The clinical features and impact of SARS-CoV-2/COVID-19 infection in children with Cystic Fibrosis (CF): A Qatari experience

Background: SARS-CoV-2 in children with cystic fibrosis (CF) has been reported to cause mild illness without pre-existing severe lung disease. This review described the clinical presentation and course of COVID-19 infection in children with CF in Qatar. Methods: The pediatric CF registry of 51 patients in Qatar was reviewed for COVID-19 cases from February 2020 to February 2022. Demographics, vaccination status, symptoms, and course were reviewed. Data were expressed as median, range, frequencies, and percentages. Results: The study included eight patients with CF below 18 years of age infected with COVID-19. The incidence of COVID-19 in children with CF was 15.7%. The median age was 11 (2-18) years. Half of the cohort were males. Seven patients were pancreatic sufficient (I1234V mutation), and one was pancreatic insufficient (3129del4 mutation). The median baseline FEV1 was 91 (78-107%) predicted. None had received CFTR modulators or undergone a lung transplant. Three patients were vaccinated before their infections. Two of them were asymptomatic. Six patients (75%) had a cough and flu-like symptoms. Three patients had a fever. Two patients were hospitalized due to pulmonary exacerbation; both had mild CF-lung disease. None required respiratory support. Conclusion: We report a favorable outcome of COVID-19 infection in children with CF, similar to published international studies. Our findings are attributable to the community-dominant milder CFTR mutation, precautionary measures, and causative COVID-19 strain. More longitudinal data are needed to study these factors as potential protective mechanisms.


INTRODUCTION
Cystic fibrosis (CF) is an inherited autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. 1 Over two thousand mutations have been identified, with F508del being the most common mutation. 1These mutations lead to multi-systematic disease involving pulmonary, gastrointestinal, reproductive, and endocrine systems. 2 The prevalence of CF in the Middle East is estimated to be 1 in 30,000-50,000. 3,4In the state of Qatar, the CF population is peculiar for the dominance of CFTR I1234V mutation, especially among Bedouin tribes 5 compared to the Arab region and worldwide.−9 The presence of homozygous CFTR I1234V mutation was first described by Abdul Wahab et al. in patients with variable disease manifestations.Those patients were from 17 families from the same Bedouin tribe, with a high consanguinity rate of 96.6%. 10 The reported Qatari pediatric population had mild to moderate respiratory symptoms and was characterized by pancreatic sufficiency.In comparison, children with CF of non-Arabic Asian descent had more severe respiratory symptoms with an earlier occurrence of Pseudomonas aeruginosa colonization and pancreatic insufficiency. 11−16 This predisposition was particularly evident during the H1N1 pandemic in 2019, which resulted in significant morbidity and mortality among CF patients. 17,18he pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a significant global health impact. 19,20

RESULTS
Eight patients with CF < 18 years of age were infected with serologically confirmed COVID-19.The diagnosis was made by obtaining nasopharyngeal swabs for either polymerase chain reaction (PCR) or rapid antigen testing (Ag).The incidence of COVID-19 among the CF pediatric population was 15 per 100 persons from 2020 to 2022.The median age at infection was 11 (2-18) years.Half of the patients were males.The median body mass index Z-score was 0.08 (-1.95 -1.64).Seven patients have been pancreatic sufficient (CFTR I1234V mutation), and one is pancreatic insufficient (3129del4 mutation).Seven patients had baseline pulmonary function testing.The median baseline FEV1 was 91 (78-107%) predicted.Before the COVID-19 infection, six patients had been colonized with Methicillin-sensitive staphylococcus aureus (MSSA), which was isolated from their sputum culture.One of them had concurrent pseudomonas aeruginosa (PsA) colonization, and another patient had a concurrent

DISCUSSIONS
This work represents the first study to describe the incidence of COVID-19 infection in our pediatric CF population.It also represents the only study that describes the clinical course of children with CF with CFTR I1234V mutation.
In Qatar, various precautionary measures were implemented in the early stages of the COVID-19 pandemic 28 to limit the spread of COVID-19 infection.These measures addressed the general population and focused on high-risk patients, including cystic fibrosis. 29The incidence of COVID-19 among our CF pediatric population was 15 per 100 persons from 2020 to 2022.However, no data about the incidence among the general pediatric population in Qatar has been published.Moreover, there was no reported data in the Arab Gulf region that reflects the pediatric CF population.However, Alyazidi et al. 30 reported COVID-19 infection in three children with CF who required hospitalization during the first year of the COVID-19 wave in three main pediatric hospitals in Oman.Only one patient with moderate-severe CF-related lung disease required respiratory support with non-invasive ventilation.
The CF Registry Global Harmonization Group published an initial report of COVID-19 cases and described a spectrum of clinical severity, with most adult cases being mild or moderate. 27However, the updated report recorded seven deaths. 31ur results were comparable to the largest pediatric international results, which reported the favorable clinical course and outcomes of SARS-CoV-2 infection in 105 children with CF who do not have pre-existing severe lung disease. 32In this study, only 24 children required hospitalization.
Those patients had lower lung function and reduced body mass index Z-scores.Only one child died due to non-COVID-19 complications.
The published data suggested that CF, unexpectedly, may represent an advantage in COVID-19 infection. 33These suggestions were based on various studies on molecular basis, cytokines, and CF medications.The innate immune response of airway epithelia to respiratory viruses was impaired in patients with CF. 14−16 Nevertheless, CF airway epithelial cells were hypothesized to display different intracellular host defenses and viral replication. 27levated interleukin-6 (IL-6) levels were linked with severe COVID-19 disease course and mortality. 34,35evertheless, the airway epithelia in CF patients  The clinical features and impact of SARS-CoV-2/COVID-19 infection in children diseases, as well as its well-established antibacterial effects.However, azithromycin had shown no clinical immunomodulatory effects in the context of COVID-19 infection. 48ven though the COVID-19 outcome is favorable in most patients with CF, independent risk factors for the severe outcome of COVID-19 infection in CF patients were identified.Those included lung transplantation, CFRD, and moderate to severe lung disease. 49Another study reported additional risk factors such as the previous need for oxygen therapy, severe lung function impairment, and CF with pancreatic insufficiency. 50 Angiotensin-converting enzyme 2 (ACE2) was found to be the host cell binding-and entry-receptor of SARS-CoV-2. 36The SARS-CoV-2 infection causes ACE2 transcriptional downregulation, leading to increased synthesis of angiotensin II, 37 which potentially leads to further lung injury. 38n CF, the effect of ACE biallelic polymorphism was studied in 180 patients with CF.The study reported that CF patients with biallelic deletion of ACE were associated with earlier clinical symptoms and a higher risk of lung deterioration than patients with ACE biallelic or monoallelic insertion polymorphisms. 39The effect of ACE polymorphisms and ACE2 downregulation exhibited in patients with CF may be attributed to the variability of the COVID-19 course in those patients. 40he presence of thick secretions and existing microbiota in the airways of patients with CF may also possess protective effects against viral infection. 41In addition, the elevated autophagy induction in patients with CF may also enhance the anti-viral response as an additional protective mechanism. 27,42ther suggested protective effects against COVID-19 were CF medications. 33The effect of inhaled dornase alfa, commonly used to manage secretions in CF patients, was studied.The proposed protective mechanism for COVID-19 infection is based on the clearance of neutrophil extracellular traps. 43In our study, only two patients were on inhaled dornase alfa and had mild symptoms.The effect of Azithromycin has also been described in a few studies where it has been either administered as a treatment for COVID-19 or has been given as maintenance therapy for patients with CF. 32,41,44,45 The proposed mechanism was immune modulation and weak anti-viral effects. 46,47zithromycin has shown immunomodulatory effects on innate and adaptive immunity in cystic fibrosis and other inflammatory respiratory

Table 2 . Summary of patients' demographics, presentation, and post-COVID-19 microbiological and radiological data and outcome. Case
Fortunately, those risk factors were absent in the reported cases in our study, except for one patient who had pancreatic insufficiency but had mild disease.