COVID

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COVID AND CYSTIC FIBROSIS

Andrew G WeberAlice S ChauMikala EgebladBetsy J BarnesTobias JanowitzNebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: A case series. medRxiv 2020 May 15;2020.05.13.20087734.doi: 10.1101/2020.05.13.20087734. Preprint  Free article [Pubmed]

Andrew Weber

Following nebulized in-line administration of dornase alfa with albuterol, the fraction of inspired oxygen requirements was reduced for all five patients. All patients remain alive and two patients have been discharged from the intensive care unit. No drug associated toxicities were identified
Conclusions. The results presented in this case series suggest that dornase alfa will be well-tolerated by critically ill patients with COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and two have recently been registered (NCT04359654 and NCT04355364). With this case series, we hope to contribute to the development of management approaches for critically ill patients with COVID-19.

See also.[Pubmed] for more detail

Dr Andrew G Weber is a Pulmonology and Critical Care Fellow in the Division of Pulmonary, Critical Care, and Sleep Medicine

Rebecca CosgriffSusannah AhernScott C BellKeith BrownleePierre-Régis BurgelCass ByrnesHarriet CorvolStephanie Y ChengAlexander ElbertAlbert FaroChristopher H GossVincent GulmansBruce C MarshallEdward McKonePeter G MiddletonRasa RuseckaiteAnne L StephensonSiobhán B Carr. A multinational report to characterise SARS-CoV-2 infection in people with cystic fibrosis. J Cyst Fibros 2020 May;19(3):355-358.doi: 10.1016/j.jcf.2020.04.012. Epub 2020 Apr 25.  Free PMC article[Pubmed]

Rebecca Cosgriff

Information is lacking on the clinical impact of the novel coronavirus, SARS-CoV-2, on people with cystic fibrosis (CF). Our aim was to characterise SARS-CoV-2 infection in people with cystic fibrosis.  Methods: Anonymised data submitted by each participating country to their National CF Registry was reported using a standardised template, then collated and summarised.
Results: 40 cases have been reported across 8 countries. Of the 40 cases, 31 (78%) were symptomatic for SARS-CoV-2 at presentation, with 24 (60%) having a fever. 70% have recovered, 30% remain unresolved at time of reporting, and no deaths have been submitted.
Conclusions: This early report shows good recovery from SARS-CoV-2 in this heterogeneous CF cohort. The disease course does not seem to differ from the general population, but the current numbers are too small to draw firm conclusions and

Rebecca Cosgriff is Director of Data & Quality Improvement at the Cystic Fibrosis Trust, London

Bruce A StantonThomas H HamptonAlix Ashare. SARS-CoV-2 (COVID-19) and cystic fibrosisAm J Physiol Lung Cell Mol Physiol  2020 Sep 1;319(3):L408-L415.doi: 10.1152/ajplung.00225.2020. Epub 2020 Jul 15.  [Pubmed]

     Bruce Stanton

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene. Although viral respiratory tract infections are, in general, more severe in patients with CF compared with the general population, a small number of studies indicate that SARS-CoV-2 does not cause a worse infection in CF. This is surprising since comorbidities including pre-existing lung disease have been reported to be associated with worse outcomes in SARS-CoV-2 infections.
Several recent studies provide insight into why SARS-CoV-2 may not produce more severe outcomes in CF. First, ACE and ACE2, genes that play key roles in SARS-CoV-2 infection, have some variants that are predicted to reduce the severity of SARS-CoV-2 infection. Second, mRNA for ACE2 is elevated and mRNA for TMPRSS2, a serine protease, is decreased in CF airway epithelial cells. Increased ACE2 is predicted to enhance SARS-CoV-2 binding to cells but would increase conversion of angiotensin II, which is proinflammatory, to angiotensin-1-7, which is anti-inflammatory. Thus, increased ACE2 would reduce inflammation and lung damage due to SARS-CoV-2. Moreover, decreased TMPRSS2 would reduce SARS-CoV-2 entry into airway epithelial cells. Second, many CF patients are treated with azithromycin, which suppresses viral infection and lung inflammation and inhibits the activity of furin, a serine protease. Finally, the CF lung contains high levels of serine protease inhibitors including ecotin and SERPINB1, which are predicted to reduce the ability of TMPRSS2 to facilitate SARS-CoV-2 entry into airway epithelial cells. Thus, a variety of factors may mitigate the severity of SARS-CoV-2 in C
Dr Bruce A Stanton is Professor in the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

Daniel PeckhamMichael F McDermottSinisa SavicAnil Mehta COVID-19 meets Cystic Fibrosis: for better or worse? Genes Immun 2020 Aug;21(4):260-262.doi: 10.1038/s41435-020-0103-y.Epub 2020 Jul 1. [Pubmed]

Daniel Peckham

Cystic fibrosis (CF) is one of the most common autosomal recessive life-limiting conditions affecting Caucasians. The resulting defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) results in defective chloride and bicarbonate secretion, as well as dysregulation of epithelial sodium channels (ENaC). These changes bring about defective mucociliary clearance, reduced airway surface liquid and an exaggerated proinflammatory response driven, in part, by infection. In this short article we explore the overlap in the pathophysiology of CF and COVID-19 infection and discuss how understanding the interaction between both diseases may shed light on future treatments.

Daniel Peckham is Professor at the Leeds Institute of Medical Research at St James’s, University of Leeds, Leeds, UK.

Valentino Bezzerri , Francesca Lucca Sonia Volpi Marco Cipolli  Does cystic fibrosis constitute an advantage in COVID-19 infection?  Ital J Pediatr  2020 Oct 6;46(1):143.doi: 10.1186/s13052-020-00909-1. Free [Pubmed]

Valentino Bezzerri

Veneto region is one of the most affected Italian regions by COVID-19. Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), may constitute a risk factor in COVID-19. Moreover, respiratory viruses were generally associated with severe pulmonary impairment in cystic fibrosis (CF). We would have therefore expected numerous cases of severe COVID-19 among the CF population. Surprisingly, we found that CF patients were significantly protected against infection by SARS-CoV-2. We discussed this aspect formulating some reasonable theories.

 Demographic and Epidemiologic Data from the Veneto Region

Condition Population Mean (years) Tested subjects (% of regional population) COVID-19 cases Rate of infection (% of regional population) COVID-19 fatalities CFR
General population 4,907,704a 45,4 465,433 (9.5%) 19,729 0.40% 2062 10.4%
CF population 532 27,5 118 (22.2%) 1 0.19% 0

 Dr Valentino Bezzerri is head of pre-clinical research Lab presso Ospedali Riuniti,  AnconaHead of preclinical research, Laboratory of Cystic Fibrosis and Shwachman-Diamond syndrome at Cystic Fibrosis Center

Colombo C, Burgel PR, Gartner S, van Konigbruggen-Rietschel S, Noehrlich L, Seet-Gaudelus I, Southern KW. Impact of COVID-19 on people with cystic fibrosis. Lancet Respir Med. 2020;8(5):e35e36. doi:10.1016/S2213-2600(20)30177-6  [Pubmed]   Free PMC article                                                                    

     Carla Colombo

Carla Colombo and colleagues briefly review certain aspects of the coronavirus pandemic as it affects people with CF.  In Lombardy there have been only 10 people with CF out of total of 42,161 infected patients. They usually acquired the infection from family members. Similar experience came from UK, Germany and Spain with no serious impact on their CF disease severity of patients. The ECFS Registry is collecting data. Features of COVID-19 are clearly differentiated from those of cystic fibrosis. Requirement for availability of medication, foods are required for affected patients. No new clinical trials are starting and support is given to subjects with CF on current trials.

The article concludes  “People with cystic fibrosis and their families have invested considerable time and energy to maintain good health and, now, on the cusp of remarkable new therapies to transform their condition, they face a global pandemic, the effect of which is unclear. Early data suggest that most patients with cystic fibrosis are doing an exceptional job avoiding SARS-CoV-19 infection, but they must remain dedicated to this task, as data are gathered from across Europe to better understand factors that affect the severity of COVID-19 in people with cystic fibrosis.

Prof. Carla Colombo is at the Cystic Fibrosis Regional Reference Center, University of Milan and the Department of Pathophysiology and Transplantation, Milan, Italy

Janusz Marcinkiewicz Henryk MazurekGrzegorz MajkaBenjamin Chain.  Are patients with lung cystic fibrosis at increased risk for severe and fatal COVID-19? Interleukin-6 as a predictor of COVID-19 outcome. Pol Arch Intern Med    2020 Oct 5.doi: 10.20452/pamw.15630. Online ahead of print.[Pubmed]Free article

Janusz Marcinkiewicz

Sars-CoV-2 (severe acute respiratory syndrome coronavirus) primarily targets the lungs resulting in pneumonia and acute respiratory distress syndrome (ARDS). Therefore, it is more likely to develop severe symptoms if patients have pre-existing lung problems Surprisingly, recent epidemiological data show that comorbid chronic respiratory conditions are not major risk factors in patients with COVID-19. An interesting example is cystic fibrosis (CF) where there is emerging evidence that severity of Sars-CoV-2 infection is milder than predicted, even though CF is frequently associated with diabetes, a strong predictor of severe Sars-CoV- 2 disease.[2] Furthermore, CF patients are at enhanced risk of severe infection with other respiratory viruses. Influenza viruses, the H1N1 pandemic in particular, have been shown to cause disease progression in CF lung disease. Therefore, many countries have categorised people with CF as highly vulnerable to COVID-19 infections and have advised them to stay at home to minimise the risk of contracting the virus.[3] The fatal outcome of COVID-19 is associated with cytokine storm and ARDS. Interleukin-6 (IL-6) is considered to be the key cytokine in pathogenesis of cytokine storm. Remarkably, IL-6 is the most frequently reported cytokine to be increased in severe COVID-19 and IL-6 elevated levels have been associated with higher mortality.[4]

We propose that constitutively low levels of IL-6 present in the inflamed airway tract of CF patients may contribute to inhibiting the cytokine storm associated with severe Sars-CoV-2 and hence limit the severity of the infection in these individuals. We investigated a group of 39 patients with advanced CF lung disease and confirmed chronic P. aeruginosa infection, and found that their sputa contained an unusual combination of high levels of pro- inflammatory IL-8 (median of 1178 pg/ml), associated with extremely low levels of the pro- inflammatory cytokine IL-6 (median of 243 pg/ml) and the anti-inflammatory cytokine IL-10 (median of 196 pg/ml) in sputum. Low sputum IL-6 levels were also associated with high TNF-alpha in an independent study of CF patients Importantly, IL-6 suppression was localised to sputum measurements, while systemic IL-6 production was normal.[5] This phenomenon is not observed in other chronic inflammatory lung diseases.

The mechanism of suppressed IL-6 production in airways of CF patients is unresolved. However, these observations have important implications for treatment of Sars-CoV-2. The association between localised suppression of IL-6 in the airways of CF patients and decreased Sars-CoV-2 morbidity provide strong support for targeting IL-6 production or IL-6 receptor blockade in COVID-19 patients. Furthermore, the localized cytokine imbalance in CF patients highlight the importance of monitoring local (sputum) cytokine levels during any therapeutic intervention.

Professor Janusz Marcinkiewicz is at Jagiellonian University Medical College, Faculty of Medicine, Chair of Immunology, Kraków, Poland.

Alexander MoellerLeo Thanikkel Liesbeth Duijts Erol A Gaillard Luis Garcia-Marcos Ahmad KantarNathalie TabinSteven TurnerAngela ZacharasiewiczMariëlle W H Pijnenburg.  COVID-19 in children with underlying chronic respiratory diseases: survey results from 174 centres.  ERJ Open Res   2020 Oct 26;6(4):00409-2020.doi: 10.1183/23120541.00409-2020.eCollection 2020 Oct. Free PMC article [Pubmed]

Alexander Moeller

Early reports suggest that most children infected with severe acute respiratory syndrome coronavirus 2 (“SARS-CoV-2”) have mild symptoms. What is not known is whether children with chronic respiratory illnesses have exacerbations associated with SARS-CoV-2 virus.
Methods: An expert panel created a survey, which was circulated twice (in April and May 2020) to members of the Paediatric Assembly of the European Respiratory Society (ERS) and via the social media of the ERS. The survey stratified patients by the following conditions: asthma, cystic fibrosis (CF), bronchopulmonary dysplasia (BPD) and other respiratory conditions.
Results: In total 174 centres responded to at least one survey. 80 centres reported no cases, whereas 94 entered data from 945 children with coronavirus disease 2019 (COVID-19). SARS-CoV-2 was isolated from 49 children with asthma of whom 29 required no treatment, 19 needed supplemental oxygen and four children required mechanical ventilation. Of the 14 children with CF and COVID-19, 10 required no treatment and four had only minor symptoms. Among the nine children with BPD and COVID-19, two required no treatment, five required inpatient care and oxygen and two were admitted to a paediatric intensive care unit (PICU) requiring invasive ventilation. Data were available from 33 children with other conditions and SARS-CoV-2 of whom 20 required supplemental oxygen and 11 needed noninvasive or invasive ventilation.
Conclusions: Within the participating centres, in children with asthma and CF, infection with SARS-CoV-2 was well tolerated, but a substantial minority of children with BPD and other conditions required ventilatory support indicating that these latter groups are at risk from SARS-CoV-2 infection.

Alexander Moeller is Professor and Head of Department, Division of Respiratory Medicine and Childhood Research Center, University Children’s Hospital Zurich,

Elliot McClenaghanRebecca CosgriffKeith BrownleeSusannah AhernPierre-Régis BurgelCatherine A Byrnes et al. The global impact of SARS-CoV-2 in 181 people with cystic fibrosis. J Cyst Fibros  2020 Nov;19(6):868-871.doi: 10.1016/j.jcf.2020.10.003. Epub 2020 Nov 4. [Pubmed]

Elliot McClenaghan

With the growing SARS-CoV-2 pandemic, we need to better understand its impact in specific patient groups like those with Cystic Fibrosis (CF). We report on 181 people with CF (32 post-transplant) from 19 countries diagnosed with SARS-CoV-2 prior to 13 June 2020. Infection with SARS-CoV-2 appears to exhibit a similar spectrum of outcomes to that seen in the general population, with 11 people admitted to intensive care (7 post-transplant), and 7 deaths (3 post-transplant). A more severe clinical course may be associated with older age, CF-related diabetes, lower lung function in the year prior to infection, and having received an organ transplant. Whilst outcomes in this large cohort are better than initially feared overall, possibly due to a protective effect of the relatively younger age of the CF population compared to other chronic conditions, SARS-CoV-2 is not a benign disease for all people in this patient group.

Elliot McClenaghan is a medical statistician at the UK Cystic Fibrosis Trust, London

 

Gennaro GiustinoLori B CroftGiulio G StefaniniRenato BragatoJeffrey J SilbigerMarco Vicenzi et al et al.. Characterization of Myocardial Injury in Patients With COVID-19. J Am Coll Cardiol 2020 Nov 3;76(18):2043-2055.dog: 10.1016/j.jacc.2020.08.069.     Free PMC article [Pubmed]

Gennaro Giustino

Background: Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis. However, the mechanisms of myocardial injury remain unclear and prior studies have not reported cardiovascular imaging data.    Objectives: This study sought to characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in patients with COVID-19.
Methods: We conducted an international, multicenter cohort study including 7 hospitals in New York City and Milan of hospitalized patients with laboratory-confirmed COVID-19 who had undergone transthoracic echocardiographic (TTE) and electrocardiographic evaluation during their index hospitalization. Myocardial injury was defined as any elevation in cardiac troponin at the time of clinical presentation or during the hospitalization.
Results: A total of 305 patients were included. Mean age was 63 years and 205 patients (67.2%) were male. Overall, myocardial injury was observed in 190 patients (62.3%). Compared with patients without myocardial injury, those with myocardial injury had more electrocardiographic abnormalities, higher inflammatory biomarkers and an increased prevalence of major echocardiographic abnormalities that included left ventricular wall motion abnormalities, global left ventricular dysfunction, left ventricular diastolic dysfunction grade II or III, right ventricular dysfunction and pericardial effusions. Rates of in-hospital mortality were 5.2%, 18.6%, and 31.7% in patients without myocardial injury, with myocardial injury without TTE abnormalities, and with myocardial injury and TTE abnormalities. Following multivariable adjustment, myocardial injury with TTE abnormalities was associated with higher risk of death but not myocardial injury without TTE abnormalities.
Conclusions: Among patients with COVID-19 who underwent TTE, cardiac structural abnormalities were present in nearly two-thirds of patients with myocardial injury. Myocardial injury was associated with increased in-hospital mortality particularly if echocardiographic abnormalities were present.

Gennaro Giustino is Cardiology Fellow at The Zena and Michael A. Wiener Cardiovascular Institute, The Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York City,

Jonathan Messika et al, and the  French Group of Lung Transplantation.  COVID-19 in Lung Transplant Recipients.  Transplantation 2021 Jan 1;105(1):177-186.doi: 10.1097/TP.0000000000003508  [Pubmed]

Jonathan Messika

Background: A concern about the susceptibility of immunocompromised patients to the worldwide pandemic of coronavirus disease 2019 (COVID-19) has been raised. We aimed at describing COVID-19 infections in the French cohort of lung transplant (LT) patients.
Methods: Multicenter nationwide cohort study of all LT recipients with COVID-19 diagnosed from March 1 to May 19, 2020. Recipient main characteristics and their management were retrieved. Hospitalization characteristics, occurrence of complications and survival were analyzed.
Results: Thirty-five LT patients with a COVID-19 infection were included. Median age was 50.4 (40.6-62.9) years, 16 (45.7%) were female, and 80% were double-LT recipients. Infection was community-acquired in 25 (71.4%). Thirty-one (88.6% required hospitalization, including 13 (41.9%) in the intensive care unit. The main symptoms of COVID-19 were fever, cough, and diarrhoea, present in 71.4%, 54.3%, and 31.4% of cases, respectively. Extension of pneumonia on chest CT was moderate to severe in 51.4% of cases. Among the 13 critically ill patients, 7 (53.9%) received invasive mechanical ventilation. Thrombotic events occurred in 4 patients. Overall survival rate was 85.7% after a median follow-up of 50 days (41.0-56.5). Four of 5 nonsurvivors had had bronchial complications or intensification of immunosuppression in the previous weeks. On univariate analysis, overweight was significantly associated with risk of death (odds ratio, 16.0; 95% confidence interval, 1.5-170.6; P = 0.02).
Conclusions: For the 35 LT recipients with COVID-19, the presentation was severe, requiring hospitalization in most cases, with a survival rate of 85.7%.

Jonathan Messika of the Hôpital Bichat-Claude Bernard, Service de Pneumologie B et Transplantation Pulmonaire, APHP.Nord-Université de Paris, Paris, France.   Physiopathology and Epidemiology of Respiratory Diseases, UMR1152 INSERM and Université de Paris, Paris, France. Paris Transplant Group, Paris, France.

See also.[Pubmed] for more detail

Dr Andrew G Weber is a Pulmonology and Critical Care Fellow in the Division of Pulmonary, Critical Care, and Sleep Medicine

Robert BainRebecca CosgriffMarco ZampoliAlexander ElbertPierre-Régis BurgelSiobhán B Carr Claudio CastañosCarla ColomboHarriet CorvolAlbert FaroChristopher H Goss  et al (19 others).  Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study. J Cyst Fibros. 2020 Dec 3;S1569-1993(20)30931-0.doi: 10.1016/j.jcf.2020.11.021.Online ahead of print. Free PMC article [Pubmed]
The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams.
Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020.
Results: Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6-15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79-104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease.
Conclusions: SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease

Robert Bain is in the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.

– Reassuring data from many countries confirming the impression that SARS-CoV-2 is usually a relatively mild illness in CF children.

Andrea LombardiElena TrombettaAlessandra CattaneoValeria CastelliEmanuele PalombaMario Tirone, et al. Early Phases of COVID-19 Are Characterized by a Reduction in Lymphocyte Populations and the Presence of Atypical Monocytes. Front Immunol 2020 Dec 9;11:560330. doi: 10.3389/fimmu.2020.560330. eCollection 2020.[Pubmed]

Andrea Lombardi

Background: Severe acute respiratory syndrome coronavirus 2 is a recently discovered pathogen responsible of coronavirus disease 2019 (COVID-19). The immunological changes associated with this infection are largely unknown.
Methods: We evaluated the peripheral blood mononuclear cells profile of 63 patients with COVID-19 at diagnosis. We also assessed the presence of association with inflammatory biomarkers and the 28-day mortality.
Results: Lymphocytopenia was present in 51 of 63 (80.9%) patients, with a median value of 720 lymphocytes/µl (IQR 520-1,135). This reduction was mirrored also on CD8+ (128 cells/µl, IQR 55-215), natural killer (67 cells/µl, IQR 35-158) and natural killer T (31 cells/µl, IQR 11-78) cells. Monocytes were preserved in total number but displayed among them a subpopulation with a higher forward and side scatter properties, composed mainly of cells with a reduced expression of both CD14 and HLA-DR. Patients who died in the 28 days from admission (N=10, 15.9%), when compared to those who did not, displayed lower mean values of CD3+ (337.4 cells/µl vs 585.9 cells/µl; p=0.028) and CD4+ cells (232.2 cells/µl vs 381.1 cells/µl; p=0.042) and an higher percentage of CD8+/CD38+/HLA-DR+ lymphocytes (13.5% vs 7.6%; p=0.026).
Discussion: The early phases of COVID-19 are characterized by lymphocytopenia, predominance of Th2-like lymphocytes and monocytes with altered immune profile, which include atypical mononuclear cells.

Dr Andrea Lombardi is Director of Medicine at the  Infectious Diseases Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy.

Hung-Hsin ChenDouglas M ShawLauren E PettyMisa GraffRyan J BohlenderHannah G Polikowsky, et al.  Host genetic effects in pneumonia.   Am J Hum Genet 2020 Dec 13;S0002-9297(20)30446-8.doi: 10.1016/j.ajhg.2020.12.010.Online ahead of print.      [Pubmed]

Hung-Hsin Chen

Given the coronavirus disease 2019 (COVID-19) pandemic, investigations into host susceptibility to infectious diseases and downstream sequelae have never been more relevant. Pneumonia is a common complication of infectious diseases, including COVID-19. Few genome-wide association studies (GWASs) of host susceptibility and severity of pneumonia have been conducted.
We performed GWASs of pneumonia susceptibility and severity in the Vanderbilt University biobank (BioVU) with linked electronic health records (EHRs), including Illumina Expanded Multi-Ethnic Global Array (MEGAEX)-genotyped European ancestry (EA, n= 69,819) and African ancestry (AA, n = 15,603) individuals. Two regions of large effect were identified: the CFTR locus in EA (rs113827944; OR = 1.84, p value = 1.2 × 10-36) and HBB in AA (rs334 [p.Glu7Val]; OR = 1.63, p value = 3.5 × 10-13).
Mutations in these genes cause cystic fibrosis (CF) and sickle cell disease (SCD), respectively. After removing individuals diagnosed with CF and SCD, we assessed heterozygosity effects at our lead variants.
Further GWASs after removing individuals with CF uncovered an additional association in R3HCC1L (rs10786398; OR = 1.22, p value = 3.5 × 10-8), which was replicated in two independent datasets: UK Biobank (n = 459,741) and 7,985 non-overlapping BioVU subjects, who are genotyped on arrays other than MEGAEX. This variant was also validated in GWASs of COVID-19 hospitalization and lung function. Our results highlight the importance of the host genome in infectious disease susceptibility and severity and offer crucial insight into genetic effects that could potentially influence severity of COVID-19 sequelae.

Hung-Hsin Chen  is Post Doctoral Fellow at the Vanderbilt Genetics Institute and Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Weber AG, Chau AS, Egeblad M, Barnes BJ, Janowitz T.  Nebulized in-line endotracheal dornase alfa and albuterol administered to mechanically ventilated COVID-19 patients: A case series.  medRxiv. 2020 May 15:2020.05.13.20087734. doi: 10.1101/2020.05.13.20087734. Preprint. Free PMC article.[Pubmed]

Andrew Weber

Following nebulized in-line administration of dornase alfa with albuterol, the fraction of inspired oxygen requirements was reduced for all five patients. All patients remain alive and two patients have been discharged from the intensive care unit. No drug associated toxicities were identified.
The results presented in this case series suggest that dornase alfa will be well-tolerated by critically ill patients with COVID-19. Clinical trials are required to formally test the dosing, safety, and efficacy of dornase alfa in COVID-19, and two have recently been registered ( NCT04359654 and NCT04355364 ). With this case series, we hope to contribute to the development of management approaches for critically ill patients with COVID-19

Morlacchi LC, Rossetti V, Gigli L, Amati F, Rosso L, Aliberti S, Nosotti M, Blasi F. COVID-19 In Lung Transplant Recipients: A Case Series From Milan, Italy. Transpl Infect Dis. 2020 Jun 8:e13356. doi: 10.1111/tid.13356. Online ahead of print. [Pubmed]

        Letzia Morlacchi

Limited data is currently available regarding the course of COVID-19 in lung and solid organ transplant recipients. We hereby present 4 cases of SARS-CoV-2 pneumonia in lung transplant recipients from our centre, set in Milan, Italy. We reduced immunosuppressive regimen in all these patients, typically holding the antiproliferative agent and augmenting steroids; everybody received hydroxychloroquine, initial empiric antibiotic treatment with piperacillin/tazobactam and high dose low molecular weight heparin. Clinical course seemed favourable in three of our patients, but one of them deteriorated after 10 days of hospitalization, probably due to an acute form of graft dysfunction triggered both by COVID19 and a nosocomial bacterial infection, and eventually died. Although short-term prognosis could be considered benign in the majority of our patients, we should carefully monitor these individuals in order to detect early sign of clinical deterioration and graft dysfunction in the next few months.

Dr Letizia Corrina Morlacchi of the Respiratory Unit and Adult Cystic, Fibrosis Centre, Internal Medicine Dept, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano; and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.

Dr Andrew G Weber of the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Northwell Health, NY.

Jordan B Dennis Andrew M Jones Emma A Davies William Welfare Peter J Barry Lisa Collier Andrew Turner Rowland J Bright-Thomas.   Influenza B Outbreak at an Adult Cystic Fibrosis Centre – Clinical Impact and Factors Influencing Spread.  J Cyst Fibros  2020 Jun 19;S1569-1993(20)30124-7. doi: 10.1016/j.jcf.2020.04.011.Online ahead of print. [Pubmed]
An outbreak of Influenza B occurred at a large United Kingdom (UK) regional adult cystic fibrosis (CF) centre in May 2016. This was late in the UK 2015-2016 influenza season and occurred on a specialist ward with strict infection control procedures. This study investigates the spread of influenza, clinical consequences and potential contributing factors.
10 of 21 inpatients developed influenza B between 5th and 12th May 2016, an attack rate of 48%. All those characterised were confirmed as the same strain of influenza B/Victoria-lineage. Influenza infection resulted in a mean FEV1 reduction of 10.5% (SD 11.3, p = 0.012), which persisted at 3 months post infection (p = 0.003). Nine of the affected cases rooms were in close proximity on the ward while patients in the two isolation rooms with enhanced ventilation did not become infected. Ventilation measurements in affected rooms ranged from 1.75 to 2.10 air changes/hour, below national recommendations. Seventy percent of affected inpatients had received the 2015/16 trivalent seasonal influenza vaccine, which did not contain a B/Victoria-lineage influenza B virus.

The authors concluded this influenza B outbreak in CF adults had a high attack rate and a significant clinical impact. Room ventilation and a limited protection from the seasonal influenza vaccine were possible contributory factors.

Jordan B Dennis  is at the Manchester Adult Cystic Fibrosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester.

Oliver J McElvaneyEoin O’ConnorNatalie L McEvoyDaniel D FraughanJennifer ClarkeOisín F McElvaneyCedric GunaratnamJames O’RourkeGerard F CurleyNoel G McElvaney.   Alpha-1 antitrypsin for cystic fibrosis complicated by severe cytokinemic COVID-19J Cyst Fibros 2020 Nov 20;S1569-1993(20)30915-2.doi: 10.1016/j.jcf.2020.11.012.Online ahead of print. [Pubmed]

    Oliver McElvaney

Background: The clinical course of severe COVID-19 in cystic fibrosis (CF) is incompletely understood. We describe the use of alpha-1 antitrypsin (AAT) as a salvage therapy in a critically unwell patient with CF (PWCF) who developed COVID-19 while awaiting lung transplantation.
Methods: IV AAT was administered at 120 mg/kg/week for 4 consecutive weeks. Levels of interleukin (IL)-1β, IL-6, IL-8, and soluble TNF receptor 1 (sTNFR1) were assessed at regular intervals in plasma, with IL-1β, IL-6, IL-8 and neutrophil elastase (NE) activity measured in airway secretions. Levels were compared to baseline and historic severe exacerbation measurements.
Results: Systemic and airway inflammatory markers were increased compared to both prior exacerbation and baseline levels, in particular IL-6, IL-1β and NE activity. Following each AAT dose, rapid decreases in each inflammatory parameter were observed. These were matched by marked clinical and radiographic improvement.
Conclusions: The results support further investigation of AAT as a COVID-19 therapeutic, and re-exploration of its use in CF.

Dr Oliver J McElvaney is pulmonary/critical care physician in the Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; Beaumont Hospital, Dublin, Ireland.

Ida MartinelliAlessandro CiavarellaMaria AbbattistaStefano AlibertiValentina De ZanChristian FolliMauro Panigada  Andrea Gori Andrea ArtoniAnna Maria IerardiGianpaolo Carrafiello  Valter MonzaniGiacomo Grasselli  Francesco Blasi Flora PeyvandiIncreasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19. Intern Emerg Med 2021 Jan 3. doi: 10.1007/s11739-020-02585-9. Online ahead of print. [Pubmed]

Ida Martinelli

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleedi

Ida Martinelli  is at the A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy

Berardis S, Verroken A, Vetillart A, Struyf C, Gilbert M, Gruson D, Gohy S. SARS-CoV-2 seroprevalence in a Belgian cohort of patients with cystic fibrosis  J Cyst Fibros. 2020 Nov;19(6):872-874. doi: 10.1016/j.jcf.2020.08.005. Epub 2020 Aug 11   Free PMC article.[Pubmed]
In Belgium, COVID-19 epidemy began on February 4, 2020 with a peak on April 10, 2020. Patients with cystic fibrosis (CF) followed in the Cliniques universitaires Saint-Luc were rapidly isolated before the government lockdown.
After the peak of the epidemy, we measured anti-SARS-CoV-2 IgM and IgG antibodies in 149 patients and collected clinical data.
Only 3 asymptomatic patients presented IgG against the virus. In one patient hospitalized for COVID-19 (positive molecular testing), we did not detect any anti-SARS-CoV-2 antibodies, as in thirty-five other symptomatic patients considered as possible cases.
Conclusions: Even if respiratory symptoms linked to CF are frequent and compatible with COVID-19, anti-SARS-CoV-2 IgG antibodies were detected only in 3 asymptomatic patients. This reassuring study concerning the risk of COVID-19 in patients with CF illustrates the difficulty to distinguish COVID-19 symptoms from respiratory exacerbations and the need of generalized molecular testing to make a precise diagnosis.

Dr Silvia Berardis is at the Centre de référence pour la mucoviscidose, Cliniques universitaires Saint-Luc, Brussels, Belgium; Department of Pediatrics, Cliniques universitaires Saint-Luc, Brussels, Belgium.

Joris R DelangheMarc L De BuyzereMarijn M Speeckaert Genetic Polymorphisms in the Host and COVID-19 Infection. Adv Exp Med Biol 2021;1318:109-118.doi: 10.1007/978-3-030-63761-3_7.  [Pubmed]

      Joris Delange

The outbreak of the COVID-19 pandemic shows a marked geographical variation in its prevalence and mortality. The question arises if the host genetic variation may (partly) affect the prevalence and mortality of COVID-19. We postulated that the geographical variation of human polymorphisms might partly explain the variable prevalence of the infection. We investigated some candidate genes that have the potential to play a role in the immune defense against COVID-19: complement component 3 (C3), galactoside 2-alpha-L-fucosyltransferase 2 (FUT2), haptoglobin (Hp), vitamin D binding protein (DBP), human homeostatic iron regulator protein (HFE), cystic fibrosis transmembrane conductance regulator (CFTR), and angiotensin-converting enzyme 1 (ACE1). In a univariate approach, ACE1 D/I, C3, CFTR, and HFE polymorphisms correlated significantly with COVID-19 prevalence/mortality, whereas Hp and FUT2 polymorphism did not show any significant correlations. In a multivariate analysis, only ACE1 D/I and C3 polymorphisms were determinants for COVID-19 prevalence/mortality. The other polymorphisms (CFTR, DBP, FUT2, HFE, and Hp) did not correlate with COVID-19 prevalence/mortality. Whereas ACE1 D/I polymorphism shows functional links with ACE2 (which is the receptor for the virus) in COVID-19, C3 can act as a critical step in the virus-induced inflammation. Our findings plead against a bystander role of the polymorphisms as a marker for historical migrations, which comigrate with causal genes involved in COVID-19 infection. Further studies are required to assess the clinical outcome of COVID-19 in C3S and ACE1 D allele carriers and to study the role of C3 and ACE1 D/I polymorphisms in COVID-19 and their potential effects on treatment response.

 Joris R Delanghe is professor in the Department of Diagnostic Sciences, Ghent University, Ghent, Belgium. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Ghent, Belgium

Margherita BaldassarriFrancesca Fava Chiara FalleriniSergio Daga Elisa Benetti Kristina Zguroet al.  On Behalf Of The Gen-Covid Multicenter StudySevere COVID-19 in Hospitalized Carriers of Single CFTRPathogenic VariantsJ Pers Med. 2021 Jun 15;11(6):558.doi: 10.3390/jpm11060558. Free PMC article [Pubmed]
The clinical presentation of COVID-19 is extremely heterogeneous, ranging from asymptomatic to severely ill patients. Thus, host genetic factors may be involved in determining disease presentation and progression. Given that carriers of single cystic fibrosis (CF)-causing variants of the CFTR gene-CF-carriers-are more susceptible to respiratory tract infections, our aim was to determine their likelihood of undergoing severe COVID-19. We implemented a cohort study of 874 individuals diagnosed with C https://www.google.com/OVID-19, during the first pandemic wave in Italy. Whole exome sequencing was performed and validated CF-causing variants were identified. Forty subjects (16 females and 24 males) were found to be CF-carriers. Among mechanically ventilated patients, CF-carriers were more represented (8.7%) and they were significantly (p < 0.05) younger (mean age 51 years) compared to noncarriers (mean age 61.42 years). Furthermore, in the whole cohort, the age of male CF-carriers was lower, compared to noncarriers (p < 0.05). CF-carriers had a relative risk of presenting an abnormal inflammatory response (CRP ≥ 20 mg/dL) of 1.69 (p < 0.05) and their hazard ratio of death at day 14 was 3.10 (p < 0.05) in a multivariate regression model, adjusted for age, sex and comorbidities. In conclusion, CF-carriers are more susceptible to the severe form of COVID-19, showing also higher risk of 14-day death.

Dr Margherita Baldassarri is in the Department of Medical Genetics, University of Siena, 53100 Siena, Italy.  Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.

Yousaf B HadiDhairya A Lakhani Syeda F NaqviNida Ul FatimaArif R Sarwari.     Outcomes of SARS-CoV-2 infection in patients with cystic fibrosis: A multicenter retrospective research network study. Respir Med 2021 Sep 8;188:106606.doi: 10.1016/j.rmed.2021.106606. Online ahead of print. Free PMC article [Pubmed]

  Yousaf Hadi

Background: In this study, we report clinical outcomes in COVID-19 infection in a large cohort of people with cystic fibrosis (pwCF) and compare these outcomes to a propensity score matched cohort of people without CF.
Methods: Analysis of a multicenter research network TriNETX was performed including patients more than 16 years of age diagnosed with COVID-19. Outcomes in COVID-19 positive pwCF were compared with a propensity-matched cohort of people without CF.
Results: A total of 507,810 patients with COVID-19 were included (422 patients, 0.08% with CF; 507,388 patients, 99.92% without CF. Mean age at COVID-19 diagnosis in CF cohort was 46.6 ± 19.3 years, with female predominance (n = 225, 53.32%). Majority of the participants were Caucasian (n = 309, 73.22%). In the crude, unmatched analysis, mortality, hospitalization, critical care need, mechanical ventilation, acute kidney injury and composite (combination of intubation and mortality) outcome at 30 days was higher in the pwCF. Following robust propensity matching, pwCF had higher hospitalization rate (RR 1.56, 95% CI 1.20-2.04), critical care need (RR 1.78, 95% CI 1.13-2.79), and acute renal injury (RR 1.60, 95% CI 1.07-2.39) as compared to patients without CF.

Conclusion: People with CF are at risk of poor outcomes with COVID-19.5.2% of these patients died within one month of COVID-19 diagnosis, and more than one in 10 patients required critical care. Therefore, the relatively young median age of cystic fibrosis patients, and lower prevalence of obesity do not protect these patients from severe disease contrary to prior reports.

Dr Yousaf B Hadi is a gastroenterology fellow in the Department of Internal Medicine, West Virginia University, Morgantown, WV, 26506, USA.

Sarath C Ranganathan Commentary on: “Evaluating barriers and promotors of telehealth during the COVID-19 pandemic at cystic fibrosis programs to inform new models of CF care”J Cyst Fibros   2021 Sep 2;S1569-1993(21)01367-9. doi: 10.1016/j.jcf.2021.08.026.Online ahead of print  Free PMC article [Pubmed]

Sarath Ranaganathan

An interesting commentary by Sarath Ranganathan commenting on recent USA experience and describing the situation regarding telehealth in Australia.

A full version is available via PubMed with useful additional references.

Pierre-Régis BurgelChristopher GossCOVID-19 outcomes in people with cystic fibrosisCurr Opin Pulm Med  2021 Nov 1;27(6):538-543.doi: 10.1097/MCP.0000000000000823. [Pubmed]

Pierre-Regis Burgel

Purpose of review: The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a dramatic impact that is still ongoing around the world. Cystic fibrosis (CF) has been identified as a possible risk factor of poor outcome.
Recent findings: Data collected by multiple National CF registries around the world have indicated that persons with CF (PwCF) are not more likely to be affected by SARS-CoV-2 than the general population. The course of SARS-CoV-2 is usually mild in PwCF who are relatively young. Severe outcomes have been described in patients with low lung function and in those with immune suppression (i.e. solid organ transplantation). Indirect impact of the pandemic on the CF community has also been observed, including difficulties in the organization of CF care, leading to a dramatic increase in telehealth for PwCF. The pandemic has further affected clinical research by complicating ongoing clinical trials. Vaccination appears important to all PwCF, with special priority on developing adequate vaccination scheme for transplant recipients. Long-term effects of COVID-19 on the CF population remains unknown.

Summary: The COVID-19 pandemic has caused significant impacts on PwCF and on healthcare professionals who provide specialized CF care

Dr Pierre-Régis Burgel is at Université de Paris, Institut Cochin, Inserm U1016. Respiratory Medicine and Cystic Fibrosis National Reference Center, Cochin Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.

Hannah R MathewMay Y Choi Michael D ParkinsMarvin J Fritzler Systematic review: cystic fibrosis in the SARS-CoV-2/COVID-19 pandemic   BMC Pulm Med 2021 May 20;21(1):173. doi: 10.1186/s12890-021-01528-0   Free PMC article [Pubmed] Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the development of life-threatening COVID-19 are believed to disproportionately affect certain at-risk populations. However, it is not clear whether individuals with cystic fibrosis (CF) are at a higher risk of COVID-19 or its adverse consequences. Recurrent respiratory viral infections are often associated with perturbation and pulmonary exacerbations of CF as evidenced by the significant morbidity observed in CF individuals during the 2009 H1N1 pandemic. The primary goal of this review was to systematically survey published accounts of COVID-19 in CF and determine if individuals with CF are disproportionally affected by SARS-CoV-2 and development of COVID-19.
Methods: We conducted a systematic literature search using EMBASE and Medline between April 28 and December 10, 2020. Six evaluable studies reporting on a total of 339 individuals with CF who developed COVID-19 were included in this study.
Results: We found that although individuals with CF generally experience acute exacerbations of lung disease from infectious agents, COVID-19 incidence estimates in CF appear to be lower than in the general population. However, there are reports of subsets of CF, such as those who had organ transplants, that may experience a more severe COVID-19 course. Potential protective mechanisms in the CF population include pre-pandemic social isolation practices, infection prevention and control knowledge, altered expression of angiotensin-converting enzyme, and the use of certain medications.
Conclusions: Although individuals with CF are at risk of acute exacerbations often precipitated by respiratory tract viral infections, published evidence to date indicated that individuals with CF do not experience higher risks of contracting SARS-CoV-2 infection. However, there is evidence that some subsets within the CF population, including those post-transplantation, may experience a more severe clinical course. As SARS-CoV-2 variants are identified and the pandemic goes through additional waves of disease outbreaks, ongoing monitoring of the risk of COVID-19 in individuals with CF is required.

Hannah R Mathew is a medical student in the Department of Biological Sciences, University of Calgary, Calgary, AB, Canada

Rachel DunkSusan Madge SARS-CoV-2 driving rapid change in adult cystic fibrosis services: the role of the clinical nurse specialistBMJ Open Qual 2021 Oct;10(4):e001427. doi: 10.1136/bmjoq-2021-001427. [Pubmed]

       Rachel Dunk

Cystic fibrosis (CF) is a genetic, life-limiting disease without a cure; Coronavirus disease (COVID-19) rapidly changed healthcare services across the globe, including redeployment of healthcare professionals. This adult CF service was challenged to continue a patient facing service within severe staffing and structural limitations.Not only were many members of the CF multidisciplinary team (MDT) redeployed at the start of the first wave, but also both the CF and ambulatory care wards were closed. Fortunately, the CF clinical nurse specialists (CF-CNSs) remained in their role. Rapid change and adaptation of the CF service was required to ensure that patients did not feel abandoned and access to treatment remained available. The role of the CF-CNS was therefore pivotal in this change.The aim of this project was to use quality improvement methodology to plan an emergency service allowing a reintroduction of ambulatory care services. Success was measured by the number of patients clinically reviewed with or without intervention, and the reasons for patients contacting the CF-CNS via email and phone were recorded.In weeks 1 and 2 of the emergency service, the CF-CNSs triaged patients by phone, then reviewed face-to-face when necessary. This first step allowed the CF-CNSs to start two patients on home intravenous antibiotics. This service continued to be developed over the following 12 weeks, leading to a total of 36 patient attendances. In March 2020, n=1187 patients made contact (mostly COVID-19, unwell and medication related), in April n=904 and May n=870 (blood test results, unwell and medication related).The motivation of the CF-CNSs was pivotal to the success of this initiative with the CF MDT available to provide some support and advice. It concluded at week 12, which then saw the opening of the formal ambulatory care ward and returning redeployed ward staff.

Rachel Dunk and Sue Madge are in the Adult Cystic Fibrosis Department, Royal Brompton Hospital, London.

Gianfranco AlicandroValeria DaccóLisa CarianiMartina ContariniLetizia Corinna MorlacchiChiara RosazzaCalogero Sathya SciarrabbaFederica FerraroBeatrice Silvia OrenaAndrea GramegnaFrancesco BlasiCarla Colombo.   SARS-CoV-2 antibodies among people with cystic fibrosis prior to the vaccination campaign: A seroprevalence study in two specialized centres in Northern ItalyJ Cyst Fibros 2021 Dec 13;S1569-1993(21)02170-6.doi: 10.1016/j.jcf.2021.12.011.Online ahead of print. Free PMC article    [Pubmed]

Gianfranco Alicandro

The prevalence of anti-SARS-CoV-2 antibodies in people with cystic fibrosis (CF) is largely unknown. We carried out a cross-sectional study between March and June 2021 with the aim of estimating the seroprevalence of anti-SARS-CoV-2 antibodies in two CF centres in Northern Italy. Total serum anti-SARS-CoV-2 (spike) antibodies levels were measured and values ≥0.8 U/mL were considered positive. Among 434 patients aged >12 years, 64 patients had a positive result (14.7%, 95% CI: 11.5-18.4), 36 (56.3%) without experiencing any COVID-19-related symptoms. Three out of 49 transplanted patients tested positive with an odds ratio for a positive result among transplanted as compared to non-transplanted patients of 0.35 (95% CI: 0.07-1.14).
No significant differences were observed between sexes, age groups, socioeconomic status and lung disease severity. In conclusion, SARS-CoV-2 has infected a relatively high proportion of our patients but in most cases the infection was asymptomatic.

Gianfranco Alicandro is in the Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Cystic Fibrosis Centre, Milan, Italy.

Eunjin HongLisa M AlmondP S ChungA Peter RaoPaul M Beringer   PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19Clin Pharmacol Ther 2022 Mar 16.doi: 10.1002/cpt.2585. Online ahead of print. [Pubmed]

      Eunjin Hong

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDI). However, CF population is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.
CYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators. When ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited.

Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with delayed resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of ETI administered concomitantly with nirmatrelvir/ritonavir in people with CF that will likely decrease the impact of the drug interaction.

Eunjin Hong is a graduate student the Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, USA.

Harriet Corvol Sandra de MirandaClémence DehillotteLydie LemonnierRaphael ChironIsabelle Danner-BoucherRebecca HamidfarVéronique HoudouinJulie MaceyChristophe MarguetMarlène Murris-EspinQuitterie ReynaudPhilippe ReixMartine Reynaud GaubertAstrid KemgangPierre-Régis BurgelFrench Cystic Fibrosis Reference Network study group. Cumulative Incidence and Risk Factors for Severe COVID-19 in French People with Cystic FibrosisClin Infect Dis 2022 Apr 27;ciac333.doi: 10.1093/cid/ciac333. Online ahead of print.     [Pubmed]

        Harriet Corvol

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), with a special emphasis on severe cases. Previous studies used hospitalization rates as proxy for severity
Objective: criteria were applied for defining severity (e.g., respiratory failure and/or death). Data were compared to those from all French pwCF using the French CF Registry.
Results: As of April 30, 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (≥18 years, odds ratio [OR] = 2.52, 95% confidence interval [CI] = 1.82-3.48) and post-transplant individuals (OR = 2.68, 95% CI = 1.98-3.63). Sixty (26.9%) patients were hospitalized, with an increased risk in post-transplant individuals (OR = 4.74, 95% CI = 2.49-9.02). In 34 (15%) cases, COVID-19 was considered severe; 28/60 (46.7%) hospitalizations occurred in patients without objective criteria of severity. Severe cases occurred mostly in adults (85.3%) and post-transplant pwCF (61.8%, OR = 6.02, 95% CI = 2.77-13.06). In non-transplanted pwCF, risk factors for severity included low lung function (median ppFEV1 54.6% vs. 75.1%, OR = 1.04, 95% CI = 1.01-1.08) and CF-associated diabetes (OR = 3.26, 95% CI = 1.02-10.4). While most cases recovered without sequelae (n = 204, 91.5%), 16 (13%) were followed for possible sequelae, and three post-transplant females died.

Conclusions: Severe COVID-19 cases occurred infrequently during the first year of the pandemic in French pwCF. Non-transplanted adults with severe respiratory disease or diabetes and post-transplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

Harriet Corvol is Head of the Pediatric Respiratory Department and Pediatric CF Center, Assistance Publique Hôpitaux de Paris (APHP), Hôpital Trousseau, Paris, France and Professor at the Sorbonne Université, Centre de Recherche Saint-Antoine, Paris, France.