Genotype-phenotype correlations in five patients harboring SERPINA1 mutations and previously showing a severe COVID-19 infection

Background/Objectives: During COVID-19 pandemic, it is essential to detect patients potentially at risk of life-threatening complications, due to possible specific genetic mutations. The aim of our work is to show a practical application of genetic testing, allowing a diagnosis of alpha 1 antitrypsin deficiency in cases with a severe clinical course during COVID-19 infection. Method(s): During hospitalization for COVID-19, we identified 5 patients (3 female, 2 males from two different families, age range 18-47 years) with a severe course of COVID-19 infection, requiring high pressure ventilation with high volume oxygen supply. Two months after discharge, those patients were reevaluated with respiratory function tests, biochemical tests, genetic counselling and genetic testing. A peripheral blood sampling for SERPINA1 genetic testing has been performed, using Sanger sequencing. Result(s): Two months after discharge, in all 5 patients respiratory function tests were consistent with a dysventilatory obstructive syndrome, in contrast with usual findings related to COVID-19 infection. Blood test still showed increase plasmatic transaminase concentration in 3 out of 5 patients, one having increased serum bilirubin as well. We performed SERPINA1 genetic testing showing homozygosity for SERPINA1 pathogenic mutations (c.193del and c.875C>T, respectively) in all 5 patients. Conclusion(s): These cases showed the importance of genetic testing for patients with unexplained severe COVID-19 infection. Genetic testing allowed the diagnosis of cases affected by alpha 1 antitrypsin deficiency, associated with dysventilatory obstructive syndrome, that may worsen the short and long term prognosis of COVID-19.

SARS-CoV-2 Infection Precipitates the Discovery of Underlying Liver Disease: A Case Report.

Since the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, numerous sequelae of this devastating virus have come to light. One organ known to be impacted by SARS-CoV-2 is the liver, as many SARS-CoV-2 patients demonstrate elevated liver enzymes on routine laboratory tests. In this case report, we present a patient with SARS-CoV-2 whose liver enzymes remained persistently elevated throughout his hospitalization. Due to the duration of his elevated liver enzymes, etiologies outside of SARS-CoV-2 were explored. This workup revealed that the patient had alpha-1 antitrypsin (A1AT) deficiency. Thus, this case serves to remind clinicians to continue investigating lab abnormalities despite a presumed etiology, such as SARS-CoV-2, so as not to miss the presentation of new diagnoses.

Improving Detection of Alpha-1 Antitrypsin Deficiency: Role of the Allergist.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that manifests as lung and/or liver disease. Because symptoms of AATD overlap with those of common pulmonary and hepatic conditions, AATD is often misdiagnosed, which has resulted in substantial underdiagnosis of AATD worldwide. Although screening patients for AATD is recommended, the lack of procedures to facilitate testing remains a barrier to accurate diagnosis of AATD. Delays in AATD diagnosis can worsen outcomes for patients by postponing appropriate disease-modifying treatments. Patients with AATD-related lung disease experience symptoms similar to other obstructive lung disorders and are often misdiagnosed for years. In addition to existing screening guidelines, we recommend that screening for AATD become a standard part of allergists' workups of patients with asthma and fixed obstructive disease, chronic obstructive pulmonary disease, bronchiectasis without known origin, and patients under consideration for treatment with biologics. This Rostrum article reviews screening and diagnostic tests available in the United States and emphasizes evidence-based strategies to increase testing frequency and improve AATD detection rates. We underscore the pivotal role of allergists in managing care for patients with AATD. Finally, we urge health care providers to be aware of potentially poor clinical outcomes among patients with AATD during the coronavirus disease 2019 pandemic.

The effect of COVID-19 pandemics on the comprehensive laboratory diagnostic of alpha-1 antitrypsin deficiency in Europe - report from the AATD LABNet

Diagnosis of alpha1-antitrypsin deficiency, a rare genetic disorder, consists of biochemical serum analysis to evaluate protein deficiency and electrophoretic abnormalities, as well as genetic analysis to identify SERPINA1 gene variants responsible for the protein deficiency. In majority of European countries diagnostic is centralized, blood and/or DNA samples are referred to dedicated reference laboratories. We aimed at analyzing data reported by the 8 leading European centers (AATD LABnet part of the EARCO ERS CRC and ERN-LUNG activities) to assess the effect of COVID-19 pandemic and healthcare disruption on the AATD diagnostic provision. In total, the number of tests dropped in 2020 vs 2019 by -20,43% (+/-13,25) for AAT concentration analysis, -25,5% (+/-12,79) for AAT phenotyping and -23,57% (+/-10,28) for SERPINA1 genotyping, while in 2021 vs 2019 by respectively -16,86% (+/-21,34), -9,2% (+/-30,38), -13,57% (+/-40,82). Specifically, diagnostics in Poland and Italy were affected the most with -48% and -28% fewer samples analyzed (2021 vs 2019, phenotyping), while in France and Portugal referrals recovered by the end of 2021, with + 18% and +29% respectively (2021 vs 2019, genotyping). Disorganization of healthcare provision due to the COVID-19 pandemic severely disrupted AATD diagnostics in Europe. In some countries the detrimental effect was temporary, while in others it continued in 2021.

Comparison of COVID-19 Outcomes With Alpha-1 Antitrypsin Deficiency Prevalence in Europe: A Cross-Sectional Study.

Introduction We hypothesized that the geographic distributions of COVID-19 and alpha-1 antitrypsin alleles prevalence are similar. We investigate whether there is a relationship between the geographical density of the COVID-19 pandemic and the distributions of alpha-1 antitrypsin alleles. Methods This research is a cross-sectional study. Alpha-1 antitrypsin PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ genotypes frequencies of European countries were compared with the case and death data related to the COVID-19 pandemic as of March 1, 2022.  Results A significant relationship was found between the rates of COVID-19 cases and the rates of individuals with alpha-1 antitrypsin PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ genotypes allele in European countries. Conclusions The findings showed that the prevalence distribution of the alleles of the gene defect that causes alpha-1 antitrypsin insufficiency is related to the prevalence of COVID-19 pandemic data.

Self-Amplifying RNA Approach for Protein Replacement Therapy.

Messenger RNA (mRNA) technology has already been successfully tested preclinically and there are ongoing clinical trials for protein replacement purposes; however, more effort has been put into the development of prevention strategies against infectious diseases. Apparently, mRNA vaccine approval against coronavirus disease 2019 (COVID-19) is a landmark for opening new opportunities for managing diverse health disorders based on this approach. Indeed, apart from infectious diseases, it has also been widely tested in numerous directions including cancer prevention and the treatment of inherited disorders. Interestingly, self-amplifying RNA (saRNA)-based technology is believed to display more developed RNA therapy compared with conventional mRNA technique in terms of its lower dosage requirements, relatively fewer side effects, and possessing long-lasting effects. Nevertheless, some challenges still exist that need to be overcome in order to achieve saRNA-based drug approval in clinics. Hence, the current review discusses the feasibility of saRNA utility for protein replacement therapy on various health disorders including rare hereditary diseases and also provides a detailed overview of saRNA advantages, its molecular structure, mechanism of action, and relevant delivery platforms.

Severe COVID-19 Illness and α1-Antitrypsin Deficiency: COVID-AATD Study.

BACKGROUND: Epidemiologic studies have reported that the geographical distribution of the prevalence of allelic variants of serine protein inhibitor-A1 (SERPINA1) and severe cases of COVID-19 were similar. METHODS: A multicenter, cross-sectional, observational study to evaluate the frequency of alpha-1 antitrypsin deficiency (AATD) in patients with COVID-19 and whether it was associated with having suffered severe COVID-19. RESULTS: 2022 patients who had laboratory-confirmed SARS-CoV-2 infection. Mutations associated with AATD were more frequent in severe COVID versus non-severe (23% vs. 18.8%, p = 0.022). The frequency of Pi*Z was 37.8/1000 in severe COVID versus 17.5/1000 in non-severe, p = 0.001. Having an A1AT level below 116 was more frequent in severe COVID versus non-severe (29.5% vs. 23.1, p = 0.003). Factors associated with a higher likelihood of severe COVID-19 were being male, older, smoking, age-associated comorbidities, and having an A1AT level below 116 mg/dL [OR 1.398, p = 0.003], and a variant of the SERPINA1 gene that could affect A1AT protein [OR 1.294, p = 0.022]. CONCLUSIONS: These observations suggest that patients with AATD should be considered at a higher risk of developing severe COVID-19. Further studies are needed on the role of A1AT in the prognosis of SARS-CoV-2 infection and its possible therapeutic role.

Expert Perspectives on the Management of Alpha 1-Antitrypsin Deficiency.

Alpha 1-antitrypsin deficiency is an inherited autosomal codominant disorder, which predisposes patients to lung and/or liver disease. Even though it is considered rare, it is one of the most frequent genetic disorders worldwide, albeit remaining underdiagnosed. Several organizations and societies, including the Portuguese Society of Pulmonology have been elaborating guidelines and recommendations for the diagnosis and management of alpha 1-antitrypsin deficiency. Nevertheless, some important matters are yet to be included in those, mainly due to lack of robust scientific evidence, and continue to represent a point of discussion. This article reviews some important scientific publications and expresses the perspectives of a group of Portuguese experts regarding the management of alpha 1-antitrypsin deficiency, namely in terms of the pre and neonatal diagnosis, the impact of the COVID-19 pandemic, the validity of replacement therapy in lung transplant-receiving, and finally, alternative strategies of alpha 1-antitrypsin deficiency treatment to improve the patients' quality of life.

A deficiência de alfa 1-antitripsina é uma doença hereditária autossómica codominante que aumenta a predisposição para o desenvolvimento de doença pulmonar e/ou hepática. Esta doença, embora seja considerada rara, é um dos distúrbios genéticos mais comuns em todo o mundo. Contudo, atualmente ainda constitui uma doença subdiagnosticada. Várias organizações e sociedades, incluindo a Sociedade Portuguesa de Pneumologia, elaboraram recomendações e diretrizes para o diagnóstico e gestão da deficiência de alfa 1-antitripsina. Porém, estes documentos ainda não abordam alguns temas relevantes associados à gestão da deficiência de alfa 1-antitripsina, principalmente devido à falta de robustez na evidência científica, que continuam a representar um ponto de discussão entre a comunidade médica. Neste artigo é feita a revisão de publicações científicas relevantes acerca da deficiência de alfa 1-antitripsina, e são descritas as perspetivas de especialistas portugueses sobre a gestão da deficiência de alfa 1-antitripsina, nomeadamente ao nível do diagnóstico pré e neonatal, do impacto da pandemia COVID-19, da validação da terapêutica de aumento em doentes que receberam um transplante pulmonar e, por fim, estratégias alternativas para a melhoria do tratamento da deficiência de alfa 1-antitripsina de modo a promover a qualidade de vida dos doentes.

COVID-19's impact on care practice for alpha-1-antitrypsin deficiency patients.

BACKGROUND: Patients with alpha-1 antitrypsin deficiency (AATD), commonly categorized as a rare disease, have been affected by the changes in healthcare management brought about by COVID-19. This study's aim was to identify the changes that have taken place in AATD patient care as a result of the COVID-19 pandemic in Spain and to propose experts' recommendations aimed at ensuring humanized and quality care for people with AATD in the post-pandemic situation. METHODS: A qualitative descriptive case study with a holistic single-case design was conducted, using focus groups with experts in AATD clinical management, including 15 health professionals with ties to the Spanish health system (12 pneumologists and 2 hospital pharmacists from 11 different hospitals in Spain) and 1 patient representative. RESULTS: COVID-19 has had a major impact on numerous aspects of AATD clinical patient management in Spain, including diagnostic, treatment, and follow-up phases. The experts concluded that there is a need to strengthen coordination between Primary Care and Hospital Care and improve the coordination processes across all the organizations and actors involved in the healthcare system. Regarding telemedicine and telecare, experts have concluded that it is necessary to promote this methodology and to develop protocols and training programs. Experts have recommended developing personalized and precision medicine, and patient participation in decision-making, promoting self-care and patient autonomy to optimize their healthcare and improve their quality of life. The possibility of monitoring and treating AATD patients from home has also been proposed by experts. Another result of the study was the recommendation of the need to ensure that plasma donations are made on a regular basis by a sufficient number of healthy individuals. CONCLUSION: The study advances knowledge by highlighting the challenges faced by health professionals and changes in AATD patient management in the context of the COVID-19 pandemic. It also proposes experts' recommendations aimed at ensuring humanized and quality care for people with AATD in the post-pandemic situation. This work could serve as a reference study for physicians on their daily clinical practice with AATD patients and may also provide guidance on the changes to be put in place for the post-pandemic situation.

New coronavirus infection (COVID-­19) and respiratory diseases / pathological conditions

The respiratory system is the main target of the novel coronavirus infection (COVID19) spread by the SARS-CoV-2 virus. The interim guidelines of the Ministry of Health of the Russian Federation “Prevention, diagnosis and treatment of a new coronavirus infection (COVID-19)” (14th version of December 27, 2021) discuss pneumonia in COVID-19 in detail. The issues of the course of other respiratory diseases (chronic obstructive pulmonary disease-COPD, bronchial asthma) are considered in them very briefly. Other diseases and pathological conditions of the respiratory organs are ignored. The federal clinical guidelines Bronchial Asthma, Chronic Obstructive Pulmonary Disease, Community-Acquired Pneumonia in Adults published in 2021 do not discuss the course of these diseases in the context of the COVID-19 pandemic. A search was made for literature on the association of major diseases and pathological conditions of the respiratory organs with the new coronavirus infection COVID-19 in the electronic search engines PubMed and Scopus. The literature sources found indicate that the new coronavirus infection COVID-19 certainly has a specific, often negative, effect on the respiratory system as a whole, and in particular, on certain respiratory diseases and pathological conditions. However, this influence is sometimes ambiguous. Thus, patients with COPD, along with patients with arterial hypertension, diabetes mellitus, and other cardiovascular and cerebrovascular diseases, belong to a vulnerable group of the population during the COVID-19 pandemic, but there was a decrease in the frequency of exacerbations of COPD during the pandemic, especially hospitalizations. due to severe exacerbations. A number of meta-analyses and systematic reviews have shown that the risk of contracting COVID-19 in people with asthma is lower than in people without asthma. There is no association between asthma and a more severe course and worse prognosis of COVID-19. The relationship of diseases/pathological conditions of the respiratory system and COVID-19, therefore, requires further study and clarification. © 2022, Remedium Group Ltd. All rights reserved.

CRYPTIC CRYPTO: PULMONARY CRYPTOCOCCOSIS IN AN IMMUNOCOMPETENT HOST

SESSION TITLE: Uncommon Presentations and Complications of Chest Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Cryptococcus is a ubiquitous fungus in the environment. Infections can occur in humans when Cryptococcus is aerosolized and inhaled. Severity of clinical presentation varies from asymptomatic pulmonary colonization to disseminated life-threatening infection such as meningitis. These infections usually occur with deficiencies in T-cell-mediated immunity, including those with HIV/AIDS and immunosuppression due to transplantation. Herein we present a case of isolated pulmonary cryptococcosis in an immunocompetent host. CASE PRESENTATION: The patient is a 36-year-old never-smoker male with history of recurrent left spontaneous pneumothorax status post VATS blebectomy, negative for alpha-1 antitrypsin deficiency and cystic fibrosis. A year later, he presented with fatigue, shortness of breath, and dry cough after a recent trip to Ohio. Viral panel including COVID-19 was negative. A chest x-ray showed a new 4 cm rounded opacity in the right middle lobe (RML). A CT scan of the chest showed 2 mass-like and nodular areas of consolidation with surrounding GGOs within the RML (Figure 1). He underwent navigational bronchoscopy with transbronchial biopsy (TBBx) of RML, BAL, and EBUS with transbronchial needle aspiration (TBNA). Cytology was negative for malignant cells. BAL showed rare yeast. Pathology of the TBBx showed the airway wall with chronic inflammation including granulomatous inflammation, positive for yeast, most consistent with Cryptococcus with positive Grocott methenamine silver (GMS) stain (Figure 2). Culture of the TBNA grew C. neoformans var. grubii. Other cultures were negative. Serum Cryptococcal antigen was positive. HIV test was negative. He started treatment with oral fluconazole with improvement of symptoms. DISCUSSION: Clinical presentation of pulmonary cryptococcosis can include a variety of symptoms in which immune status is critical for determining the course of infection. Infection can vary from asymptomatic infection to severe pneumonia and respiratory failure, and meningitis. Similarly, imaging findings can also vary and be characterized as pulmonary nodules, consolidations, cavitary lesions, and/or a diffuse interstitial pattern. The diagnosis of Cryptococcus is made using histology, fungal cultures, serum cryptococcal antigen, and radiography in the appropriate clinical and radiological context. Treatment recommendations are determinant on immune status of the patient as well as symptoms. Asymptomatic and localized disease in immunocompetent patients can be monitored and mild/moderate disease can be treated with fluconazole. Those with severe or disseminated infection warrant induction therapy with an amphotericin B and flucytosine CONCLUSIONS: Clinical and radiological presentation of cyptococcosis varies depending on immune status. Disease can occur in both immunocompromised and competent hosts. Immune status determines disease course and treatment. Reference #1: Huffnagle GB, Traynor TR, McDonald RA, Olszewski MA, Lindell DM, Herring AC, et al. Leukocyte recruitment during pulmonary Cryptococcus neoformans infection. Immunopharmacology. 2000 Jul 25;48(3):231–6. Reference #2: Kd B, Jw B, Pg P. Pulmonary cryptococcosis. Semin Respir Crit Care Med [Internet]. 2011 Dec [cited 2022 Apr 2];32(6). Available from: https://pubmed.ncbi.nlm.nih.gov/22167400/ Reference #3: Ms S, Rj G, Ra L, Pg P, Jr P, Wg P, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis Off Publ Infect Dis Soc Am [Internet]. 2000 Apr [cited 2022 Apr 1];30(4). Available from: https://pubmed.ncbi.nlm.nih.gov/10770733/ DISCLOSURES: No relevant relationships by Mina Elmiry No relevant relationships by Brenda Garcia No relevant relationships by Zein Kattih no disclosure on file for Priyanka Makkar;No relevant relationships by Jonathan Moore

COVID-19 IN LUNG TRANSPLANT RECIPIENTS: A SINGLE CENTER EXPERIENCE

SESSION TITLE: Lung Transplantation: New Issues in 2022 SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Immunosuppressed patients are more susceptible to severe infection due to COVID-19. Management of lung transplant recipients is especially difficult due to constant exposure of the graft to the environment, leading to increased risk of rejection and requiring higher levels of maintenance immunosuppressive regimens. Mortality rates for lung transplant recipients with COVID-19 infection have ranged from 15% to 40% in published case series. We report our centers experience in managing lung transplant recipients with COVID-19 infections in a moderate-volume lung transplant center in Grand Rapids, Michigan. METHODS: This is a single center review of all lung transplant recipients with a COVID-19 diagnosis from March 2020 to December 2021. Recipients’ demographics and baseline characteristic, as well as their management, post infectious complications, and mortality data, were reviewed. RESULTS: In 2019, our center performed 48 lung transplants. During the study period, 42 of the 219 (19%) lung transplant recipients followed at our center had COVID-19 infections diagnosed by nasal or nasopharyngeal PCR testing. Twenty-four (57%) were male, mean age of 60.5 (range 25-77). Thirty-six (86%) patients had bilateral lung transplants. The diagnosis leading to their transplantation were COPD (N=18, 43%), idiopathic pulmonary fibrosis (N=12, 29%), cystic fibrosis (N=5, 12%), other pulmonary fibrosis (N=3, 7%), alpha-1 antitrypsin deficiency (N=2, 5%), Sarcoidosis (N=1, 2%), and ARDS (N=1, 2%). Almost all patients were on standard three drug immunosuppressive regimens which included a steroid, calcineurin inhibitor, and nucleotide-blocking agent, at the time of diagnosis. Mean time from transplant to diagnosis of COVID-19 was 34.6 months (range 1 to 104 months). Fifteen (36%) of the patients were unvaccinated. Once diagnosed, patients were advised to monitor their home spirometry and vitals at least daily. They were evaluated weekly via telemedicine by a physician or advanced practice provider. They received the following treatments: monoclonal antibody (N=31, 74%), increased steroids (N=5, 12%), remdesivir (N=2, 5%), Tocilizumab (N=1, 2%). Eleven (26.2%) patients required hospitalization, 4 (10%) required ICU admission and intubation. Mean length of stay was 7.5 days (median of 3 days). Three (7%) patients required oxygen at discharge. Of the 42 infected patients, 3 (7.1%) died on day 3, 16 and 326 days from the date of infection. CONCLUSIONS: Our center reports a lower mortality rate than previously published data in lung transplant recipients infected with COVID-19. We attribute this to availability of the vaccine, early detection and treatment, as well as close monitoring of the patients. CLINICAL IMPLICATIONS: Though COVID-19 infection can have devastating complications in lung transplant recipients, vaccinations and monoclonal antibody treatment reduce morbidity and mortality in this population. DISCLOSURES: No relevant relationships by Phillip Camp research relationship with United Therapeutics Please note: 2016- ongoing by Reda Girgis, value=Grant/Research research relationship with Pfizer Please note: 2014-2020 by Reda Girgis, value=Grant/Research Speaker/Speaker's Bureau relationship with Boehringher Ingelheim Please note: 2016-ongoing by Reda Girgis, value=Honoraria Speaker/Speaker's Bureau relationship with Genentech Please note: 2016-ongoing by Reda Girgis, value=Honoraria no disclosure on file for Ryan Hadley;No relevant relationships by Sheila Krishnan No relevant relationships by Edward Murphy No relevant relationships by Gayathri Sathiyamoorthy

The Effect of Cocooning on Patient-Reported Pulmonary Exacerbation Frequency in A ZZ Alpha-1 Antitrypsin Deficient Irish Population

Rationale: It has been suggested that individuals with ZZ alpha-1 antitrypsin deficiency (AATD) might suffer from more severe and prolonged pulmonary exacerbations compared to their MM counterparts due to the loss of immunomodulatory AAT protein. During the COVID-19 pandemic it was advised that individuals with ZZ AATD should, where practicable, cocoon to avoid contracting COVID-19. Methods: A survey of ZZ AATD individuals attending the Irish National Centre for Expertise for AATD was conducted 1 year into the COVID-19 pandemic. It evaluated the effects of cocooning on patient-reported exacerbation frequency during the 1-year COVID-19 period versus the 2 years prior to COVID-19. 184 individuals were contacted by phone, mail, or email. Results: 114 (62%) individuals successfully completed the survey. 73 (64%) cocooned during the pandemic, with men (39) and women (34) almost equally likely to cocoon. Those who cocooned tended to have a lower baseline FEV1 (% predicted). Women who cocooned had a mean FEV1 of 73.5% compared to a mean of 97.5% for women who did not cocoon. Men who cocooned had a mean FEV1 of 52.8% compared to a mean of 78.9% for men who did not cocoon. Men benefited from lower rates of exacerbation due to cocooning. They suffered an average of 0.92 exacerbations during the cocooning period versus 1.56 exacerbations per year prior to the pandemic (P = 0.0298). Women, regardless of cocooning status and non-cocooning men also demonstrated a trend towards fewer exacerbations but these were not statistically significant. In terms of hospitalisations, there were no differences observed between men or women based on cocooning status. This was likely due to the low rate of hospital admissions during the 3-year period. 14 (12%) of 114 respondents contracted COVID-19, 7 (50%) of whom were hospitalised. There was a single fatality from COVID-19. Conclusion: Further work needs to be done to establish the effects of risk reduction behaviours such as cocooning on exacerbation frequency and which groups may benefit most from this strategy. Our survey suggests that men with more advanced respiratory disease were most likely to benefit from a cocooning strategy and this may be applicable to non-COVID threats in the future.

Low Prevalence of Mild Alpha-1-Antitrypsin Deficiency in Hospitalized COVID-19-Patients.

Introduction: Alpha-1-antitrypsin (AAT) has been shown to inhibit SARS-CoV-2 cell entry and suggested as a therapeutic agent for COVID-19. Furthermore, epidemiological association of high prevalence of Alpha-1-antitrypsin deficiency (AATD) and regional severity of COVID-19-impact has been hypothesized. In our study setting, the estimated prevalence rates of mild (PI*MZ, PI*SS or PI*MS) and moderate-to-severe AATD (PI*ZZ or PI*SZ) are high, 9% and 0.2%, respectively. Our primary aim was to examine the prevalence rate of AATD among hospitalized COVID-19-patients. Methods: In this prospective observational study, enrollment occurred from December 2020 to January 2021 in two COVID-19-units at Skåne University Hospital, Lund, Sweden. Case definition was a patient hospitalized due to COVID-19. Patients were screened for AATD with PI-typing and if results were inconclusive, PCR for the S- and Z-genes were performed. Patients were categorized as severe or moderate COVID-19 and 30-day-mortality data were collected. The primary outcome was prevalence rate of AATD. The secondary outcome investigated association between presence of mild AATD and severe COVID-19. Results: We enrolled 61 patients with COVID-19. Two patients out of 61 (3%) had mild AATD (PI*MZ) and none had moderate-to-severe AATD. 30/61 (49%) had severe COVID-19. Both patients with mild AATD developed severe COVID-19. Yet, presence of AATD was not significantly associated with severe COVID-19 (p=0.24). Conclusion: Mild AATD (PI*MS or PI*MZ) was rare in a small cohort of hospitalized patients with COVID-19 in a study setting with a high background prevalence of AATD.

Attitudes Towards Vaccination for Coronavirus Disease 2019 in Patients with Severe Alpha-1 Antitrypsin Deficiency.

Patients with severe alpha-1 antitrypsin deficiency (AATD) are at increased risk for the development of chronic obstructive pulmonary disease (COPD), particularly if they smoke. This, coupled with their predilection for dysregulated inflammation and autoimmunity, makes affected individuals priority candidates for vaccination against coronavirus disease 2019 (COVID-19). To promote vaccine uptake effectively, an understanding of the factors motivating people to proceed with vaccination is essential. The attitudes of patients with AATD towards COVID-19 vaccination have yet to be described. We prospectively studied 170 Pi*ZZ genotype AATD patients, 150 patients with nonhereditary (Pi*MM genotype) COPD and 140 Pi*MM genotype individuals without lung disease receiving first-dose vaccination with ChAdOx1 nCoV-19 (AstraZeneca). Patient attitudes towards vaccination and motivations for getting vaccinated were assessed at the time of the vaccine being offered. Following completion of the 2-dose vaccine series, Pi*ZZ patients were then re-assessed regarding their attitudes towards booster vaccination. The most common primary motivation for accepting vaccination in Pi*ZZ participants ≥50 years old was a fear of illness or death from COVID-19. In contrast, Pi*ZZ patients <50 years most often cited a desire to socialize. The motivation pattern of younger Pi*ZZ AATD patients was similar to that of non-deficient individuals of comparable age, whereas older Pi*ZZ individuals were more closely aligned with Pi*MM COPD and differed from age-matched controls without lung disease. When considering booster vaccination, Pi*ZZ patients were increasingly motivated by a desire to reacquire social freedoms. A desire to reduce the risk of transmission was not a prominent consideration in any of the groups studied. The most commonly cited reason for booster hesitancy was a lack of incentive, given that no additional social freedoms were available to triple-vaccinated individuals compared to those who were double-vaccinated at the time. Taken together, these data may inform policymakers attempting to promote vaccine uptake among patients with AATD.

eP520: Screening results in 186 any-health-status adults in primary care clinics receiving clinical NGS for 431 health risk and recessive genes

Introduction: The ACMG has recommended returning clinically relevant results for certain genes when identified in research or as secondary findings in diagnostic testing. Research studies have shown that genomic population screening detects patients with previously unrecognized and often actionable health risks or genetic conditions, with acceptably low levels of harm. Cascade testing of relatives at risk is enabled. Screening for recessive disorder carrier status with gene sequencing panels is common in clinical practice. Preventative screenings routinely occur in primary care settings. The cost of reliably sequencing of many genes in a clinically reliable fashion is approaching levels where offering genomic screening tests may be contemplated for entire populations, and the results used for preventative health purposes, including clinical correlation, early screening, and education. In anticipation of universal genome sequence-based screening, integrated with existing health risk screenings, we piloted a novel implementation of clinical genomic population screening in primary care, mostly family medicine clinics. Screening involved clinical sequencing and reporting of 431 genes where variants are associated with personal health risks or recessive disease carrier status. Methods: Interested primary care providers (PCPs) in two Family Medicine practice systems were invited to participate and given onboarding education. Adult patients with any health status were introduced to The Genomic DNA Test and provided test information by their PCPs in the context of preventative health assessment. Patient education materials included paper, online, and video information, a ‘hotline,’ and optional free genetic counseling. Patients completing a bespoke, health system-approved, written clinical consent provided blood or occasionally saliva samples that were NGS sequenced according to validated procedures in a commercial CLIA-certified genetic testing laboratory. Laboratory reports were returned to the PCP and patient after a local genetics professional added a 1-to-3-page messaging document, the Genomic Medicine Action Plan (GMAP). The PDF-format reports and GMAP were placed in the patient’s electronic health record. Only pathogenic (P) and likely pathogenic (LP) variants were reported. Variant classification was according to Sherloc, the performing laboratory’s system. Patients or providers could request free post-test genetic counseling locally, and the performing lab offered free family member testing and limited-cost partner testing for health risk panel genes and recessive disorder panel genes, respectively. Patients with health risk results were defined as being heterozygous for a P/LP variant for a dominant condition or for a recessive condition where some heterozygotes are symptomatic or co-dominant, hemizygous for a P/LP variant for an X-linked recessive condition, or bi-allelic and plausibly in trans for an autosomal (or X-linked in a female) recessive condition. Many such conditions that are common have reduced or low penetrance, and were characterized as increased risk compared to those not having those variants. When increased risk was identified, the GMAP recommended appropriate medical responses and/or patient education. As part of quality assessment of the pilot, the frequencies of reported results and certain events are monitored. Results: Between November 2019 and October 2021, 186 patients with a median age of 58 years were tested by 20 PCPs at no cost to patients or insurance. Testing volumes declined during the COVID-19 pandemic and when other health system events made high demands on PCPs and their staff. Only 13.3% of patients had no reportable variants in any of the 431 genes. Eighty point nine percent were carriers for at least one recessive disease. The most common recessive genes showing carrier status were HFE, SERPINA1, GALT, CFTR, BTD, F5, DHCR7, PC, GAA, GJB2, PMM2, PAH, and PKHD1. Twenty-six percent had at least one potential health risk result identified, 20% if the common thrombophilias are excluded. The most common category was hereditary cancer risk (7.5%), followed by F5, F2, and SERPINC1 thrombophilia variants (6.5%), hereditary hemochromatosis 1 (HFE) (4.3%), cardiovascular disorders, mostly cardiomyopathies (3.8%), alpha-1-antitrypsin deficiency or other pulmonary disorder (3.8%), familial Mediterranean fever heterozygotes (1.6%), G6PD deficiency (1.1%), and lipid disorder (0.5%). Two patients had health risks in two areas, and two in three areas. Interestingly, BRCA1 and BRCA2 variants were only identified in males. Thirteen patients, about 7%, had an amended report issued during the period. This happened when an unreported variant of uncertain significance was reclassified as LP or P, or when LP became P, and the performing laboratory issued an amended report. Surprisingly few patients took advantage of the free genetic counseling. No patient adverse events were reported by the participating PCPs despite ongoing outreach, nor by patients. Conclusion: Genomic population health screening can be successfully implemented in primary care settings with use of limited but essential genetic professional assistance, after careful planning and input from other medical specialties. A significant proportion of adults not selected for health status harbors germline genetic variants associated with increased health risk. In the absence of a culture where routine genomic screening is expected and where patient genomic competency is high, PCP capacity limits are a barrier to universality. Inclusion of genes for both health risk results with variable degrees of penetrance and for recessive carrier status, and multiple simultaneous results, dictates careful messaging of the implications, while doing so in a primary care setting begs a concise and efficient process. Rates of carrier detection were in-line with predictions based on general population frequencies. Rates of health risk detections were higher than earlier research programs because a larger number of genes with a much broader scope of health risk was included, including disorders with low penetrance yet meaningful clinical relevance and carefully-designed care pathways meant to optimize care while avoiding unnecessary additional testing. We conclude that genomic population health screening of primary care patients where large numbers of genes are clinically sequenced is feasible in a real-world health system, and that value exists for some tested patients now. Research to overcome certain technical limitations of current clinical genomic testing methods and to better stratify risk level in the context of incomplete penetrance should enhance the value of universally-offered genomic population health screening in the future.

A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites. The aim of this review was to investigate the spectrum of AAT molecular interactions, with newer studies supporting a potential therapeutic paradigm for AAT augmentation therapy in disorders in which a chronic immune response is strongly linked.

Alpha 1 Antitrypsin Therapy in Patients with Alpha 1 Antitrypsin Deficiency: Perspectives from a Registry Study and Practical Considerations for Self-Administration During the COVID-19 Pandemic.

Alpha 1 Antitrypsin deficiency (AATD) is a hereditary condition characterized by low serum Alpha 1 Antitrypsin (AAT) levels and a predisposition towards early-onset emphysema. Infusion of AAT is the only disease-modifying therapy that can sufficiently raise plasma AAT levels above the putative protective threshold and reduce the decline in lung density loss. Several randomized controlled trials (RCTs) and registry studies support the clinical efficacy of AAT therapy in slowing the progression of AATD-related emphysema and improving survival outcomes. The COVID-19 pandemic has prompted physicians to develop additional strategies for delivering AAT therapy, which are not only more convenient for the patient, but are "COVID-19 friendly", thereby reducing the risk of exposing these vulnerable patients. Intravenous (IV) self-administration of AAT therapy is likely to be beneficial in certain subgroups of patients with AATD and can remove the need for weekly hospital visits, thereby improving independence and well-being. Increasing the awareness of self-administration in AATD through the development of formal guidelines and training programs is required among both physicians and patients and will play an essential role, especially post-COVID-19, in encouraging physicians to consider self-administration for AATD in suitable patients. This review summarizes the benefits of AAT therapy on the clinical endpoints of mortality and quality of life (QoL) and discusses the benefits of self-administration therapy compared with conventional therapy administered by a healthcare professional. In addition, this review highlights the challenges of providing AAT therapy during the COVID-19 pandemic and the potential considerations for its implementation thereafter.

In Vitro Investigations on Optimizing and Nebulization of IVT-mRNA Formulations for Potential Pulmonary-Based Alpha-1-Antitrypsin Deficiency Treatment.

In vitro-transcribed (IVT) mRNA has come into focus in recent years as a potential therapeutic approach for the treatment of genetic diseases. The nebulized formulations of IVT-mRNA-encoding alpha-1-antitrypsin (A1AT-mRNA) would be a highly acceptable and tolerable remedy for the protein replacement therapy for alpha-1-antitrypsin deficiency in the future. Here we show that lipoplexes containing A1AT-mRNA prepared in optimum conditions could successfully transfect human bronchial epithelial cells without significant toxicity. A reduction in transfection efficiency was observed for aerosolized lipoplexes that can be partially overcome by increasing the initial number of components. A1AT produced from cells transfected by nebulized A1AT-mRNA lipoplexes is functional and could successfully inhibit the enzyme activity of trypsin as well as elastase. Our data indicate that aerosolization of A1AT-mRNA therapy constitutes a potentially powerful means to transfect airway epithelial cells with the purpose of producing functional A1AT, while bringing along the unique advantages of IVT-mRNA.