Severe COVID-19 May Be More Likely in CF Carriers Than Patients

Cystic fibrosis (CF) carriers — and especially men with mutations in only one copy of CFTR, the gene associated with CF — are at a higher risk of developing a severe COVID-19 infection, one that carried a greater need for ventilation and could be quickly fatal, according to a study in Italy.

This is in sharp contrast with what has been reported for CF patients, who appear not to be more susceptible to the SARS-CoV-2 virus, which causes COVID-19, or to a more severe infection.

This difference may be due to patients’ long-standing use of masks and the nature of standard CF  treatment, which works to normalize CFTR protein function and so reduce inflammation and the likelihood of lung infections.

Given the relatively high numbers of CF carriers around the world, these findings suggest that carrier status in hospitalized COVID-19 patients should be investigated to identify those at risk of severe disease, and who could benefit from closer surveillance or more aggressive treatment, the researchers noted.

The study, “Severe COVID-19 in Hospitalized Carriers of Single CFTR Pathogenic Variants,” was published in the Journal of Personalized Medicine.

While most COVID-19-infected patients show mild symptoms, about 15% develop severe complications like respiratory insufficiency, which can require ventilation and intensive care. Typically, such complications are associated with an abnormal, excessive inflammatory and immune response, known as a cytokine storm.

Determining the risk factors for severe COVID-19 infections is of utmost priority, maximizing the use of available resources, and allowing for early intervention in high-risk patients.

While people carrying mutations in only one of the two copies of the CFTR gene — called CF carriers — do not develop the full-blown disease, they have lower CFTR protein levels and/or function, evidence of greater lung inflammation, and are more susceptible to CF-related conditions, such as lung infections, including pneumonia.

To understand whether CF carriers are at a greater risk of severe COVID-19 infection, researchers in Italy compared the clinical course of CF carriers to noncarriers, all diagnosed with COVID-19.

This study was part of the GEN-COVID study (NCT04549831), an Italian initiative involving multiple hospitals, primary care centers, and public health units in Italy, with the aim of identifying genetic drivers of COVID-19 clinical variability.

Researchers analyzed genetic and clinical data of 874 adults (496 men and 377 women) diagnosed with COVID-19 during the country’s first pandemic wave. These patients had a mean age of 59.9, and their most common, pre-existing chronic health condition was high blood pressure (27.8%), followed by diabetes (12.2%).

Genetic testing revealed that 40 patients (24 men and 16 women; 4.58%) were CF-carriers, and one man carried two disease-causing CFTR mutations, and as such, had CF.

Results showed that six (8.7%) CF carriers were mechanically ventilated, five of whom were men. These ventilated patients were significantly younger than noncarriers undergoing mechanical ventilation (mean age, 51 vs. 61.4).

Notably, among all patients, men were more likely to be hospitalized (59.5%) and to undergo invasive mechanical ventilation (74.3%), and male CF carriers were significantly younger relative to noncarriers.

The observed higher frequency of hospitalizations and more severe complications among men in the whole patient population, and among CF carriers in particular, “confirms a world trend that identifies the male sex as a relevant risk factor for severe COVID-19,” the researchers wrote.

Hospitalized CF carriers were also 69% more likely to develop an abnormal inflammatory response, and 54% more likely to have respiratory difficulties suggestive of acute respiratory distress syndrome (ARDS) than were noncarriers. ARDS is a type of respiratory failure due to fluid buildup in the tiny air sacs in the lungs.

People with a single CFTR mutation were also significantly more likely to die in the first 14 days after hospital admission than noncarriers, independent of age, sex, and simultaneous health conditions.

At later time points, however, being a CF carrier was not associated with an increased risk of death, suggesting that COVID-19-related death “is determined by time-dependent factors and that CFTR-related early events like cytokine storm may be responsible for early death,” the researchers wrote.

These findings suggest that CF carriers “may be prone also to develop a severe manifestation of COVID-19, and even at a younger age compared to noncarriers,” the team added.

This increased carrier risk of severe COVID-19 infection may be due to several CF-related factors,  the researchers suggested. They identified as possible causes the acidification of airway surface liquid that impairs immune response, and carriers’ fewer or faulty CFTR proteins, increasing inflammation in the lungs.

Notably, the milder forms of COVID-19 that appear to affect CF patients may be explained by their habit of “always wear[ing] protective masks” and treatment “with modulators that re-establish CFTR function,” the researchers wrote.

While future, larger studies are needed to confirm these findings, data suggest that CF carrier status, given its high frequency, “should be investigated in COVID-19 hospitalized patients in order to identify subjects that, being at risk of severe disease, would benefit of intensive surveillance and personalized therapy,” the team concluded.