Discussion:
In this study we performed a retrospective analysis of children reported
to have CRMS in the CFFPR. Our results show that for the first 9-10
years of life, the large majority of infants with CRMS remain healthy
and do not convert to CF. In contrast to children with CF, their ppFEV1
and nutritional indices are normal. However, a small percentage of
children do develop clinical features concerning for CF, such as a
respiratory culture positive for Pa.
Although several studies of prevalence and outcomes of CRMS/CFSPID, most
studies have been limited to children ≤3 years old [7, 8]. Grove, et
al performed a retrospective study of 29 infants with CRMS who were
followed for 2-10 years and reported that 48% converted to CF [15].
However, many of these children were diagnosed on the basis of
non-specific clinical signs, such as cough. More recently, Muncket al reported the results of a prospective matched cohort study
of infants with CF and CFSPID [16]. Comparison of their results to
ours is difficult because a large percentage (32%) of the CFSPID
infants were later diagnosed with CF due to reclassification of their
CFTR mutations as CF-causing. With that caveat in mind, their cohort
also demonstrated normal nutritional and FEV1 indices.
However, chest computed tomography revealed the presence of
bronchiectasis in 8% of the cohort, highlighting the potential for lung
disease in CRMS/CFSPID infants. Terlizzi et al reported that 10%
of CFSPID infants followed for up to 6 years converted to CF, based on
an elevation of sweat chloride ≥60 mmol/L [17]. However, they did
not report on any clinical features of these infants. Gonska, et al
prospectively followed a cohort of infants with CRMS/CFSPID in Canada
and Verona up to age 7 years [9]. Similar to our study, they found
that nutritional indices and lung function were normal at age 7 years.
Our study complements that of Gonska, et al and other by analyzing a
larger, more diverse cohort of infants with CRMS/CFSPID followed at
>100 CF Care Centers across the USA. We also analyzed
microbiologic outcomes at different ages and showed that in contrast to
infants/children with CF, Pa prevalence in CRMS/CFSPID declined with
age. Taken together, the studies cited above and our results indicate
that infants who meet a CFF guideline definition of CRMS may still
present with clinical features concerning for CF even in childhood, and
they support the need for continued close monitoring of this infants.
There are several limitations of our study, but also some strengths. Not
all CRMS infants are entered into the CFFPR, either because their care
teams or the families do not wish to enroll them. This may have resulted
in underreporting of the true prevalence of CRMS. There were also many
patients with incomplete genetic or sweat chloride data, which precluded
us from being able to assign a guideline diagnosis of CF or CRMS. The
CFFPR collects only limited clinical symptom and physical exam findings,
such as cough or wheeze; having such data may have provided more insight
into why some children were classified as CF despite not meeting sweat
chloride or CFTR mutation criteria for this diagnosis. There is also
variation in care amongst CF Centers, such as frequency of respiratory
cultures and follow up sweat testing, which may have affected the
consistency of some of our outcome measures. The loss to follow up rate
was higher in the CRMSc/CRMSg compared to the other groups (Tables S3,
S4, and S5). This may have resulted in selection bias towards retaining
only those infants with more symptoms or concerns for CF. Thus we need
to be circumspect in comparing clinical outcomes between the CRMSc/CRMSg
and CFc/CRMSg groups. Since follow up sweat testing was performed at the
discretion of clinical care teams, we could not perform any analysis of
serial sweat testing. Strengths of our study include the large number of
patients in our study cohort followed at a large number of different CF
Centers and the long follow up time.
In summary, this large registry-based analysis of CRMS infants up to
ages 9-10 years shows that the large majority remain well, do not
convert to a CF diagnosis, and have normal nutritional and pulmonary
indices. However, a small proportion do develop clinical features
concerning for CF. These results support continued close monitoring of
these infants at least into early childhood. Future research should
include longer follow up to ascertain the risk of CFTR-related disorder
in these children and to identify any other risk factors for development
of CF other than initial sweat chloride concentration.
Acknowledgements
The authors would like to thank the Cystic Fibrosis Foundation for the
use of CF Foundation Patient Registry data to conduct this study.
Additionally, we would like to thank the patients, care providers, and
clinic coordinators at CF centers throughout the United States for their
contributions to the CF Foundation Patient Registry. We also thank Ase
Sewall for her assistance with data preparation.