A Prospective, Multicenter, Collaborative Study to Determine the Prevalence of Nontuberculous Mycobacteria (NTM) in Pediatric Patients With Cystic Fibrosis in Florida

Non-tuberculous Mycobacteria (NTM) are a heterogeneous group of organisms that have been
increasingly reported in North America 1, 2 and recognized to be a pulmonary pathogen in non
immunocompromised persons, in middle age-elderly people, non smoking women, apart from the
high risk population with underlying lung disease, and also in Cystic fibrosis (CF)
population.

Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasians, a result
of mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. The carrier rate is
estimated at 1:25, and 1:3500 live births in Caucasians are affected with CF. A broadening
spectrum of mutations of the CFTR gene has been identified in recent years and a widening
array of disorders, particularly of the respiratory system, is expected to be associated
with some of these genetic abnormalities. The predisposition to specific airway infections
may be a feature of some of these mutations as well as many modifying genes that could alter
the course of the disease.

The disease predominantly affects the GI tract and the respiratory system. Infectious
complications of the latter are the predominant determinants of morbidity and life
expectancy in these patients.

Patients with cystic fibrosis are also at high risk of suffering from chronic airway
infections, and one of the increasingly identified microorganisms is non-tuberculous
mycobacteria. NTM has been shown to be a potential contributor to the decline in lung
function, the major determinant of outcome and longevity of these patients.

Since patients with CF have chronic bacterial pulmonary infections as their disease
progresses, the clinical signs and symptoms of NTM are often difficult to distinguish from
the underlying disease. Such potential underestimation of the contribution of NTM to the
decline of lung function in cystic fibrosis may be an added risk to the eventual outcome of
these patients. A variety of microorganisms traditionally considered colonizers of the
airways, have been increasing in frequency and assuming new clinical significance5, 6, and
previously unknown types of known organisms are taking on a new and ominous clinical
significance.7 To the practicing clinician NTM appears to be increasing in incidence among
the CF population, but the significance of this observation has not been firmly established.
The concept of "colonization," defined as the isolation of the organism from the respiratory
tract without evidence of tissue invasion, was supported by several investigators in the
past, mainly in association with M. avium-complex infection.8, 9 With the emergence of high
resolution CT scanning (HRCT), it now appears that many of these patients have features of
parenchymal involvement, usually of a nodular pattern, suggesting that the term
"colonization," at least in some patients, may be erroneous10, this notion has also been
supported by direct bioptic evidence11, indicating the possibility that the full
significance of infection with NTM may be underappreciated in patients with CF. It has been
proposed that rather than using terminologies such as colonization and active disease, the
distinction should be between patients who require immediate therapy on the basis of the
rapid progression of their disease and those in whom the decision can be delayed.12 The
repeated isolation of the same Mycobacterium from a patient with CF may be indicative of
indolent infection and these patients may be at risk of developing clinical symptoms that
will ultimately require treatment. This observation is supported by a series of autoptic
studies13 indicating that patients with CF who have multiple positive sputum cultures for
NTM are more likely to have histologic evidence of granulomatous mycobacterial disease. An
additional study11 reports of a patient who had bioptic evidence of granulomas with NTM
infection resulting in fulminant disease some 14 years later, suggesting that frank
infections may be subclinical for a long period of time. The predictable but variable
progression of the lung disease inherent to CF cannot be easily uncoupled from a possible
contribution that chronic infection with NTM may add to the slope of such decline. Thus the
role of such silent infections in exacerbating the decline of pulmonary function in such
patients remains to be elucidated. From the clinical perspective subtle changes on serial
high resolution computerized tomography of the chest (HRCT) may enable earlier diagnosis and
intervention prior to the development of cavitation and/or irreversible lung damage.10 Of
the NTM, Mycobacterium abscessus is a member of the rapidly growing mycobacteria. With
improvements in identification, it is now known that this organism accounts for
approximately 80% of rapidly-growing mycobacterial respiratory disease isolates.9 Prior to
the 1990s, there were few reports of clinically important NTM infection complicating CF of
which seven were cases of M. abscessus.11 Although the natural history of this disease can
vary, it appears to follow a more fulminant course in patients with underlying lung diseases
such as cystic fibrosis.14 The treatment of M. abscessus is complex. The isolates are
uniformly resistant to standard antituberculosis drugs and are generally susceptible only to
parenteral antibiotics and the newer oral macrolides. The organism is notoriously difficult
to eradicate. In a report of 154 patients infected with rapidly growing mycobacteria14, only
10 patients infected with M. abscessus exhibited a "cure," the latter being defined as a
return of respiratory symptoms to baseline and reversion of sputum to smear and culture
negativity for at least 1 year. It has been noted for many years that the rates of infection
and morbidity with and from NTM in non-CF patients have been increasing.1, 9 This notion has
been recently supported by a report on the prevalence of mycobacterial infection in Ontario.
The prevalence rose significantly (p<0.001) from 9.1/100,000 in 1997 to 16.5/100,000 in
2002, and 14.2/100,000 in 2003. A coincidental significant (<0.001) decline in the rate of
M. tuberculosis infection from 6.9/100,000 in 1997 to 5.4/100,00 in 2003 was noted15.
Whether such a trend of increasing prevalence of NTM also occurs in CF has not been formally
addressed in the literature.

A number of studies from the US and Europe addressing the epidemiology of NTM in cystic
fibrosis has been published. These studies suggest a large variability in the incidence and
the nature of the infecting organisms between various regions of the world, and various
institutions. While the clinical impression would support a trend of increasing prevalence
of NTM in CF parallel to non-CF patients, the absence of repeated studies and the
limitations imposed by the inconsistencies amongst centers and regions, does not allow a
firm statement on this subject.

The increasing rates of infection and morbidity from NTM in non-CF patients 1, 2 is likely
similarly trending amongst patients with CF. In the US, a 1992 study from the University of
North Carolina at Chapel Hill 3 revealed a high prevalence of CF patients with NTM infection
in the southeastern United States. Of 87 patients studied 17 (19.5%) had at least one
positive culture for NTM. A 1993 study was reported from the University of Washington 4
revealing a prevalence of 12.5% amongst their 64 adult patients.

The key publications on prevalence of NTM in patients with CF in the US by Olivier et al5
revealed an overall prevalence of 13%, with the most common organisms in adults being M.
avium- complex (MAC).

Data on the prevalence and significance of NTM infections in younger patients with CF are
less clear. Several studies suggest that NTM infection in CF pediatric population is low 3-7
but the numbers vary around the globe. A study from Necker Hospital for Sick Children in
Paris8 revealed a prevalence of 5 % in children with a mean age of age 11.9 y o (2.5 to 22 y
o). It also revealed that M. abscessus was the prevailing organism among the pediatric
population, rather than MAC, the commonest organism in adults.

The Olivier studies 5 confirmed that the prevalence of NTM is particularly high in the
southeastern USA, as previously suggested by a study from the adult CF center of the
University of North Carolina at Chapel Hill 3 that revealed a prevalence of 19.5%. It is
therefore of particular interest that a recent pediatric study from the same medical center
9 retrospectively reviewed CF patients younger than 12 years old and found 6.1% overall
prevalence of NTM in BALs over 3 years, and 3.9 % using medical record examination over a
10- year period.

This information that is collected will help to deepen the understanding of the nature of
the microbiology of our CF pediatric population, and to what extent NTM play a role in the
colonization and possible disease causation in this region of the country. The investigators
think this role is underestimated. Once the information becomes available, The investigators
will be able to make better plans of dealing with this infection.

Inclusion Criteria:

- Patients that have a diagnosis of Cystic Fibrosis and are 18 or below years of age

Exclusion Criteria:

- Patients that are above 18 years of age and or patients that do not have the
diagnosis of Cystic fibrosis