Discussion
This study found that neonatal complications, low FEV1/FVC, low FEF25-75
and low body mass index were associated with increased mortality in
Indian children with cystic fibrosis. European cystic fibrosis society
patient registry database of 2007 suggested that low BMI, chronic
pancreatic insufficiency, chronic colonisation with Pseudomonas and
development of cystic fibrosis-related diabetes mellitus increases the
risk of having poor lung function as demonstrated by poor FEV1 value
(8). However, our study patients did not have a statistically
significant incidence of CFRD, chronic colonisation with Pseudomonas or
chronic pancreatic insufficiency. Moreover, as per the natural history
of the disease, the complications like CFRD usually develop in the
second decade of life. In our study population, most children had died
just after the first decade of life at an average age of 13.5 years
(95% CI- 8.3 -17.0).
Earlier studies done in adults reported that low FEV1 was associated
with increased mortality (8). It has been demonstrated by Kerem et al.
that patients with an FEV1 value < 30% predicted to have a
40- 50% chance of dying with two years in a cohort followed up for 12
years (9). FEV1 was the strongest predictor of mortality in a study
conducted by Huang et al., although the authors mentioned that other
lung function test indices were not strong predictors of mortality (10).
There was a trend of low FEV1 in the died group in our study (Table 1),
but it was not a predictor of mortality in COX regression analysis. A
possible explanation may be early death (average age at death 13.5
years) in our cohort before they had very low FEV1. FEV1 is effort
dependent and FEV 25-75 is relatively less dependent on patient’s
effort. However, low FEF25-75 and the low ratio of FEV1/FVC is a
relatively novel finding of the present study.
The case fatality rate in our study was 18.0%. A study done by Courteny
et al. indicated an average case fatality rate of 24.6 in adults (11).
Lower BMI and lower PFT results are in general associated with higher
mortality reported from various studies from different parts of the
world (12-14), as seen in our study.
The average age at death was 13.5 years in our study, which is much
lower than the average life expectancy of CF patients in western
countries (15). This is possibly due to the early diagnosis and
availability of CF specific drugs in western countries. CF in developed
countries is no longer a paediatric disease than developing countries
where it still qualifies to be a disease of children. Most children had
died in the first half of the second decade of their lives. This
shortened life span in developing countries like India is attributed to
delay in diagnosis and lack of proper medical facilities even after
diagnosing disease. Because of the lack of national guidelines and
support, most children are treated symptomatically without giving them
advanced care in CF specific drugs. Since the cost of CF specific drug
therapy is exorbitantly high, most parents cannot bear the cost of
treatment and hence prefer symptomatic medical/surgical management as
necessary. Average age at which symptoms appeared first and at which
diagnosis of CF was confirmed was 6 months (95 %- 1.5,24) and 60 months
(95%- 17,120) in the group that had died during the period of the
study. Even in our study, the time lag between the onset of symptoms to
diagnosis of CF was around two to four years. This delay is attributed
to lack of suspicion at primary/secondary care centres due to lack of
awareness, non-availability of diagnostic tests, and further delay in
referral to higher centres equipped with CF specific care. Most children
had poor nutrition status at the diagnosis itself. Family history of CF
was found in very few children in our study, and it did not contribute
to increased mortality.
We had more representation of male children in our study cohort;
however, the death rate at the end of the study period was higher in
female children (Figure 1). This corresponds to the earlier studies
conducted by Kerem et al. (9) and Rosenfeld et al. (16) in the adult
population. Although the exact cause as to why female children have
higher mortality is not known to us, it may be related to better
nutritional status and better medical care given to male children in
India. However, further research is required to know the exact cause of
higher mortality in female children because even in developed countries
where no preferential treatment is given to male children, mortality is
reported higher in female children (9,16).
Homozygous Delta F 508 is the commonest mutation in western countries
and is associated with higher mortality. A mutation study revealed that
heterozygous delta F508 is the most common mutation in this study
cohort. An earlier study done by Connor et al. found that heterozygous
delta F508 mutation was associated with a reduced risk of mortality
compared to homozygous delta F508 mutation (17). Another study done by
Johansoen et al. (18) suggested that homozygous delta F508 has a higher
risk of mortality than other mutations. If we compare the studies of
Connor et al. and Johansoen et al., it is evident that the presence of
heterozygous delta F508 mutation was associated with lower mortality.
However, there was no association between the type of mutation and the
risk of mortality in our study. This is possible because we could not do
a complete mutation study of the entire study cohort due to the lack of
facilities and heterogeneous mutation profile in our population.
BMI was a significant predictor of mortality in our study. This is again
corresponding to an earlier study by Kerem et al. (9), Bell SC et al.
(19) and Fired et al. (20). However, Courteny et al. conducted a study
on predicting mortality in adult CF patients and found no correlation of
increased mortality with BMI (11).
There was no significant association of any lab parameter with the
mortality on bivariate analysis. Although airway colonisation was seen
in almost 2/3rd of our study population, it did not contribute to
overall mortality. The most common bacteriological agent for
colonisation was Pseudomonas, followed by staphylococcus and
Burkholderia. Age of colonisation and the organism of colonisation had
no bearing on overall mortality in our study. This contrasts to earlier
studies where early colonisation and colonisation with species like
Burkholderia were found to significantly contribute to mortality in
patients with CF (20-24). A possible explanation for not finding an
association between airway colonization and increased mortality in our
study may be, that other factors like poor nutrition and not been able
to afford the treatment contributed more to early mortality.
CF-related complications like ABPA, CF-related liver disease and
Pulmonary artery hypertension was found in very few children, and it did
not contribute to mortality.
The strengths of our study are that it was conducted over a large cohort
that was followed over ten years and is likely to represent the
disease-specific traits in the Indian population. This is one of the
first few studies with a relatively large number of patients where we
have tried to analyse the predictors of mortality in Indian children
with CF.
There are few limitations also of our study. Few data were missing due
to the retrospective nature of the study. We had no access to newer CF
specific drugs like lumacaftor, Ivacaftor and Tezacaftor due to lack of
funds, which might have some survival benefits. Finally, we could not do
a complete genetic analysis of all the patients.