HYPERSENSITIVITY PNEUMONITIS PRESENTING AS SEVERE CYSTIC LUNG DISEASE FOLLOWING COVID-19 INFECTION

SESSION TITLE: Dirty Jobs: Occupational Lung Diseases SESSION TYPE: Case Reports PRESENTED ON: 10/18/2022 11:15 am - 12:15 pm INTRODUCTION: Hypersensitivity Pneumonitis (HP) is a group of immunologically mediated lung diseases. It develops in susceptible individuals with exposure to provoking antigens along with influence from genetic and environmental factors. There remains no standardized approach for assessing the various forms of HP and the diverse nature of the disease makes it difficult and often underdiagnosed. Cystic disease is not uncommon in HP, but the advanced cystic disease seen in our young patient was unique and likely compounded by her pregnancy as well as a previous illness with COVID-19. CASE PRESENTATION: A 26-year-old female construction worker at 12 weeks gestation, with a past medical history of polysubstance abuse and previous COVID-19 infection ten months prior, presented with progressively worsening dyspnea of 9 months. She was admitted with acute hypoxic respiratory failure due to recurrent right pneumothorax requiring multiple thoracenteses and eventually chest tube placement. CT Chest demonstrated severe cystic interstitial fibrosis with emphysematous changes. Initial lung biopsy showed interstitial fibrosis as a possible sequela of COVID-19. Due to her pregnancy and medical complications, she was transferred to a transplant center where she continued to have recurrent pneumothoraces requiring video-assisted thoracoscopic surgery. Autoimmune workup, HP panel, and extended myositis panel were negative. However, a repeat lung biopsy pointed to subacute HP. Despite steroid and immunosuppressant initiation, her hospital course was complicated by cardiac arrest and brain death. She went on to become an organ donor. DISCUSSION: Diffuse cystic lung diseases are characterized by parenchymal destruction of the airway walls leading to expansion of the distal airspaces forming multi-lobular cysts. A broad differential diagnosis for this exists including infection, Langerhans histiocytosis, lymphangioleiomyomatosis, interstitial pneumonia, and HP. The first step to evaluate HP is a detailed history of potential exposures. Our patient worked in construction and was exposed to commonly demonstrated antigens used in paint, plastic, and wood manufacture. Pregnancy appears to trigger symptoms in some patients, seen in prior case reports. Our patient's symptoms began after her COVID infection. Though not clearly studied, some studies have proposed that dysregulation of COVID - 19 immune response triggers interstitial fibrosis as a long-term sequela. Early diagnosis and treatment with steroids are vital to the treatment and prevention of complications such as recurrent pneumothorax. CONCLUSIONS: Covid-19 is an emerging risk factor for the propagation of various immune-mediated diseases. Progression of disease may occur even after the infection has been cured and limited data is available regarding its relation. Early recognition and treatment can be effective life-saving measures in these patients. Reference #1: Baldi BG, Carvalho CRR, Dias OM, Marchiori E, Hochhegger B. Diffuse cystic lung diseases: differential diagnosis. J Bras Pneumol. 2017;43(2):140-149. Reference #2: Densem C, Niven R, Barber P, Bishop P. Development of cryptogenic fibrosing alveolitis during pregnancy. J R Soc Med. 1998;91(11):591-593. Reference #3: Ambardar SR, Hightower SL, Huprikar NA, Chung KK, Singhal A, Collen JF. Post-COVID-19 Pulmonary Fibrosis: Novel Sequelae of the Current Pandemic. J Clin Med. 2021;10(11):2452. Published 2021 Jun 1 DISCLOSURES: No relevant relationships by Anastasia Brit No relevant relationships by Steven Colby No relevant relationships by Patrick Koo No relevant relationships by Vishruth Vyata No relevant relationships by Harika Yadav

COVID 19 in a family with rare genetic disease of the nervous system

We present familial tuberous sclerosis (TS) case complicated by COVID-19. COVID-19 aggravates the course of TS and may lead to a fatal outcome. We review the role of mTORC1 (mechanistic/mammalian Target of Rapamycin Complex 1) in the development and functions of the nervous system and the pathogenesis of TS and COVID-19 with emphasis on the involvement of the brain and lungs. We observed that COVID-19 worsens the course of epilepsy in patients with TS. In TS patients, lymphangioleiomyomatosis may predispose to SARS-CoV-2 invasion into the respiratory system because of the increased expression of ACE2 and TMPRSS2 in type II pneumocytes and thus may worsen the prognosis. We also review the current data on the continuation/termination of everolimus administration in patients with TS associated with COVID-19.

Advances and applications of dextran-based nanomaterials targeting inflammatory respiratory diseases

Dextran, a hydrophilic polysaccharide consists essentially of α-1,6 linked glucopyranoside residues that form the parent chain, along with α-1,2/3/4 linked residues that constitute its side chain. A considerable biocompatibility, stability under mildly acidic and basic conditions, solubility in water, non-immunogenicity, and presence of chemically modifiable –OH groups make dextran an ideal candidate for development of drug delivery vehicles and excipients. The presence of α-1,6 linkages in the parent chain provides enhanced chain mobility that determines the aqueous solubility of dextran, while its metabolism by the digestive enzymes to generate physiologically harmless degradation products validates its biocompatibility. Native dextran can be tuned for the development of pH-sensitive delivery systems by chemical modification that ensure an optimal drug concentration at the target site, and lowered dosing frequency that may ensure an overall improved patient compliance. The physicochemical properties of dextran can be changed by performing a chemical modification predominantly at the –OH group to obtain ester, ether, acetal, and dialdehyde of dextran. The review presented by us is a comprehensive account of the chemical modification strategies for native dextran and their clinical applications in containing pulmonary diseases. Furthermore, the presented review highlights the importance of nanomaterials derived from chemically modified dextran for the management of an optimal respiratory health by containing the inflammatory respiratory diseases.

Effects of Sirolimus on Anti-Spike Protein Antibody Levels Following Vaccination of Patients with Lymphangioleiomyomatosis

Rationale: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease, affecting mostly women, and associated with cystic lung destruction, abdominal tumors and lymphatic involvement. LAM occurs in a sporadic form (S-LAM) and a component of an autosomal-dominant, neurocutaneous syndrome, tuberous sclerosis complex (TSC). Lung destruction results from the proliferation of cancer-like LAM cells, which have mutations in one of the two TSC genes, resulting in activation of the mechanistic target of rapamycin (mTOR) pathway that drives increased cell growth and size. The mTOR inhibitor, rapamycin (sirolimus), stabilizes disease progression and is FDA-approved for treatment of LAM. COVID-19 may pose a greater risk to patients with lung disease and to those who are taking immunosuppressive medications, such as sirolimus. The impact of sirolimus on response to COVID-19 vaccination in patients with LAM is not well understood. Objectives: We conducted a multicenter observational study to determine if LAM patients treated with or without sirolimus, respond to the Pfizer and Moderna vaccines by production of antibodies against the SARS-CoV-2 Spike protein. Methods: Anti-Spike protein antibodies were measured using the Cobas 6000 Analyzer to determine response to vaccination. Anti-nucleocapsid antibodies, measured to assess infection, were only positive in one patient. Results: Serology was determined on 30 women with a confirmed diagnosis of LAM. The median age of our cohort was 53.5 years (range 37 -76years). Thirty-one patients were treated with sirolimus, and 7 patients were not on sirolimus. Of the 23 patients treated with sirolimus, 12 received the Moderna vaccine and 11 received the Pfizer vaccine. Of the patients not taking sirolimus, 4 received the Moderna vaccine and 3 received the Pfizer vaccine. Serology data were collected 94 days, +/-57 days after the second vaccination. Anti-Spike antibody levels, assessed on 2 patients following a third dose of the Pfizer vaccine, showed an increased antibody response. A widespread serological response was observed. The median anti-Spike antibody level was 1033U/ml in LAM patients on sirolimus, and was comparable to the level of 1077U/ml units in LAM patients not on sirolimus. Two LAM patients treated with sirolimus did not have detectable antibody titers following the Pfizer vaccination. Conclusions: Majority of the LAM patients on sirolimus mount a response to the COVID-19 vaccines at levels that are comparable to those of LAM patients not on sirolimus. Those patients taking sirolimus who have low or no serological response after two doses of mRNA vaccines may respond to a 3rd vaccination.

Acute Hypoxemic Respiratory Failure Due to COVID-19 in a Patient With Underlying Lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare disorder that can cause lesions that develop into cysts, most commonly in the lung parenchyma and renal angiomyolipomas. We report a case of a young female with LAM who was admitted to the hospital for a COVID-19 infection, with the objective of discussing the management of LAM with concurrent COVID-19 infection. She ultimately showed overall clinical improvement after receiving dexamethasone and remdesivir, while holding her outpatient mammalian target of rapamycin (mTOR) inhibitor. When patients with rare diseases acquire COVID-19, an individualized approach to treatment is often most effective as information and studies may be limited.

Increased expression of angiotensinconverting enzyme 2 (ACE2), TMPRSS2 and furin in idiopathic pulmonary fibrosis (IPF) and lymphangioleiomyomatosis (LAM) patients' lung tissue: Implications for COVID -19

Background and Aims: Patients with chronic lung disease are highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to COVID-19. ACE2 is the main receptor for SARS-CoV-2 attachment. Our previous study reported higher ACE2 levels in smokers and COPD patients. Current study investigates if patients with interstitial lung diseases (ILDs) such as IPF and LAM have elevated levels of ACE2, transmembrane peptidase serine 2 (TMPRSS2) and Furin, increasing their risk for SARS-CoV-2 infection. Methods: Surgically resected lung tissue from IPF, LAM patients and normal controls (NC) was immunostained for ACE2, TMPRSS2 and Furin. Percentage ACE2 expression was measured in small airway (SA) epithelium and alveolar areas. Analysis was done using computer-assisted Image- ProPlus 7.0 software. Results: Compared to NC, the percentage ACE2 expression significantly increased in the SA epithelium of IPF (p<0.01), LAM (p<0.001) and in alveolar areas of IPF (p<0.001), LAM (p<0.001). We also observed elevated TMPRSS2 and Furin expression in the same lung tissue areas of IPF and LAM against NC. There was significant positive correlation between smoking history and ACE2 expression in the IPF for SA epithelium (r=0.81, p<0.05) and alveolar areas (r=0.94, p<0.01). Conclusions: This study has investigated the ACE2, TMPRSS2, and Furin in resected lung tissue of IPF and LAM, which suggests that people with ILDs are at higher risk of developing severe COVID-19 infection. To further understand and provide potential therapeutic targets for ILDs, we need to explore other cell types such as type II pneumocytes, alveolar macrophages and endothelial cells.

COVID-19 in a patient with sporadic lymphangioleiomyomatosis awaiting lung transplantation.

Coronavirus disease 2019 (COVID-19) is an emerging viral disease with a mortality that depends on the individual's condition. Underlying comorbidities are major risk factors for COVID-19-related morbidity and mortality. However, information regarding the clinical course of COVID-19 in patients with rare respiratory system diseases is lacking. Here, we present a case of severe COVID-19 in a patient with advanced sporadic lymphangioleiomyomatosis (LAM) who was awaiting lung transplantation. She experienced a marked worsening of her respiratory status despite the limited size of the infiltrations seen on chest computed tomography. She responded to treatment with dexamethasone and remdesivir, and did not require mechanical ventilation. She recovered her pre-COVID-19 respiratory function. This case illustrates that patients with severe lung parenchymal destruction due to advanced LAM are at risk of worsening hypoxemia, but may not have a bad outcome if managed appropriately. Prevention and early diagnosis of COVID-19 are crucial in patients with advanced LAM. Future studies are needed to improve understanding of the clinical features and optimal treatment of COVID-19 in patients with LAM.

CT findings of pulmonary cysts.

Pulmonary cysts are thin-walled radiolucent lesions that may appear in a variety of uncommon disorders known as diffuse cystic lung diseases (DCLD) that essentially includes lymphangioleiomyomatosis (LAM), Langerhans cell histiocytosis (LCH), lymphocytic interstitial pneumonia (LIP), Pneumocystis jiroveci pneumonia (PJP), and Birt-Hogg-Dubé syndrome (BHDS). Moreover, they have been reported in several cases of coronavirus disease 2019 (COVID-19). The purpose of this review is to provide a practical approach for evaluating lung cysts when encountered on CT. We describe the imaging findings of DLCD emphasising their differences in terms of shape and distribution of the cysts, as well as their association with other findings such as nodules or ground-glass opacities, which may help in making a confident diagnosis. We also discuss the link between pulmonary cysts and COVID-19.