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1.
Meditsinskiy Sovet ; JOUR(18):154-161, 2022.
Article in Russian | Scopus | ID: covidwho-2091327

ABSTRACT

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.

2.
Int J Mol Sci ; 23(21)2022 Oct 25.
Article in English | MEDLINE | ID: covidwho-2090204

ABSTRACT

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.


Subject(s)
COVID-19 , RNA , Humans , RNA/genetics , Vaccines, Synthetic , RNA, Messenger/genetics
3.
Chest ; 162(4):A2006-A2007, 2022.
Article in English | EMBASE | ID: covidwho-2060886

ABSTRACT

SESSION TITLE: Occupational and Environmental Lung Disease Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: We describe a case of acute progression of chronic hypersensitivity pneumonitis (HP) in an adult, previously misdiagnosed as COPD for 13 years due to severe emphysematous changes seen on imaging. He was also found to have acutely worsened disease as a result of Covid-19. CASE PRESENTATION: A 64-year-old male presented to the pulmonary clinic with dyspnea on minimal exertion. He reported respiratory complaints for 13 years, treated with 2 L/min of oxygen overnight, and budesonide-formoterol and tiotropium inhalers. These complaints were previously associated with brief occupational mold exposure and possible COPD. His respiratory distress worsened one year ago when he was hospitalized for Covid-19. On discharge, his oxygen requirement had increased to 6 L/min. CT chest showed air-trapping in the mid-zones bilaterally, mosaic attenuation, and peri-bronchial thickening. PFTs showed an FEV1 33% and FVC 55% of predicted, consistent with severe obstruction and reduction in lung volume. As the patient was a lifetime non-smoker, alternative diagnoses were pursued. Alpha-1 antitrypsin levels and immunologic testing, including scleroderma and myositis panels, were within normal limits. Positive findings included CCP IgG/IgA antibodies at 96 units and HP panel positive for pigeon serum antibodies. Prompted by this testing, the patient revealed that he had parakeets in his home for the past 15 years. He also reported significant symptom improvement on occasions that he took a course of steroids. Based on these findings, a diagnosis of chronic fibrotic hypersensitivity pneumonitis with bronchiolitis obliterans was considered. The patient's severe airflow obstruction and respiratory failure precluded surgical lung biopsy. Empiric management was initiated with 30 mg of prednisone daily with a slow taper and instruction to eliminate exposure to exotic birds. DISCUSSION: HP is commonly caused by inhalation of and sensitization to an aerosolized environmental antigen;a common subtype is bird fancier's lung due to repetitive exposure of avian antigen. Continuous antigen exposure increases the risk for development of fibrosis, which was also seen in our patient. The most commonly described radiologic findings in HP are ground-glass opacities, ill-defined centrilobular nodules, and focal areas of air trapping resulting in mosaic attenuation and fibrosis. More than 20% lymphocytosis on bronchoalveolar lavage is also a sensitive tool in detecting alveolitis. The relationship between Covid-19 and disease progression in HP is not well studied. CONCLUSIONS: Chronic hypersensitivity pneumonitis from avian antigens, or Bird fancier's lung, can present with severe emphysematous changes on CT imaging, along with obstructive pattern of PFTs. This should be an important differential, especially in patients who are non-smokers. Covid-19 causes disease progression in HP, this relationship needs to be further explored. Reference #1: Funke M., Fellrath J.-M. Hypersensitivity pneumonitis secondary to lovebirds: a new cause of bird fancier's disease. Eur. Respir. J. 2008;32:517–521. DOI: 10.1183/09031936.00108507 Reference #2: Pereira C., Gimenez A., Kuranishi L., Storrer K. Chronic hypersensitivity pneumonitis. J. Asthma Allergy. 2016;9:171–181. DOI: 10.2147/JAA.S81540 Reference #3: C.S. Glazer, C.S. Rose, D.A. Lynch Clinical and radiologic manifestations of hypersensitivity pneumonitis J. Thorac. Imag., 17 (4) (2002), pp. 261-272. DOI: 10.1097/00005382-200210000-00003 Morell F, Roger A, Reyes L, Cruz MJ, Murio C, Muñoz X Bird fancier's lung: a series of 86 patients. Medicine (Baltimore). 2008;87(2):110-130. DOI: 10.1097/MD.0b013e31816d1dda DISCLOSURES: No relevant relationships by Momina Amjad No relevant relationships by Amit Chopra No relevant relationships by Rafeh Safdar

4.
Chest ; 162(4):A1265, 2022.
Article in English | EMBASE | ID: covidwho-2060791

ABSTRACT

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

5.
Chest ; 162(4):A575, 2022.
Article in English | EMBASE | ID: covidwho-2060636

ABSTRACT

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

6.
Chest ; 162(4):A546-A547, 2022.
Article in English | EMBASE | ID: covidwho-2060624

ABSTRACT

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

7.
Mayo Clin Proc Innov Qual Outcomes ; 6(6): 511-524, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2031555

ABSTRACT

Objective: To assess the clinical and immunological benefits of passive immunization using convalescent plasma therapy (CPT). Materials and Methods: A series of subclass analyses were performed on the previously published outcome data and accompanying clinical metadata from a completed randomized controlled trial (RCT) (Clinical Trial Registry of India, number CTRI/2020/05/025209). The subclass analyses were performed on the outcome data and accompanying clinical metadata from a completed RCT (patient recruitment between May 15, 2020 and October 31, 2020). Data on the plasma abundance of a large panel of cytokines from the same cohort of patients were also used to characterize the heterogeneity of the putative anti-inflammatory function of convalescent plasma (CP) in addition to passively providing neutralizing antibodies. Results: Although the primary clinical outcomes were not significantly different in the RCT across all age groups, significant immediate mitigation of hypoxia, reduction in hospital stay, and significant survival benefit were registered in younger (<67 years in our cohort) patients with severe coronavirus disease 2019 and acute respiratory distress syndrome on receiving CPT. In addition to neutralizing the antibody content of CP, its anti-inflammatory proteome, by attenuation of the systemic cytokine deluge, significantly contributed to the clinical benefits of CPT. Conclusion: Subgroup analyses revealed that clinical benefits of CPT in severe coronavirus disease 2019 are linked to the anti-inflammatory protein content of CP apart from the anti-severe acute respiratory syndrome coronavirus 2 neutralizing antibody content.

8.
Journal of General Internal Medicine ; 37:S476-S477, 2022.
Article in English | EMBASE | ID: covidwho-1995788

ABSTRACT

CASE: A 58 year-old undomiciled man with no medical history presented with three days of anorexia, malaise, abdominal pain, and decreased urination. Exam was notable for scleral icterus. Lab-work revealed sodium 133 mEq/L, BUN 132mg/dL, creatinine 8.82 mg/dL, platelet 64 K/uL, total bilirubin 6.4 mg/dL, direct bilirubin 5 mg/dL. Lab-work two years prior was normal. HCV antibody was reactive, urinalysis revealed microscopic hematuria, and cocaine was detected on toxicology. Abdominopelvic CT, MRCP and renal sonogram were non-pathologic. On hospital day 5 his creatinine downtrended but total bilirubin continued to rise to a peak of 11.2 mg/dL and a leukocytosis without fever developed (peak 21.2 K/uL). Ceftriaxone was started empirically and a workup of blood cultures, viral serologies, ANA, alpha-1 antitrypsin, complement, cryoglobulin, ceruloplasmin level, microsomal, smooth muscle and antimitochondrial antibodies was normal. Review of his history suggested exposure to rodents as he slept close to a dumpster. Pending Leptospirosis serology, the antibiotics were adjusted to doxycycline. At discharge, the WBC and platelet counts normalized while the bilirubin and creatinine downtrended. IgM serology for leptospira later resulted positive. IMPACT/DISCUSSION: Leptospirosis is a worldwide zoonotic disease commonly associated with moist environments, poor housing and inadequate sanitation. Rodents are important reservoirs, shedding spirochetes through urine. Human infection results from exposure to animal urine, contaminated soil or water, or infected animal tissue. Portals of entry include cuts, mucous membranes or conjunctivae. Person-toperson transmission is rare. The incubation period is 5-14 days and illness severity ranges from subclinical to life-threatening. Disease manifestations include jaundice with acute kidney failure (Weil's disease), rash, conjunctival suffusion, hyponatremia, thrombocytopenia, microscopic hematuria, myocarditis, pulmonary hemorrhage, and meningitis. A biphasic illness, the acute febrile bacteremic phase can last 2-9 days followed by a period of apparent improvement. An “immune” phase then follows characterized by development of complications, as in our patient. During this phase, leptospires are absent from blood but may appear in the urine. While human cases of leptospirosis are rarely reported in the US outside of Puerto Rico and Hawaii (in the absence of travel), there was a significant rise reported to the NYC DOH in 2021. A potential explanation is an increase in housing insecurity and disruptions to waste management as a consequence of the COVID-19 pandemic. CONCLUSION: Leptospirosis is an important consideration in at-risk populations who may unknowingly be exposed due to living conditions. Our case of unexpected Weil's disease in an urban setting underscores the importance of a thorough social history as well as timely recognition of uncommon infections as possible reversible causes of multi- organ failure in the context of a changing world climate.

9.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-342167

ABSTRACT

Protein glycosylation is a complex and heterogeneous post-translational modification. Specifically, the human plasma proteome is rich in glycoproteins, and as protein glycosylation is frequently dysregulated in disease, glycoproteomics is considered an underexplored resource for biomarker discovery. Here, we present OxoScan-MS, a data-independent mass spectrometric acquisition technology and data analysis software that facilitates sensitive, fast, and cost-effective glycoproteome profiling of plasma and serum samples in large cohort studies. OxoScan-MS quantifies glycosylated peptide features by exploiting a scanning quadrupole to assign precursors to oxonium ions, glycopeptide-specific fragments. OxoScan-MS reaches a high level of sensitivity and selectivity in untargeted glycopeptide profiling, such that it can be efficiently used with fast microflow chromatography without a need for experimental enrichment of glycopeptides from neat plasma. We apply OxoScan-MS to profile the plasma glycoproteomic in an inpatient cohort hospitalised due to severe COVID-19, and obtain precise quantities for 1,002 glycopeptide features. We reveal that severe COVID-19 induces differential glycosylation in disease-relevant plasma glycoproteins, including IgA, fibrinogen and alpha-1-antitrypsin. Thus, with OxoScan-MS we present a strategy for quantitatively mapping glycoproteomes that scales to hundreds and thousands of samples, and report glycoproteomic changes in severe COVID-19.

10.
Infect Dis (Lond) ; 54(12): 846-851, 2022 12.
Article in English | MEDLINE | ID: covidwho-1984985

ABSTRACT

INTRODUCTION: Alpha 1 antitrypsin (A1AT) is the major human blood serine protease inhibitor. Transmembrane serine protease 2 (TMPRSS2), which is crucial for SARS-CoV-2 cell entry, is inhibited by A1AT. Therefore, we hypothesized that individuals with diminished levels of A1AT may be more prone to SARS-CoV-2 infection and severe COVID-19 disease. Our aim in this study was to evaluate the level of A1AT in hospitalized COVID-19 patients in comparison to hospitalized patients with non-COVID-19 pneumonia. METHODS: We conducted an observational prospective study between October 2020 and April 2021 in Rabin Medical Centre in Israel. A1AT levels were measured from the routine serum samples of hospitalized patients with COVID-19 and non-COVID-19 pneumonia (control group). The primary outcome was A1AT level, secondary outcomes were clinical outcomes and predictors of morality. RESULTS: Overall, 145 patients were included in the study, 98 in the COVID-19 group and 47 in the control group. The median A1AT level was 222 mg/dL (interquartile range (IQR) 188-269) and 258 mg/dL (IQR 210-281) in the COVID-19 and control groups, respectively (p = .045). Multivariate analysis for independent risk factors for mortality among COVID-19 patients showed that diabetes mellitus (p = .02), older age (p = .04), and high A1AT levels (p = .04) were all associated with increased mortality. CONCLUSION: Patients admitted due to severe COVID-19 had lower A1AT levels in comparison to patients admitted due to non-COVID pneumonia. This observation may suggest an association between mildly diminished A1AT and higher risk of SARS-CoV-2 infection with severe COVID-19 disease.


Subject(s)
COVID-19 , Pneumonia , alpha 1-Antitrypsin Deficiency , Humans , alpha 1-Antitrypsin , SARS-CoV-2 , Prospective Studies , Serine Proteinase Inhibitors , Serine Proteases
11.
Israel Medical Association Journal ; 24(7):441-443, 2022.
Article in English | EMBASE | ID: covidwho-1965529
12.
Acta Med Port ; 2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1955243

ABSTRACT

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.

13.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927711

ABSTRACT

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.

14.
Int J Gen Med ; 15: 5843-5848, 2022.
Article in English | MEDLINE | ID: covidwho-1917086

ABSTRACT

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.

15.
Journal of Cellular and Molecular Anesthesia ; 7(2):109-115, 2022.
Article in English | EMBASE | ID: covidwho-1897266

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) had a pandemic spread worldwide. Most infected patients had a good prognosis, but some developed severe illnesses, which led to fatalities. It is urgent to define markers that reveal the severity of the disease. This study aimed to introduce the main plasma protein biomarkers involved in severe conditions versus mild infection states. Materials and Methods: A total of 91 significant differentially expressed proteins (DEPs) in the sera of the patients with the severe condition versus mild states were extracted from an original article. The protein interaction is included in a network designed via STRING database and Cytoscape software to find the critical proteins which differentiate severe conditions versus mild states. Results: A total of 6 hub nodes identified as critical target proteins were: APOB, SERPINA1, CP, ORM1, HASPA8, and VW, according to the Degree value of nodes. Conclusion: The expression of different biomarkers in the sera of COVID-19 patients can be considered differential markers that separate severe conditions from mild states;however, a more thorough investigation is required.

16.
Med (N Y) ; 3(4): 233-248.e6, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1882364

ABSTRACT

Background: Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15). Methods: Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1ß, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints. Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1ß, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients. Conclusions: In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic. Funding: ECSA-2020-009; Elaine Galwey Research Bursary.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , alpha 1-Antitrypsin Deficiency , COVID-19/complications , Humans , Interleukin-10/therapeutic use , Interleukin-6/therapeutic use , Interleukin-8/therapeutic use , Respiratory Distress Syndrome/drug therapy , alpha 1-Antitrypsin/therapeutic use , alpha 1-Antitrypsin Deficiency/drug therapy
17.
Curr Issues Mol Biol ; 44(5): 2122-2138, 2022 May 10.
Article in English | MEDLINE | ID: covidwho-1869490

ABSTRACT

Neutrophils play a pathogenic role in COVID-19 by releasing Neutrophils Extracellular Traps (NETs) or human neutrophil elastase (HNE). Given that HNE is inhibited by α1-antitrypsin (AAT), we aimed to assess the content of HNE, α1-antitrypsin (AAT) and HNE-AAT complexes (the AAT/HNE balance) in 33 bronchoalveolar lavage fluid (BALf) samples from COVID-19 patients. These samples were submitted for Gel-Electrophoresis, Western Blot and ELISA, and proteins (bound to AAT or HNE) were identified by Liquid Chromatography-Mass Spectrometry. NETs' release was analyzed by confocal microscopy. Both HNE and AAT were clearly detectable in BALf at high levels. Contrary to what was previously observed in other settings, the formation of HNE-AAT complex was not detected in COVID-19. Rather, HNE was found to be bound to acute phase proteins, histones and C3. Due to the relevant role of NETs, we assessed the ability of free AAT to bind to histones. While confirming this binding, AAT was not able to inhibit NET formation. In conclusion, despite the finding of a high burden of free and bound HNE, the lack of the HNE-AAT inhibitory complex in COVID-19 BALf demonstrates that AAT is not able to block HNE activity. Furthermore, while binding to histones, AAT does not prevent NET formation nor their noxious activity.

18.
Chronic Obstr Pulm Dis ; 9(2): 266-273, 2022 Apr 29.
Article in English | MEDLINE | ID: covidwho-1856402

ABSTRACT

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.

19.
mBio ; 13(3): e0089222, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1832359

ABSTRACT

The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19. IMPORTANCE Identification of host factors affecting individual SARS-CoV-2 susceptibility will provide a better understanding of the large variations in disease severity and will identify potential factors that can be used, or targeted, in antiviral drug development. With the use of an advanced lung cell model established from several human donors, we identified cellular protease inhibitors, serpins, as host factors that restrict SARS-CoV-2 infection. The antiviral mechanism was found to be mediated by the inhibition of a serine protease, TMPRSS2, which results in a blockage of viral entry into target cells. Potential treatments with these serpins would not only reduce the overall viral burden in the patients, but also block the infection at an early time point, reducing the risk for the hyperactive immune response common in patients with severe COVID-19.


Subject(s)
Antiviral Agents , COVID-19 , Serine Proteinase Inhibitors , Serpins , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Plasminogen Activator Inhibitor 1 , SARS-CoV-2 , Serine Endopeptidases , Serine Proteinase Inhibitors/pharmacology , Serpin E2 , Serpins/genetics , Virus Internalization , alpha 1-Antitrypsin
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