Review of Rapid Advances in Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease that was previously a fatal pediatric disease with no treatment; however, due to scientific advancements, the median age of survival for the CF population born in 2018 has increased from 29 in 1989 to 47.4 in 2018. This is an innovative era for the treatment of CF as advanced research continues to evolve and novel treatments for the disease and related illnesses are discovered.

Latest in cystic fibrosis.

Cystic Fibrosis (CF) is a genetic disease affecting multiple organs. There are about 30,000 patients with CF in the United States, resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, as well as its protein product. The life expectancy of CF patients has increased steadily over recent years, with the current expectation being for them to live into their late 30s. This is due to increased understanding, and therapeutic advances in the CF treatment armamentarium.

Short- and Long-Term Complications of Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in preterm infants of low birthweight who required postnatal respiratory support. Although overall incidence rates have not changed, recent advancements in medical care have resulted in lower mortality rates, and those affected are beginning to live longer. As a result, the long-term repercussions of BPD are becoming more apparent. Whereas BPD has been thought of as a disease of just the lungs, resulting in abnormalities such as increased susceptibility to pulmonary infections, impaired exercise tolerance, and pulmonary hypertension, the enduring complications of BPD have been found to extend much further. This includes an increased risk for cerebral palsy and developmental delays, lower intelligence quotient (IQ) scores, impaired executive functioning, behavioral challenges, delays in expressive and receptive language development, and an increased risk of growth failure. In addition, the deficits of BPD have been found to influence much more than just physical health; BPD survivors have been noted to have higher rates of health care use, starting with the initial hospitalization and continuing with therapy and specialist follow-up, as well as impairments in quality of life, both physical and psychological, that continue into adulthood. The long-term consequences of BPD may best be addressed through future research, including better understanding of the pathophysiologic mechanisms leading to BPD, further comparisons between newborns with BPD and those without, and long-term assessment and management of BPD patients as adults.

COVID-19 Presenting With Diabetic Ketoacidosis: A Case Series.

OBJECTIVE: Diabetes mellitus has been recognized as one of the comorbidities that predict the severity of illness in patients infected with COVID-19. The characteristics of patients presenting with diabetic ketoacidosis (DKA) and COVID-19 infection have not been described. METHODS: We describe 5 patients with DKA and concomitant COVID-19 admitted to the intensive care unit of an academic medical center. Three patients had type 1 diabetes mellitus, and 2 patients had type 2 diabetes mellitus. RESULTS: While DKA with an infectious etiology is a common presentation, we observed that the patients with DKA precipitated by COVID-19 presented with atypical symptoms. COVID-19 infection was revealed during search for an etiology of DKA. CONCLUSION: It is prudent to have a low threshold to screen for COVID-19 infection in patients with DKA.

High-frequency percussive ventilation for airway clearance in cystic fibrosis: a brief report.

Exacerbations of cystic fibrosis (CF) lung disease are characterized by increased inspissation of abnormally viscid pulmonary secretions with resultant plugging of small airways, worsened ventilation/perfusion mismatch, and increased physiological deadspace. In this circumstance, hypoxic respiratory failure necessitating mechanical ventilation can be life-threatening. We present such a case of CF lung disease poorly responsive to conventional mechanical ventilatory strategies, in which high-frequency percussive ventilation (HFPV) using volumetric diffusive respiration mobilized copious amounts of inspissated pulmonary secretions and improved refractory hypoxia. Subsequent transient hypercarbia necessitated titrating ventilator parameters to return the PaCO(2) to baseline; the voluminous clearance of secretions and improvement in oxygenation were sustained. HFPV appears unique in its ability to function as a methodological continuum from noninvasive percussion to invasive percussive ventilation for airway clearance, a fundamental tenet of the CF treatment paradigm.

Portopulmonary hypertension.

It has been widely accepted that development of porto-pulmonary hypertension (POPH) is independent of the cause of portal hypertension. The degree of hepatic damage and liver function do not correlate with predisposition to POPH or its severity. However, portal hypertension has been confirmed as a prerequisite for developing pulmonary hypertension. Transthoracic echocardiography is the best screening test for the presence of POPH, but a diagnosis of POPH can be established only by right heart catheterization. Randomized controlled trials comparing the efficacy and safety of different pharmacologic strategies are lacking in patients with POPH. The general management includes diuretics and oxygen supplementation. Notably, moderate to severe POPH predisposes candidates for orthotopic liver transplantation to a higher risk of perioperative mortality. Vasomodulating pharmacologic agents are used in patients with moderate to severe POPH to decrease pulmonary arterial hypertension, thereby permitting liver transplantation to be performed safely. Epo-prostenol is the best-studied medication, and bosentan appears promising.

Ivacaftor for the Treatment of Cystic Fibrosis Coexisting with Trisomy 21: A Case Report.

The association between cystic fibrosis (CF) and trisomy 21, or Down Syndrome (DS) is rare, and it pertains a poor prognosis with the majority of patients dying in infancy. We report a case of a 28-year-old male with DS and moderate CF (ΔF508/G551D, FEV1 1.92 L, 60% predicted at the age of 18 years) diagnosed in childhood. The patient's lung function continued to deteriorate over time (FEV1 nadir of 1.29 L), and he was started on ivacaftor in the year 2012 following ivacaftor release and approval. FEV1 and FVC improved significantly along with an increase in the patient's body mass index. Ivacaftor potentiates the open-channel probability of the G551D-CFTR. It has been shown to improve lung function, symptoms, weight, and sweat chloride concentration and decrease the risk of pulmonary exacerbations in patients with severe pulmonary CF (G551D). Our case argues against the reported literature of poor prognosis when the two chronic diseases coexist as only one case report in the literature described a DS patient with CF surviving into adulthood. In our patient, treatment with ivacaftor resulted in an increase in FEV1 and weight that exceeded the response observed in the ivacaftor landmark trial. Genetic studies are underway to understand the genetic basis of the large variation in DS phenotypes, which is probably caused by allelic heterogeneity on multiple chromosomes. The latter may explain the enhanced response observed in our patient and suggests that although patients with concomitant DS and CF may have worse lung disease, their response to novel therapies may be intensified. Further studies are needed in this subset of patient population to better characterize CF with trisomy and other genetic disorders.

Residual Volume and Total Lung Capacity to Assess Reversibility in Obstructive Lung Disease.

BACKGROUND: Reversibility of obstructive lung disease is traditionally defined by changes in FEV1 or FVC in response to bronchodilators. These may not fully reflect changes due to a reduction in hyperinflation or air-trapping, which have important clinical implications. To date, only a handful of studies have examined bronchodilators' effect on lung volumes. The authors sought to better characterize the response of residual volume and total lung capacity to bronchodilators. METHODS: Responsiveness of residual volume and total lung capacity to bronchodilators was assessed with a retrospective analysis of pulmonary function tests of 965 subjects with obstructive lung disease as defined by the lower limit of normal based on National Health and Nutritional Examination Survey III prediction equations. RESULTS: A statistically significant number of subjects demonstrated response to bronchodilators in their residual volume independent of response defined by FEV1 or FVC, the American Thoracic Society and European Respiratory Society criteria. Reduced residual volume weakly correlated with response to FEV1 and to FVC. No statistically significant correlation was found between total lung capacity and either FEV1 or FVC. CONCLUSIONS: A significant number of subjects classified as being nonresponsive based on spirometry have reversible residual volumes. Subjects whose residual volumes improve in response to bronchodilators represent an important subgroup of those with obstructive lung disease. The identification of this subgroup better characterizes the heterogeneity of obstructive lung disease. The clinical importance of these findings is unclear but warrants further study.

Epoprostenol-induced hypersplenism in portopulmonary hypertension.

Portopulmonary hypertension (POPH) is a not infrequent but serious complication of liver cirrhosis. Continuous intravenous epoprostenol infusion is a treatment option for this condition. Progressive splenomegaly with pancytopenia (hypersplenism) is associated with epoprostenol use in POPH. After recognizing a case of epoprostenol-induced hypersplenism that resolved upon stopping the drug, the authors retrospectively reviewed all patients treated with epoprostenol at the center for both POPH and pulmonary hypertension due to other causes. Five of 11 patients with POPH developed hypersplenism secondary to epoprostenol. In 1 patient, and possibly in a second, the hypersplenism resolved upon discontinuation of epoprostenol. None of 9 patients with pulmonary hypertension due to other causes developed splenomegaly. This report confirms hypersplenism as a complication of epoprostenol therapy for POPH. Furthermore, the authors demonstrate for the first time that hypersplenism may be reversed by stopping the medication and propose a mechanism for this phenomenon.

Stratified assessment of the role of inhaled hypertonic saline in reducing cystic fibrosis pulmonary exacerbations: a retrospective analysis.

Objective Limited data exist concerning the role of inhaled hypertonic saline (HS) in decreasing pulmonary exacerbations in cystic fibrosis (CF), especially as more advanced stages of CF lung disease were excluded in prior studies. Herein, the authors retrospectively determined the efficacy of inhaled HS in reducing CF pulmonary exacerbations when stratified according to the severity of CF lung disease. Stratification was based on the framework of the Pulmonary Therapeutics Committee's published gradation of obstructive lung physiology in CF, that is, mild (FEV(1) >70%), moderate (FEV(1) 40-70%) and severe (FEV(1) <40%) lung disease, respectively. Design A retrospective review of the Port CF database over a 3-year period performed at an academic CF care centre. Results 340 pulmonary exacerbations were identified; inhaled HS was being used in 99 of these cases. Univariate analysis demonstrated a significant reduction in pulmonary exacerbations only in mild obstruction (OR=0.09, CI 0.01 to 0.81, p=0.012); however, multivariate logistic regression that adjusted for confounding variables showed a reduction in pulmonary exacerbations across the entire spectrum of obstructive lung disease when using inhaled HS, that is, mild obstructive CF lung disease (OR=0.17, CI 0.05 to 0.58, p=0.004), moderate obstructive CF lung disease (OR=0.39, CI 0.16 to 0.93, p=0.034), as well as severe obstructive CF lung disease (OR=0.02, CI 0.001 to 0.45, p=0.015). Moreover, inhaled HS appeared reasonably well tolerated across all stages of lung-disease severity, and was discontinued in only 7% of cases (n=4) with severe lung disease. Conclusion In this study, inhaled HS appeared to reduce pulmonary exacerbations in CF lung disease at all stages of obstruction. This underscores the importance of therapeutic inhaled HS in CF lung disease, regardless of the severity of lung obstruction.