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New and Emerging Respiratory Tract
Infections in People with Cystic Fibrosis
In cystic fibrosis, mutations in the CFTR gene lead to biochemical alterations in the
respiratory tract, which, in some way, seem to predispose the lungs to bacterial
This article addresses four questions:
What unusual bacteria can be found in the lungs of people with CF, What is the prevalence and the clinical relevance of these organisms, What is the potential impact of these organisms on the CF community, and How will these bacteria affect future maintenance and treatment of CF patients?
Respiratory Tract Infections in CF
Airway infections in people with CF (PWCF) are characterized by intercurrent acute
exacerbations with fever, weight loss, increased cough, change in volume, colour or
appearance of sputum, increased respiratory rate and appearance of infiltrates on chest
radiographs. Typically, periods of relative well-being are followed by episodes of these
pulmonary exacerbations, which result in progressive deterioration in lung function.
Although the median survival age of CF patients has doubled from 14 to 28 years
between 1969 and 1990 (largely because of improvement of antimicrobial therapy),
chronic pulmonary infection is still one of the most important causes of death.
Common bacterial pathogens in young children with CF are Staphylococcus aureus and
Haemophilus influenzae. During adolescence Pseudomonas aeruginosa infection
becomes common. The overall P. aeruginosa colonization rate in US CF patients is
approximately 60%, ranging from approximately 20% in children younger than 1 year to
more than 80% in patients aged 26 years or older.
Novel Bacteria
1. The Burkholderia cepacia Complex
“…‘cepacia syndrome’ is characterised by pneumonia and sepsis…”
Burkholderia cepacia is originally known as the causative agent of soft-rot on onions (see
Figure 1). The first reports of infection of CF patients with B. cepacia appeared in the
late 1970s and early 1980s. In 1984 the increasing prevalence of B. cepacia infection
among patients receiving care in the Toronto CF center (Canada) and the occurrence in
some patients of a rapidly progressing deterioration in respiratory function was described.
This so-called ‘cepacia syndrome’ is characterised by pneumonia and sepsis, and was
observed in as many as 20% of infected patients. Similar increases of respiratory tract
infection with B. cepacia were subsequently noted in other CF treatment centers in
North-America and Europe.
Initial studies (performed from the early 1990s on) showed that there was a remarkable
diversity among presumed B. cepacia isolates. During the past few years, several
taxonomic studies (taxonomy is the field in biology which aims to classify all living
organisms into groups on the basis of similarity) have indicated that strains (specific
‘individuals’ within the total population of a bacterial species) initially identified as B.
cepacia actually represent a complex of several closely related species. This group,
collectively referred to as the B. cepacia complex, currently consists of nine species.
Some of those species were given their own species name, while others are still waiting
for a new formal name and are currently designated as B. cepacia ‘genomovars’ (see
Table: Distribution of species among B. cepacia complex isolates recovered from people
with CF in the USA, Canada and Italy (in %)
Clustering of new cases in some centers and the decrease of colonisation of new patients following segregation of colonised and non-colonised patients in other centers suggested that B. cepacia complex strains could be transmitted between CF patients; subsequent studies (employing state-of-the art molecular epidemiological tools) showed that B. cepacia complex strains can spread between CF patients via simultaneous hospital admissions or social contact. As a result of these findings new guidelines were issued to reduce the risk of B. cepacia complex acquisition. These included discontinued sponsorship and support of CF summer camps and segregation of colonised patients. ___________________________________________________________________
“…infection control measures have a tremendous impact on the life of PWCF…”
These infection control measures have a tremendous impact on the life of PWCF and are not accepted by all CF patients and care-givers. Recent observations (including the observation that strict infection control measures have reduced but not eliminated new infections) have suggested that novel B. cepacia complex strains can be acquired from the environment; subsequently, several studies have showed that B. cepacia complex can indeed be recovered from some agricultural soils.
Figure 1:
B. cepacia isolates infecting onions.
All nine species belonging to the B. cepacia complex have been identified in CF sputum
cultures, but the distribution of these species among CF patients is quite disproportionate
(see Table). It is clear that B. cepacia genomovars III and II (renamed Burkholderia
) are most frequently recovered from infected CF patients worldwide. From
molecular epidemiologic studies, it is also clear that a few specific strains (e.g. the ET12
clone and the PHDC clone) of B. cepacia genomovar III have been identified as infecting
large numbers of patients. Whether or not this indicates that B. cepacia genomovar III (or
specific strains of B. cepacia genomovar III) are per se more virulent is at present unclear
since rigorous comparisons of clinical outcome between persons infected with different
B. cepacia complex species or specific strains have not yet been undertaken. At present,
the data only suggest an enhanced capacity for human infection by specific strains of B.
genomovar III, for which the biological basis is at present still unknown.
2. Other Burkholderia Species
Burkholderia gladioli is a well-known plant-pathogen, which is traditionally isolated
from gladioles and rice. However, CF patients seem to be especially prone to infections
with this organism. Nevertheless, compared to B. cepacia, the prevalence of B. gladioli
infection in the CF population is quite low.
Occasionally, other Burkholderia species can be found in CF patients as well. These
include Burkholderia pseudomallei (the causative agent of the tropical disease
melioidosis) and Burkholderia fungorum (a soil bacterium which is occasionally found in
human clinical samples as well). B. pseudomallei infections in CF patients appear to be
mostly travel-associated, since infections with this organism are usually associated with
travel to Southeast-Asia, an area where B. pseudomallei is frequently found.
3. Ralstonia and Pandoraea Species
Bacteria belonging to the genera Ralstonia (in particular Ralstonia pickettii and Ralstonia
) and Pandoraea (in particular P. apista) can also be found in CF patients.
Their occurrence and clinical role have not been systematically investigated and initial
data seem to suggest that their prevalence is, at present, rather low (e.g. 1.1% of all
Canadian CF patients is colonised with Ralstonia pickettii; an equal percentage is
colonised by species belonging to the genus Pandoraea).
Figure 2:
A Pandoraea isolate growing on an agar-based medium containing antibiotics and specific dyes.
4. Achromobacter xylosoxidans
(previously known as Alcaligenes xylosoxidans) is an
opportunistic human pathogen, capable of causing a wide variety of infections. A.
is also capable of causing persistent infection of the respiratory tract of
persons with CF, but its precise role in pulmonary decline is not clear. This species is
quite prevalent in CF (it infects approximately 9% of all patients in the US). At present
there is little evidence that this organism is acquired by patient-to-patient cross-infection.
5. Stenotrophomonas maltophilia is increasingly being recognised as an important cause
of hospital-acquired infections in debilitated and immunosupressed individuals and this
organism is also resistant to many currently available antimicrobial agents. This organism
was first isolated from CF patients in the mid 1970s and its prevalence has been rising
since then. There are large regional differences in prevalence of this organism, with
prevalence in North-America (1.8 –10.3%) being lower than in most European countries
(up to 25%). Duration of hospitalisation, mechanical ventilation, the use of nebulisers and
the amount of antibiotics received seem to be important risk factors for acquisition of S.
. Until now, there are very few reports documenting patient-to-patient spread
and since this organism is widespread in the environment, environmental acquisition
seems likely. The exact role of this bacterium in respiratory disease is unclear as different
studies have shown different clinical outcomes.
6. Enteric bacilli
Members of the bacterial family of the Enterobacteriaceae (e.g. Escherichia coli,
Klebsiella pneumoniae and Serratia marcescens) can occasionally be found in the lungs
of PWCF as well. They are usually transient colonisers and are in general not associated
with severe disease.
7. Mycobacteria
______________________________________________________ “…increasingly being recovered from the respiratory tract…” ______________________________________________________
Nontuberculous mycobacteria are increasingly being recovered from the respiratory tract
of PWCF. The most prevalent species are Mycobacterium chelonae, Mycobacterium
and Mycobacterium fortuitum, although other species have been found as well.
Nevertheless, non-tuberculous mycobacteria infections in CF are still rare. In addition,
studies have shown that their clinical impact appears to be minimal. It should however be
noted that the recovery of these slow-growing organisms is not straightforward as they
are often overgrown by other organisms present in CF sputum – hence, their prevalence
and clinical impact may have been underestimated.
Occasionally, Mycobacterium tuberculosis (the causative agent of tuberculosis) is
recovered from the sputum of CF patients as well. It remains to be determined whether
people with CF are more susceptible to tuberculosis than people without CF.
8. Other Organisms
Various recent studies have identified a wide range of additional bacteria that can
colonise the respiratory tract of PWCF. These include Inquilinus limosus, various
Acinetobacter species, Bordetella hinzii, Comamonas testosteroni, Moraxella osloensis
and others. Most of these organisms are only found occasionally and are generally
considered to be not dangerous for healthy human beings. The clinical role of these and
other unusual (as yet not identified) bacteria in CF lung disease is unclear, although it
seems that at least some of these organisms are capable of prolonged colonisation or spread among CF patients. PRACTICAL IMPLICATIONS The finding of these rather unusual bacteria in the lungs of PWCF shows that there is still much to learn about the respiratory micro flora in these patients. The data presented in several recent studies suggest that the CF lung seems to be an ecological niche suitable for the growth of a wide variety of bacteria not commonly associated with human disease. Factors that account for the association between typically non-pathogenic species and the respiratory tract of CF patients are unknown, but the elucidation of these factors may provide important insights into the pathophysiology of CF infection. This would be an important first step towards the development of effective therapies. _______________________________________________________________________
“…misidentification as B. cepacia complex can have a significant
medical, social, and psychological impact …”
Another important issue is that the majority of the above-mentioned bacteria pose a challenge to clinical microbiology laboratories. Most of these bacteria have only recently been described and they can either not be identified by the lab or are often misidentified as B. cepacia complex. This misidentification as B. cepacia complex can have a significant medical, social, and psychological impact and should therefore be avoided at all cost. Accurate identification of these unusual organisms is also important to identify outbreaks or to assess their clinical impact. Recently, a lot of work has been done to improve the existing methodologies and to ‘invent’ new approaches to avoid these misidentifications. These include the use of state-of-the-art molecular-biological tools, including the polymerase chain reaction (PCR). However, these novel methods are not (yet) available in all clinical microbiology laboratories; therefore unusual isolates recovered from CF specimens should be sent to reference laboratories capable of providing more in-depth analyses of these isolates. Examples of these laboratories include: the CFF Burkholderia cepacia Research Laboratory and Repository at the University of Michigan, Ann Arbor, MI, USA; the B. cepacia complex Research and Referral Repository for Canadian CF Clinics at the University of British Columbia, Vancouver, BC, Canada and the Edinburgh Cystic Fibrosis Microbiology Laboratory and Repository at the University of Edinburgh, Scotland, UK. It should be noted that several other laboratories also provide services for the identification of CF isolates. More information can be obtained from the national CF charitable organisations.
Although systematic studies regarding antimicrobial resistance have only been performed
for members of the B. cepacia complex and for S. maltophilia, it is obvious from
anecdotal data that at least some strains of most of the above-mentioned organisms are
highly resistant to various antibiotics. Since the resistance patterns of the different strains
and species may vary, susceptibility testing can be useful in designing treatment
strategies. The combined use of multiple antibiotics may show increased activity;
therefore it is useful to test multiple antibiotic combinations (‘synergy testing’). To aid in
susceptibility testing and synergy studies on multiply resistant organisms isolated from
CF patients, the CF Referral Center for Susceptibility and Synergy Studies of Resistant
Organisms (Columbia University, New York, NY, USA) was established.
Eradication of B. cepacia complex organisms from the lower respiratory tract appears to
be virtually impossible, but antibiotic therapy can lead to decreased bacterial density and
decreased bacterial virulence production, and hence to a decrease in inflammation and
clinical improvement. Examples of antimicrobial combinations that have been shown to
show synergy include ciprofloxacin/piperacillin, tobramycine/piperacillin and
trimethoprim/ceftazidime. Most S. maltophilia strains appear to be susceptible to
trimethoprim-sulfamethoxazole (alone or in combination with ticarcillin-clavulanate or a
broad spectrum cephalosporin). In addition, new quinolone antibiotics (like sparfloxacin)
may be useful for the treatment of S. maltophilia infections as well.
It is at present unclear what the impact of these organisms will be on lung transplantation
practices. Many treatment centers consider B. cepacia complex infection an absolute
contraindication to lung transplantation, but as stated higher, additional studies will be
required to better define the relative risks associated with each species of the B. cepacia
complex. At present, no data are available on the outcome of lung transplantations
involving patients colonised with any of the other organisms discussed above.
“…there is still a lot to learn…”
It should be clear that there is still a lot to learn about respiratory tract infections in people with CF. Nevertheless, it should also be clear that significant progress has been made over the last 15 years. It can be expected that these advances in our understanding of the biodiversity of agents responsible for respiratory infections will eventually lead to an improvement of the quality of life of people with CF. Tom Coenye, PhD Laboratorium voor Microbiologie Universiteit Gent K.L. Ledeganckstraat 35
B-9000 Gent
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