerns pertained to efficacy, safety and combination regimens. Conclusion: Our SLR supports the use of RTX, TCZ and nintedanib for SSc-ILD patients and underlines the need for more data about upfront combination versus monotherapy. It also highlighted the need to identify predictors supporting drug choice according to both pulmonary and extra-pulmonary manifestations.

Perioperative Concerns for Patients with Prior SARS-CoV-2 Infection: Our Experience

Methodology and case description: Case 1: A 55-year-old hypertensive male with complaints of chest pain presented to the cardiology department. He underwent angiography to reveal triple vessel disease and was scheduled for coronary artery bypass graft surgery. During preoperative evaluation, patient gave a history of having suffered from mild COVID-19, getting cured with conservative management under home isolation 3 months back. Examination revealed bilateral basal crepitations. Chest X-ray was indicative of fibrosis basal areas of both lungs (right > left) which was confirmed by HRCT chest. Preoperatively the patient was optimised with antifibrotic agent nintedanib and methylprednisolone. He was reviewed after 1 month and had shown significant-resolution radiologically as well as clinically (improved breath holding time, saturation and lung auscultation). Intraoperative course was uneventful and the patient was ventilated with low tidal volume. Postoperatively, the patient was extubated on day 1. Patient experienced difficulty in expectoration which was improved by N-acetyl cysteine administered intravenously and via nebulisation along with active vigorous physiotherapy. Patient was discharged on the 7th postoperative day. Case 2: A 37-yearold female, a known case of severe mitral stenosis, moderate pulmonary hypertension, moderate tricuspid regurgitation was under conservative management with diuretics and beta-blockers and was being planned for mitral valve replacement. The patient had developed COVID-19 infection 1 month back and was treated under home isolation and conservative management. However, the patient presented with an increase in exercise intolerance post COVID infection. Suspecting the possibility of fluid overload/ heart failure and pulmonary hypertension, the diuretic dose was increased post admission, but to no avail. Chest X-ray and HRCT chest were done which highlighted the possibility of allergic bronchopulmonary aspergillosis;which has been described as one of the rare findings coexisting with active COVID-19 infection. This was confirmed by the serum IgE levels and presence of eosinophilia in the complete blood picture. The patient was initiated on itraconazole and methylprednisolone which resulted in improvement in breathlessness over the next 3 weeks. The patient was subsequently posted for surgical replacement of the mitral valve. Intra-operative and post-operative course was uneventful and the patient was discharged on 5th post-operative day. Conclusion: These 2 cases who had suffered from mild COVID-19 infection presented significant challenges for safe intra- and post-operative conduct of anaesthesia. These challenges were overcome by efficient prehabilitation and optimisation of the patient and optimal post-operative critical care. Intra-operative course is often just a small segment of the overall hospital course of the patient and the role of critical care in the pre-surgical, extra-hospital care along with post-operative care needs acknowledgement and recognition.

Nintedanib vs pirfenidone in the management of COVID-19 lung fibrosis: A single-centre study.

BACKGROUND: COVID-19 pneumonia is complicated with residual lung fibrosis, as evidenced by imaging and postmortem pathological findings. In addition to steroids, we compared the efficacy of nintedanib and pirfenidone in the management of COVID-19 lung fibrosis measured by CT severity score (CTSS). METHODS: All cases of COVID-19 pneumonia diagnosed as COVID-19 positive by RT-PCR having SpO2 ⩽ 96% and CTSS ⩾ 10 even after 15 days were included in the study. The patients were divided into three groups. All three groups received steroids at a dose of 1 mg/kg body weight of prednisolone or equivalent. The first group received steroids alone, the second group received pirfenidone with steroids and the third group received nintedanib with steroids. All patients were followed up at 6 and 12 weeks. The primary endpoint of our study was to find out any improvement in CTSS. RESULTS: Out of 90 patients, 56 patients completed the study. Among three groups, 19 (33.9%) patients received steroids (control) only, 16 (28.6%) patients received steroids with pirfenidone and 21 (37.5%) patients received steroids with nintedanib. The study population had a mean (±SD) age of 52.5 ± 10.1 years, mean (±SD) C-reactive protein of 97.1 ± 102.2 mg/L (normal <6 mg/L), mean (±SD) serum ferritin 459.4 ± 305.5 ng/mL (normal <250 ng/mL), mean (±SD) serum d-dimer level 2.1 ± 2.6 µg/mL (normal <0.5 µg/mL) and mean (±SD) CTSS of 16.9 ± 4.3. There was significant improvement in CTSS in group receiving nintedanib compared to pirfenidone at 12 weeks (3.67 ± 1.21 vs 9.07 ± 1.12) with a p-value <0.01. CONCLUSION: Along with steroids in the treatment of COVID-19 lung fibrosis, there was a significant improvement in lung CTSS with nintedanib compared to pirfenidone.

New Era in Systemic Sclerosis Treatment: Recently Approved Therapeutics.

Systemic sclerosis (SSc) is a chronic autoimmune disease with a poor prognosis. Among the various complications of SSc, treatment options for the fibrotic lesions, skin sclerosis, and SSc-associated interstitial lung disease (SSc-ILD) have been limited. However, since 2019, the efficacy and safety of nintedanib, tocilizumab, and rituximab for SSc or SSc-ILD have been demonstrated in double-blind, randomized, placebo-controlled trials, respectively. The antifibrotic agent nintedanib was approved for SSc-ILD in all regions of the United States, Europe, and Japan after the SENSCIS study confirmed that it suppressed the reduction in forced vital capacity (FVC), a measure of SSc-ILD. Tocilizumab, an anti-interleukin-6 receptor antibody, was approved for the treatment of SSc-ILD in the United States after the FocuSSced study showed that it inhibited the decrease in FVC. Rituximab, an anti-CD20 antibody, showed improvement in both modified Rodnan skin score, a measure of skin sclerosis, and FVC in the DESIRES study, and was approved in Japan for the treatment of SSc itself. With the development of these three drugs, SSc treatment is entering a new era. This paper outlines the latest advances in SSc therapeutics, focusing on nintedanib, tocilizumab, and rituximab.

Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders.

The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis.

Antifibrotic Risk of Bleeding with Anticoagulation -A Case Report

Introduction: Antifibrotic drugs, including nintedanib and pirfenidone, are approved for the treatment of idiopathic pulmonary fibrosis (IPF). Pirfenidone blocks the synthesis of TGF-beta and does appear to increase the risk of CV or bleeding events. Nintedanib is a Vascular Endothelial Growth Factor Receptors (VEGFR) inhibitor and may increase the risk of bleeding. Bleeding events were reported in 10% of patients in clinical trials (despite excluding patients at risk of bleeding including those on con-current anticoagulation (AC) or antiplatelet (AP) therapy. Consequently, nintedanib is relatively contraindicated for patients with IPF on anticoagulation or antiplatelet therapy. However, results from real-life data demonstrate that 17.8% of our patients with IPF are on anticoagulation or antiplatelet therapy. The overall incident of bleeding events in those patients taking either or with nintedanib is similar to that reported for Nintedanib alone. We describe two patients with antifibrotic and anticoagulation therapy to highlight how to manage these patients. Case 1. A 67-year-old female with history of acute pulmonary embolism secondary to COVID-19 on anticoagulation therapy presents for workup of acute respiratory distress syndrome or suspected exacerbation of underlying IPF-usual interstitial pneumonia. Patient treated as IPF with pirfenidione. Case 2. A 69-year-old man with a history of atrial fibrillation on anticoagulation therapy presents for follow-up of progressive fibrosing interstitial lung disease secondary to hypersensitivity pneumonitis. Nintedanib initiated for progressive fibrosing lung disease. Discussion: Concomitant use of anticoagulation and/or antiplatelet therapy with antifibrotics doesn't increase bleeding risk. Conclusion. Anticoagulation and/or antiplatelet therapy should not be a reason to withhold antifibrotic therapy in patients with IPF.

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.