Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: an international observational study


                  Background
                  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.
               
                  Methods
                  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.
               


Introduction
The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a profound impact around the world.(1, 2) A spectrum of respiratory disease has been observed ranging from mild (asymptomatic or flu-like symptoms) to severe (acute respiratory distress syndrome, fulminant respiratory failure and high mortality). (2) Various extrapulmonary manifestations of COVID-19 have also been recognised that include haematological, renal, gastrointestinal, cardiovascular and neuropsychiatric problems. (3) The presence of co-morbidities, including underlying respiratory problems, has been identified as a key risk factor for severe disease along with older age.(4-6) Current reports suggest that SARS-CoV-2 infection is generally less severe in children than in adults. (6,7) Most children remain asymptomatic or experience only mild symptoms during infection. (5,6) Notably, a rare multisystem inflammatory syndrome in association with SARS-CoV-2 infection has been described in a small subset of children and young people. (8) In view of the severity of COVID-19 and high transmissibility of SARS-CoV-2, advice was issued in many countries at the outset of the global pandemic for people with cystic fibrosis (CF) and their families to strictly isolate to reduce the chances of contracting the virus. (9,10) Respiratory viruses are known to cause pulmonary exacerbations and substantial morbidity in people with CF. (11) There is some evidence to suggest that the innate immune response of CF airway epithelia to respiratory viruses is impaired. (12)(13)(14) During the 2009 influenza A (H1N1) pandemic infection was associated with substantial morbidity in people with CF and a high mortality rate in those admitted to intensive care. (15,16) Conversely, other aspects of CF airway pathophysiology may mitigate against severe COVID-19 disease. (17,18) CF airway epithelial cells may be less susceptible to coronavirus infection due to altered intracellular processes involved in host defence and viral replication, for example autophagy, unfolded protein response and NOD-, LRR-and pyrin domaincontaining protein 3 inflammasome.(17) SARS-CoV-2 has also been shown to mimic the proteolytic activation of the epithelial sodium channel by furin cleavage. (19) This provides a potential mechanism for reduced entry of SARS-CoV-2 in to CF airway epithelial cells. Increased understanding about SARS-CoV-2 infection in the paediatric age group is crucial to provide accurate and balanced advice that will keep children with CF safe, and recognise the relative risks, but also enable them to lead their lives in the most fulfilling way possible during the ongoing pandemic. This is particularly important given the associated disadvantages and substantial negative effects on quality of life, mental health, schooling and delivery of healthcare of strict isolation measures. (8,(24)(25)(26)(27)(28) Here we detail the clinical course and outcomes of SARS-CoV-2 infection in 105 children with CF collated by an international collaborative group and representing the only large dataset thus far reported.

Study design
The 'Cystic Fibrosis Registry Global Harmonization Group' is a collaborative international group of patient registries. At the start of the COVID-19 pandemic the group set up fortnightly videoconferences to share experience. Nineteen countries participated in the study that ran between 1 February and 7 August 2020.
Children were defined as individuals aged less than 18 years. Cases were included if they had a confirmed diagnosis of CF and were either diagnosed with SARS-CoV-2 infection via a polymerase chain reaction (PCR) test on a respiratory sample or a clinical diagnosis of COVID-19 was made in a hospital setting. Cases reported via antibody testing alone or self-reporting were excluded.
CF centres that had reported SARS-CoV-2 cases to their registry were asked to complete an anonymised data collection form and a designated country representative then collated all national cases for the study. Representatives

Data analysis
The United Kingdom CF Registry team and the Children's Respiratory Group from Newcastle University performed analyses of pooled cases submitted by participating countries. Data were regarded as missing where specific information was not available at the time of data collection. Results were summarised in tables as numbers and proportions for categorical data and median values with interquartile ranges for continuous data. For categories where some data were missing, the number of cases where data were available was cited in the table. BMI Z-scores adjusted for age and sex were calculated using the World Health Organisation Child Growth Standards. (29,30) As age was recorded in years, age +0·5 years was used in this calculation for each child. Normality of data was assessed with Shapiro Wilk testing. Subgroup analyses of hospitalised and non-hospitalised cases were performed using either Mann-Whitney test for continuous data or Fisher's exact test for categorical data using GraphPad Prism software (version 8·4·3). P values of <0·05 were considered statistically significant.

Information governance and ethics
Each participating country was responsible for ensuring research ethics or institutional approvals were in place for this work as per their individual patient registries.

Role of the funding source
The funding source had no involvement in the collection, analysis or interpretation of data, writing or decision to submit for publication.

Results
Data on 105 cases of SARS-CoV-2 infection in children with CF were analysed.

Case demographics
Case demographics and features of pre-existing CF disease in the cohort are summarised in Table 1. Median age was ten years and 54% were male. Forty-three (41%) children were homozygous for the F508del CFTR mutation. Median best ppFEV 1 within 12 months prior to infection for those over the age of five years was 94%. Thirty-one had Pseudomonas aeruginosa respiratory infection and 31 were on long-term azithromycin treatment. Fifty children were on a CFTR modulator. None were on an active list awaiting transplantation and two children were post-transplant (one lung and one liver). 1 (1%) The proportion of each value was calculated from the non-missing data in each group as depicted by n. Abbreviations: CFTR: cystic fibrosis transmembrane conductance regulator; ppFEV1: percent predicted forced expiratory volume in one second; IQR: interquartile range; PCR: polymerase chain reaction.

Symptoms, acute treatments, management and outcome
A summary of the symptomatology, management and treatment of cases is provided in Table 2. Where relevant data were available, just over a quarter of children were asymptomatic. In those with symptoms, fever (73%) and altered cough (72%) were the most common features with 23% experiencing gastrointestinal symptoms. Other less frequently reported symptoms were fatigue, headache and rhinitis each reported in two cases and loss of smell and taste experienced by one child.
Varied levels of care were required with 71% of children being managed in the community and the remainder admitted to hospital. One child was admitted to intensive care six weeks after acute SARS-CoV-2 infection. A range of treatments were used, these included oral (37%) or intravenous (46%) antibiotics with the majority of intravenous antibiotics being administered in hospital. Four children received azithromycin acutely, five antiviral medications and one additional corticosteroids. Of those who were hospitalised, six required new supplementary oxygen therapy, two required non-invasive ventilation and one invasive ventilation.
At the time of writing, only two cases were described as unresolved, however no formal follow up information is available at this stage. Both solid organ transplant recipients recovered from COVID-19. There were no deaths directly attributed to COVID-19. One child died approximately six weeks after testing positive for SARS-CoV-2. This child had been unwell with deteriorating health during the preceding year including several severe pulmonary exacerbations requiring intensive care admission. During the COVID-19 illness the child was treated with intravenous antibiotics, lopinavir/ritonavir and managed in a ward setting. The child recovered from that acute illness and became negative on repeat SARS-CoV-2 testing.
However, six weeks later the child experienced a further severe pulmonary exacerbation requiring admission to intensive care, intubation and mechanical ventilation, and sadly died from respiratory failure.

Characteristics associated with hospitalisation for COVID-19 illness
The characteristics of children admitted to hospital with COVID-19 were compared with those managed in the community in an exploratory analysis using hospitalisation as the best available surrogate of disease severity in our dataset (Table 3). There were no statistically significant differences between sex and CFTR genotype in each group. Although the median age was higher in children admitted to hospital, this was not statistically significant. Median BMI Z-score was lower in children admitted to hospital. No pancreatic sufficient children were admitted to hospital with COVID-19. Around half of children with CF-related diabetes were admitted to hospital. Children admitted had a lower median ppFEV 1 (73%) than those managed in the community (97%). Significantly fewer children were hospitalised who were receiving CFTR modulator therapy, however, it should be noted that access to modulator drugs varied between countries. 6 (15%) 34 (85%) The proportion of each value is calculated from the non-missing data in each group as depicted by n. † Statistical analysis performed using Fisher's exact test; *statistical analysis performed using Mann-Whitney test. # no statistical testing performed on allergic bronchopulmonary aspergillosis group due to small numbers. Abbreviations: CFTR: cystic fibrosis transmembrane conductance regulator; ppFEV1: percent predicted forced expiratory volume in one second; IQR: interquartile range.

Discussion
We describe to our knowledge the first case series of SARS-CoV-2 infection in children with CF. Information was captured on 105 children across 13 countries with a spread of ages ranging from infants through to adolescents. Some of these cases were included within a predominantly adult series, where, crucially, no analysis of the paediatric age group was performed.(23) Specific data on children are urgently required to inform decisions around education for example. (28) The majority of children experienced a relatively mild illness. Over two thirds were managed in the community and of the 24 admitted to hospital six required a period of supplementary low flow oxygen and two needed non-invasive ventilation during their admission.
One child was admitted to intensive care, however, this case appears to have been exceptional as discussed below. Two children at the endpoint of data collection were in a recovery phase with the remainder having made a full recovery. This is a diverse cohort from multiple countries and in-depth comparisons as to how We compared the characteristics of children admitted to hospital with those managed in the community as the best available surrogate of COVID-19 disease severity in our dataset. Children admitted to hospital had lower lung function, reduced BMI Z-scores and were less likely to be maintained on a CFTR modulator.
No differences in gender were found.
Importantly, these comparisons were performed with caution and are exploratory due to the relatively small overall numbers, prevalence of missing data, variable access to CFTR modulators internationally and the important caveat that some children were likely to have been tested for SARS-CoV-2 in association with a hospital admission for other reasons.