Pulmonary exacerbations in adults with cystic fibrosis (CF) fall into three distinct groups based on inflammatory markers in their bloodstream, a pilot study has discovered.

These unique inflammatory profiles corresponded to different times from the onset of symptoms to hospitalization, to the rate of lung function decline before hospitalization, and to the response to antibiotic treatment, according to researchers.

Patients with low levels of inflammatory markers had longer times from symptom onset to hospitalization and less decline in lung function, but fewer completely responded to antibiotics. In contrast, those with a more pro-inflammatory signature saw a quicker lung function decline and a shorter time to hospitalization, but most responded better to treatment.

Further studies are needed to evaluate CF treatment outcomes or management approaches guided by these findings, the researchers noted in the pilot study, “Pulmonary exacerbation inflammatory phenotypes in adults with cystic fibrosis,” which was published in the Journal of Cystic Fibrosis.

Pulmonary exacerbations are significant events with CF, marked by the acute worsening of lung symptoms, typically due to infection and inflammation.

Emerging evidence suggests some patients hospitalized with a pulmonary exacerbation have low systemic (bodywide) inflammation levels based on standard C-reactive protein (CRP) blood tests. These people may not mount a robust immune response to infection or noninfectious causes may drive their exacerbation with minimum inflammation.

Whether distinct systemic inflammatory profiles can be identified in those with a pulmonary exacerbation and whether they can predict treatment outcomes remains unclear. Also, because CRP results can be influenced by age, sex, socioeconomic status, and body fat content, a broader profile using multiple inflammation-related markers may improve classification.

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Identifying exacerbation subtypes by immune profiles

Researchers in Canada collected blood samples from 28 adults with CF who were admitted to a local hospital for a pulmonary exacerbation that required intravenous (IV, into the vein) antibiotic treatment.

They measured the levels of six inflammation-related blood proteins: interleukin-1-beta (IL-1-beta), IL-6, IL-10, TNF-alpha, calprotectin, and CRP.

Respiratory symptoms began three or more weeks before a hospitalization in 16 (43%) cases, acutely, one week or less, in 10 (27%), and between 1-3 weeks in 10 (27%).

Blood tests showed three distinct subtypes of pulmonary exacerbation based on immune profiles: a pauci-inflammatory subtype (low immune response), a pro-inflammatory subtype, and another pro-inflammatory response dominated by immune neutrophil cells.

The pauci-inflammatory subtype was marked by lower levels of all six inflammatory markers. Neutrophil counts were also lower in this group compared with the other subtypes.

Higher levels of IL-6 and IL-1-beta were found in the pro-inflammatory and neutrophil-predominant subtypes, with elevated calprotectin associated solely with the neutrophil type, although not with a statistical difference relative to the pro-inflammatory subtype.

The pro-inflammatory signature was marked by higher TNF-alpha and IL-10 levels compared to the other two subtypes, demonstrating “a distinct nonneutrophilic pro-inflammatory” type, the researchers noted.

Ahead of a hospital admission, those with neutrophil-predominant exacerbations had a sharper drop in lung function and a shorter time between the onset of symptoms and hospitalization. Half (50%) of them were acute cases compared with 17% in the pauci-inflammatory group and 14% in the pro-inflammatory group. In comparison, more of those with pauci-inflammatory exacerbation events had a more prolonged symptom onset of three or more weeks.

At admission to the hospital for pulmonary exacerbation, there was no significant difference between these subtypes regarding lung function and symptoms scores using the CF Respiratory Symptom Diary-Chronic Respiratory Infection Symptom Score (CFRSD-CRISS).

Antibiotic treatments lasted for a median of 14 days for all three subtypes. Two exacerbation events (17%) in the neutrophil-predominant group were treated with systemic corticosteroids.

With treatment, greater lung function improvements occurred in the neutrophil-predominant subtype, followed by the pauci-inflammatory and pro-inflammatory clusters. These improvements were maintained throughout post-treatment follow-up.

While the neutrophil-predominant cluster saw the greatest reduction (improvement) in symptom CFRSD-CRISS scores from admission to the end of treatment, the differences were not statistically significant between groups, “suggesting that symptoms were not reflective of the type of inflammation during [pulmonary exacerbations],” the researchers wrote.

Lastly, four of 18 (22%) pulmonary exacerbations in the pauci-inflammatory subtype failed to recover to 90% of pretreatment lung function following antibiotics. In contrast, 1 of 12 (8%) in the neutrophil-predominant and none in the pro-inflammatory cluster failed to recover.

Because the pauci-inflammatory cluster had the longest time from symptom onset to hospitalization and responded less to treatment, “the inflammatory phase may have already been resolved and the optimal treatment window missed with the establishment of irreversible airway damage,” the researchers said, noting more research is needed “along with carefully designed clinical trials to evaluate treatment outcomes of therapies or management approaches guided by these [subtypes].”

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