Pulmonary Flares Raise Risk of Death, Lung Transplant With CFRD

Exacerbations tied in analysis to 15% of risk two years after CFRD diagnosis

Somi Igbene, PhD avatar

by Somi Igbene, PhD |

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Pulmonary exacerbations — the flares that cause a sudden worsening in respiratory symptoms — contribute to the higher mortality and lung transplant rates seen in people with cystic fibrosis-related diabetes (CFRD), an analysis of adults in a U.K. CF registry reported.

“These findings have important implications for clinical teams. Importantly, they reinforce the need to reduce the risk of pulmonary exacerbations at every opportunity, with particular focus on treatments known to be effective,” the researchers wrote.

Treatments noted include “inhaled antibiotics for bacterial suppression, mucoactive therapies such as dornase alfa [brand name, Pulmozyme] and more recently CFTR modulators, which have a marked effect on exacerbation risk,” they added.

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The study, “Mediation of the total effect of cystic fibrosis-related diabetes on mortality: A UK Cystic Fibrosis Registry cohort study,” was published in the journal Diabetic Medicine.

CFRD is a common complication of cystic fibrosis, with the U.K. researchers noting it affects about one-third of CF patients there ages 16 or older and up to 50% of those older than 40. CF patients in the U.K. are screened routinely for this complication so that insulin treatment can begin promptly, but still have poorer outcomes.

In addition,”unlike other forms of diabetes, the primary cause of death for people with CFRD is pulmonary failure,” the scientists noted.

CFRD diagnosed in one-third of CF patients over age 16 in UK

CFRD is associated with poorer lung function, more pulmonary exacerbations, and lower nutritional status, all of which are known to affect survival. A research team in the U.K. performed a mediation analysis, which tests the extent to which one variable affects an outcome directly or via other pathways, to determine how these three factors might determine a mortality or lung transplant risk in people with CFRD.

Data covered adults with CF and annual review records in the UK Cystic Fibrosis Registry stretching from January 2010 through mid-December 2020. Information collected at these reviews included CFRD status, usually diagnosed via an oral glucose tolerance test, and pulmonary exacerbations, as defined by the total days each year that an intravenous (IV) antibiotic was needed.

People diagnosed with CFRD prior to a first review visit, those older than 51 at the start of follow-up, and patients with fewer than two assessments of lung function (FEV1%, the percent predicted forced expiratory volume in one second)  and body mass index (a measure of body fat) were among those excluded from analyses.

Two separate analyses looked at the influence of pulmonary exacerbations, nutritional status and lung function on mortality and transplant rates. The main mediation analysis included people without CFRD and those with CFRD undergoing insulin treatment. A second, sensitivity analysis included all patients in the main analysis plus those with CFRD who had not started using insulin.

A total of 2,750 CF patients (59% male, median age of 21 for all) were in the main analysis.

During the study’s years, 599 of them were diagnosed with CFRD, 260 died, and 123 needed a lung transplant. Mortality and transplant rates were higher among people with CFRD than those without this complication. The estimated mortality and transplant rate for a 30-year-old man without CFRD was 1.3% and 3.6% for a similar man with CFRD. Likewise, the mortality and transplant rate for a 30-year-old woman with CFRD was 4.5%, and 1.6% for a woman that age without CFRD.

Exacerbations contribute to risk after a CFRD diagnosis

Pulmonary exacerbations also were seen to be the strongest contributor to mortality and transplant rates among people with CFRD, while lung function and nutritional status lacked significant effect. Exacerbations accounted for 15% of mortality and transplants at two years after a CFRD diagnosis, rising to 20% at three years and 24% at four years.

Similar results — with the “strongest evidence” — were seen among patients in the sensitivity analysis. Pulmonary exacerbations here accounted for 20% of deaths or lung transplants at two years after a CFRD diagnosis, and 28% and 32% of these rates three and four years later, respectively.

“In this study, we found greater mortality/transplant rate in adults with CFRD compared to those without for both men and women,” the researchers wrote. “The mediation analysis suggested that pulmonary exacerbations mediate a portion of the effect of CFRD on mortality or transplant, but there was little evidence that lung function and nutritional status were significant mediators.”

In this regard, the researchers believe other pathways may be involved and recommend more research. They also wonder if the search for these pathways should begin before a CFRD diagnosis, as physiological changes may have already started.

Given that pulmonary flares are known to result in “worse long-term outcomes … this study adds an important extra dimension to discussions with adults with CFRD about optimal management and [treatment] adherence,” the investigators concluded.

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