Cystic fibrosis airway inflammation enables elexacaftor/tezacaftor/ivacaftor-mediated rescue of N1303K CFTR mutation.

Rescue of N1303K CFTR by highly effective modulator therapy (HEMT) is enabled by CF airway inflammation. These findings suggest that evaluation of HEMT for rare CFTR mutations must be performed under inflammatory conditions relevant to CF airways. https://bit.ly/3tTcoJE.

Alterations in lipids after initiation of highly effective modulators in people with cystic fibrosis.

Risk of cardiovascular disease (CVD) may be changing in people with cystic fibrosis (pwCF) with widespread use of highly effective modulator therapy (HEMT). We performed a retrospective analysis of patients who had lipids checked before and after initiation of ivacaftor or elexacaftor/tezacaftor/ivacaftor. We hypothesized that HEMT negatively impacts lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL], TC/HDL ratio). 41 adult patients were included. Paired t-tests showed statistically significant increases in TC (mean difference 16.3 mg/dL, p = 0.007, n = 40), LDL (mean difference 17.1 mg/dL, p < 0.001, n = 35), and TC/HDL ratio (mean difference 0.40, p = 0.014, n = 39) after HEMT initiation. HDL was unchanged (mean difference -1.5 mg/dL, p = 0.69, n = 39). Linear mixed models showed CF liver disease was associated with significantly blunted changes in TC and LDL. Family history of CVD risk factors was associated with significantly accentuated increases in TC and LDL. These data suggest a role for more lipid screening in pwCF.

Stelara struck: a case of noninfectious pneumonitis secondary to ustekinumab.

BACKGROUND: We describe a case of acute hypoxic respiratory failure due to drug induced lung disease secondary to ustekinumab, which is a monoclonal antibody used to treat psoriasis, psoriatic arthritis, and inflammatory bowel disease. CASE PRESENTATION: A 33-year-old man with a history of Crohn's disease presented with fevers, myalgias, and abdominal pain, and subsequently developed acute hypoxemic respiratory failure approximately 2 weeks after restarting ustekinumab for his Crohn's disease. Cross-sectional chest imaging showed ground glass opacities and bilateral consolidations. Due to progressive hypoxia, he ultimately required intubation and mechanical ventilation. Broad infectious and autoimmune work up was negative, making drug induced interstitial lung disease (DILD) the leading consideration. He was treated with high dose steroids with dramatic improvement in his respiratory status. At follow up, his imaging findings had largely resolved, and his pulmonary function tests were normal. CONCLUSIONS: For patients presenting with acute hypoxic respiratory failure, it is critical to identify the underlying cause. In addition to testing for common respiratory infections that can cause respiratory failure, patients should also be evaluated for risk factors for developing atypical or opportunistic infections as well as inflammatory pneumonitis. Due to receiving ustekinumab, our patient was both at risk for developing an opportunistic infection as well as DILD. Although rare, DILD is a recognized toxicity of ustekinumab. Ustekinumab can cause significant lung injury, as in our patient, but with steroids and avoidance of future doses of the medication, our patient demonstrated good recovery. Reassuring outcomes have similarly been described in the literature; however, this case provides further details about outcomes with long-term follow-up clinical, imaging, and pulmonary function testing data available. We recommend consideration of high dose steroids for these patients for whom DILD is suspected.

Current state of CFTR modulators for treatment of Cystic Fibrosis.

Small molecular modulators of the cystic fibrosis transmembrane conductance regulator protein are transforming the care of people with cystic fibrosis. Highly effective modulators are now approved for nearly 90% of the adult CF population. They dramatically improve lung function, respiratory symptoms, and reduce pulmonary exacerbations. Recent efforts are expanding the availability of these therapies to a growing number of pediatric patients. The impact of modulators on extrapulmonary CF manifestations varies, although profound improvements in nutrition have been demonstrated. Observational studies and real-world research suggest that treatment benefits are sustained over time, and that maximal impact may be obtained with early use. The development of alternative approaches to restoring cystic fibrosis transmembrane conductance regulator (CFTR) function is needed for those with ineligible mutations.

Acute ST-elevation myocardial infarction in two young women with cystic fibrosis and cystic fibrosis-related diabetes.

Ischemic heart disease is rarely reported in people with cystic fibrosis (PwCF) despite multiple potential risk factors. Here we report two cases of ST elevation myocardial infarction (STEMI), both in young women with cystic fibrosis (CF) and cystic fibrosis related diabetes (CFRD). These cases illustrate the importance of considering myocardial injury/infarction in the differential diagnosis of patients with CF and chest pain or shortness of breath, and addressing the growing risk of cardiovascular disease (CVD).

Nutrition and Markers of Disease Severity in Patients With Bronchiectasis.

BACKGROUND: Increasing numbers of patients are being diagnosed with bronchiectasis, yet much remains to be elucidated about this heterogeneous patient population. We sought to determine the relationship between nutrition and health outcomes in non-cystic fibrosis (non-CF) bronchiectasis, using data from the U.S. Bronchiectasis Nontuberculous Mycobacterial Research Registry (U.S. BRR). METHODS: This was a retrospective, observational, longitudinal study using 5-year follow-up data from the BRR. Bronchiectasis was confirmed on computed tomography (CT). We stratified patients into nutrition categories using body mass index (BMI), and correlated BMI to markers of disease severity. RESULTS: Overall, n = 496 patients (mean age 64.6- ± 13 years; 83.3% female) were included. At baseline 12.3% (n = 61) were underweight (BMI < 18.5kg/m2), 63.9% (n = 317) had normal weight (BMI ≥ 18.5kg/m2 and <25.0kg/m2), 17.3% (n = 86) were overweight (BMI ≥ 25.0kg/m2 and < 30.0kg/m2), and 6.5% (n= 32) were obese (BMI ≥ 30kg/m2). Men were overrepresented in the overweight and obese groups (25.6% and 43.8% respectively, p < 0.0001). Underweight patients had lower lung function (forced expiratory volume in 1 second [FEV1] % predicted) than the other weight groups (64.5 ± 22, versus 73.5 ± 21, 68.5 ± 20, and 76.5 ± 21 in normal, overweight, and obese groups respectively, p = 0.02). No significant differences were noted between BMI groups for other markers of disease severity at baseline, including exacerbation frequency or hospitalization rates. No significant differences were noted in BMI distribution between patients with and without Pseudomonas, non-tuberculous mycobacteria, or by cause of bronchiectasis. The majority of patients demonstrated stable BMI over 5 years. CONCLUSIONS: Although underweight patients with bronchiectasis have lower lung function, lower BMI does not appear to relate to other markers of disease severity in this patient population.