Mucus Plugging in Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is much better understood than it was two decades ago (1–3). It had been thought to be quite a rare condition diagnosed primarily by ciliary biopsy. We now know that it is at least twice as common as previously believed (4). Ciliary biopsy is frequently both unnecessary and unhelpful (1, 2), and clearly defining the phenotype and genotype are key elements of the diagnostic process (2). Indeed, we have gone in two decades from not knowing the precise genetic basis of PCD to currently knowing more than 50 different genetic causes of the condition (5). This astonishing increase in knowledge has been thanks to the visionary leadership of the U.S. National Heart, Lung, and Blood Institute–sponsored Genetic Diseases of Mucociliary Clearance Consortium (GDMCC), the PCD Foundation, and European equivalents of these organizations (1–3, 6).

In this issue of AnnalsATS, Kinghorn and coworkers (pp. 539–547) from the GDMCC have made an additional advance that is important for pediatric providers (7). The authors have used a systematic analytic approach to PCD chest computed tomography (CT) scans, known as the Melbourne-Rotterdam Annotated Grid Morphometric Analysis for PCD (MERAGMA-PCD), to reevaluate chest CT scans performed on 141 children with established PCD who had participated in the GDMCC. They report that, even in childhood, almost all CT scans are abnormal. Individual CT scans showed disease in an average of 4.6% of total lung volume, with significant contributions from atelectasis and mucus plugging. Moreover, bronchiectasis was present in a mean of 1.5% of total lung volume (range, 0–4.1%).

We would like to point out that there are some striking similarities between the Kinghorn study and a previous analysis of chest CT scans performed on adults with asthma in the SARP (Severe Asthma Research Program) cohort. Dunican and coworkers showed in the adult SARP cohort that 27.4% of subjects with asthma had high mucus plugging scores, versus essentially none of the control subjects (8). Similarly, in the current PCD study, approximately 30% of the children with PCD had high mucus plugging scores. In contrast, in a separate chest CT scan analysis comparing PCD to cystic fibrosis (CF)—before the advent of universal newborn screening and modulator CF therapies (9–11)—mucus plugging was much less common in CF than in PCD. Both the Kinghorn and colleagues and Dunican and colleagues papers called attention to a distinctive mucus plugging phenotype in PCD (Kinghorn and colleagues) and asthma (Dunican and colleagues).

In both PCD and asthma, many subjects had bronchiectasis, but in neither cohort did having a high mucus plugging score predict that the bronchiectasis score would also be high. For example, in the asthma cohort, only 27.5% of the patients with high mucus scores had bronchiectasis. Similar trends are evident in Figure 2 of Kinghorn’s PCD study. Indeed, the distinct mucus plugging subpopulation, on a relatively uniform background of structural lung changes, calls into question the value of the aggregate MERAGMA-PCD overall score in which all components are simply added. The CT seems most valuable in distinguishing those who do and do not have mucus plugging. In any event, in both childhood PCD and in severe asthma, there is a subpopulation of patients with extensive mucus plugging that is, to a certain extent, independent of the severity of bronchiectasis.

There are important limitations to the PCD analysis. For example, the length of time between PCD diagnosis and CT scan was not uniform, nor could treatment effects be accounted for. Differences in mucus plugging score, for example, could simply represent different frequencies of airway clearance treatment. Markers of type 2 inflammation, such as sputum or circulating eosinophil counts, were not available for analysis. These types of data, along with the longitudinal repeatability of the MERAGMA-PCD data, will be critical to understanding the proposed high mucus phenotype. There was some suggestion that subjects with genotypes associated with loss of inner dynein arms or with mixed tubular defects had more mucus plugging but not much difference in bronchiectasis when compared with other children in the PCD cohort. If this association between genotype and mucus plugging bears out in longitudinal analysis, it will be interesting. Patients with certain defects caused by loss of CCDC39 and CCDC40, for example, may have a more rapid loss of lung function overall than other patients with PCD (12, 13). However, there remains a complex landscape of lung biology between genotype and phenotype. Mucus plugging is not a structural lung disease per se, either in PCD or in asthma. Causative inferences regarding the relationships between genotype, mucus plugging, and change in forced expiratory volume in 1 second over time cannot yet be drawn.

Clearly, the MERAGMA-PCD system for chest CT analysis is an important advance. Scans were read in a uniform and repeatable way at a single center (Rotterdam). This approach will likely become useful to identify mucus plugging. Moving forward, however, it may be advisable for the GDMCC to compare notes with the SARP radiology investigators regarding uniformity of scanning procedures. The SARP also performed childhood scans, with strict parameters monitored closely by the SARP data safety monitoring board (DSMB). All makes of CT scanners were used in such a way as to generate digitally comparable data, validated on a shared “phantom” dummy with established densities. Inspiratory volumes, cuts, and other parameters were strictly uniform across all sites, and extensive details about treatment and laboratory values at the time of each scan were available for analysis. There may be things that the GDMCC can learn from the SARP, and vice versa.

In summary, Kinghorn and coworkers have applied an important tool for evaluating airway disease in PCD—the MERAGMA-PCD system for chest CT analysis. In addition, they have demonstrated that there is a large subset of children with PCD with a striking degree of mucus plugging, a finding with some similarities to the adult SARP cohort. Continuing to standardize scanning procedures and evaluating these children longitudinally will be vital. Moving forward, several research questions regarding high mucus score phenotypes could be considered (Table 1).

Table 1.

Primary ciliary dyskinesia and asthma subpopulations with increased mucus plugging: proposed research questions

Pathophysiology: possibilities in terms of commonalities between high mucus phenotypes in PCD and asthma

It is a coincidence: mucus plugs in PCD and asthma have little in common in terms of composition, pathogenesis, or management implications; or

PCD causes antigen stasis, leading to an asthma-like phenotype with a local Th2 response in some patients with PCD; and/or

Asthma causes ciliary dysfunction in some patients, leading to poor mucus clearance; and/or

Heterozygosity of PCD genes (or mild PCD) underlies asthma and/or poor clearance of mucus plugs in some patients with asthma; and/or

Adult severe asthma is, in some patients and to some extent, a slowly progressive form of what we see in childhood PCD.

Therapeutic possibilities

Treatment of high mucus phenotypes may be completely different in the two conditions; or

PCD treatments (airway clearance techniques, mucolytics) may have value in the high mucus phenotype of asthma; and/or

Antiinflammatory asthma treatments may have value in the high mucus PCD phenotype.

Definition of abbreviations: PCD = primary ciliary dyskinesia; Th2 = T-helper cell type 2.