The earliest descriptions of lung disease in people with cystic fibrosis (CF) showed the involvement of 3 interacting pathophysiologic elements in CF airways: mucus obstruction, inflammation, and infection. Over the past 7 decades, our understanding of CF respiratory microbiology and inflammation has evolved with the introduction of new treatments, increased longevity, and increasingly sophisticated laboratory techniques. This article reviews the current understanding of infection and inflammation and their roles in CF lung disease. It also discusses how this constantly evolving information is used to inform current therapeutic strategies, measures and predictors of disease severity, and research priorities.
Key points
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Cystic fibrosis (CF) lung disease involves a cycle of mucus obstruction, inflammation, and infection in the airways, and each of these elements affects the others as disease progresses.
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Observations from the earliest studies of CF disease in the 1930s and 1940s showed these elements, but the understanding and treatment of each has evolved over time.
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CF respiratory microbiology has also evolved as new treatments have been introduced, as people have lived longer with this disease, and as detection methods have become more sophisticated.
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The CF airway also shows altered host-defense, and imbalances in the airway environment are important for pathophysiology and may indicate both new treatment directions and useful disease biomarkers.
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Because most information regarding the relationships between infection, inflammation, and disease severity come from observational studies, their causal relationships are not always clear.
Introduction
The earliest published descriptions of cystic fibrosis (CF) lung disease described the following triad of pathophysiologic elements that still form the basis of most current models:
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Airway obstruction
- •
Infection
- •
Inflammation
In her landmark 1938 publication describing the pathologic and clinical features of children who died of this disorder, Dorothy Andersen identified the common features of “bronchitis, bronchiectasis, pulmonary abscesses arising in the bronchi,” which were plugged with “tenacious, greenish gray mucopurulent material,” and that “ Staphylococcus aureus was the usual bacteriologic agent.” From these findings, she and others began treating children with CF with antibiotics targeting S aureus , specifically sulfonamides and penicillin. This approach was followed by several important developments. First, the children generally improved clinically. Second, cultures showed that they were increasingly infected with penicillin-resistant S aureus , as well as pathogens not seen before antibiotics, including Pseudomonas aeruginosa .
These early observations are instructive on many levels. The primary defect that causes CF, mutational dysfunction of the CF transmembrane conductance regulator (CFTR), leads to a cycle in the airways of defective mucus clearance, obstruction, infection, and inflammation. Improvements in nutrition, mucus clearance, and treatment of inflammation and infection have led to dramatic improvements in CF respiratory morbidity and mortality ; however, current treatments have not been able to halt disease progression. As patients live increasingly longer, their respiratory microbiology evolves, perhaps driven by elements of care intended to mitigate their lung disease (such as antibiotics and attending clinics at CF care centers). Put differently, the treatments that have so greatly helped people with CF are often followed by microbiological changes, which in turn may alter their clinical course. The causal relationships between specific pathogens, clinical changes, and constantly evolving therapies are difficult to sort out.
Andersen and di Sant’Agnese made special mention of the apparent link between infection and inflammation. Although these are omnipresent features of CF lung disease, the causal relationships between them are controversial. Observations from a variety of studies of patients and, most recently, animals engineered with CFTR mutations have led some investigators to postulate that infection is required for CF airway inflammation, whereas others have suggested that inflammation can precede infection. Although these disputes continue, great progress has been made in defining the mediators and mechanisms driving the intense inflammation within CF airways, identifying not only new candidate therapeutic targets but also promising biomarkers of early disease.
This article reviews the current understanding of the roles of infection and inflammation in CF lung disease pathogenesis. Although these two features of the CF airway are mechanistically linked by data from observational studies and, as a result, in current pathophysiologic models, for simplicity this article considers them separately. Although this article touches on therapeutic approaches to both infection and inflammation, clinicians are currently experiencing a period of particularly rapid evolution in CF treatment strategies and protocols. Therefore, where appropriate, this article refers readers to recent, in-depth reviews of CF therapeutic strategies for more information. Similarly, there have been several excellent reviews of CF respiratory microbiology and inflammation in general that readers may find useful.
Introduction
The earliest published descriptions of cystic fibrosis (CF) lung disease described the following triad of pathophysiologic elements that still form the basis of most current models:
- •
Airway obstruction
- •
Infection
- •
Inflammation
In her landmark 1938 publication describing the pathologic and clinical features of children who died of this disorder, Dorothy Andersen identified the common features of “bronchitis, bronchiectasis, pulmonary abscesses arising in the bronchi,” which were plugged with “tenacious, greenish gray mucopurulent material,” and that “ Staphylococcus aureus was the usual bacteriologic agent.” From these findings, she and others began treating children with CF with antibiotics targeting S aureus , specifically sulfonamides and penicillin. This approach was followed by several important developments. First, the children generally improved clinically. Second, cultures showed that they were increasingly infected with penicillin-resistant S aureus , as well as pathogens not seen before antibiotics, including Pseudomonas aeruginosa .
These early observations are instructive on many levels. The primary defect that causes CF, mutational dysfunction of the CF transmembrane conductance regulator (CFTR), leads to a cycle in the airways of defective mucus clearance, obstruction, infection, and inflammation. Improvements in nutrition, mucus clearance, and treatment of inflammation and infection have led to dramatic improvements in CF respiratory morbidity and mortality ; however, current treatments have not been able to halt disease progression. As patients live increasingly longer, their respiratory microbiology evolves, perhaps driven by elements of care intended to mitigate their lung disease (such as antibiotics and attending clinics at CF care centers). Put differently, the treatments that have so greatly helped people with CF are often followed by microbiological changes, which in turn may alter their clinical course. The causal relationships between specific pathogens, clinical changes, and constantly evolving therapies are difficult to sort out.
Andersen and di Sant’Agnese made special mention of the apparent link between infection and inflammation. Although these are omnipresent features of CF lung disease, the causal relationships between them are controversial. Observations from a variety of studies of patients and, most recently, animals engineered with CFTR mutations have led some investigators to postulate that infection is required for CF airway inflammation, whereas others have suggested that inflammation can precede infection. Although these disputes continue, great progress has been made in defining the mediators and mechanisms driving the intense inflammation within CF airways, identifying not only new candidate therapeutic targets but also promising biomarkers of early disease.
This article reviews the current understanding of the roles of infection and inflammation in CF lung disease pathogenesis. Although these two features of the CF airway are mechanistically linked by data from observational studies and, as a result, in current pathophysiologic models, for simplicity this article considers them separately. Although this article touches on therapeutic approaches to both infection and inflammation, clinicians are currently experiencing a period of particularly rapid evolution in CF treatment strategies and protocols. Therefore, where appropriate, this article refers readers to recent, in-depth reviews of CF therapeutic strategies for more information. Similarly, there have been several excellent reviews of CF respiratory microbiology and inflammation in general that readers may find useful.
Cystic fibrosis microbiology
The Evolving Role of Methodology
Dorothy Andersen and her contemporaries identified several important characteristics of CF lung disease. For example, she and others who later built on her work noted that the microbes infecting CF lungs were nearly always confined to airway luminal mucus, rather than invading tissue. The role of S aureus was highlighted; however, other bacteria were quickly recognized as important CF pathogens. Blending observations from culture and microscopy, two of the most sophisticated methods available at the time, provided higher sensitivity and yielded a richer depiction of infection pathogenesis than either method alone. As both treatments and laboratory methods have evolved, so has the understanding of the pathogenesis of CF respiratory infections and the spectrum of likely pathogens. Before discussing the most common pathogens, it is instructive to consider how improvements in treatment, innovations in clinical microbiology, and increases in patient longevity combine to create constant evolution in CF microbiology.
CF clinical microbiology generally relies on conventional laboratory cultivation of respiratory samples (eg, sputum, bronchoalveolar lavage fluid (BALF), oropharyngeal swabs, or sinus samples) to identify and study causative organisms. Using these techniques, bacteria and fungi can be identified, enumerated, isolated, and characterized; their growth characteristics and in vitro antibiotic susceptibilities are defined. These methods are invaluable for diagnosing infections in individual patients, directing antibiotic treatment, and generating epidemiologic information that informs our models of CF infection pathogenesis. Despite the enormous utility and power of these conventional methods, recent work with advanced laboratory techniques has added to the ever-growing list of CF-associated microbes. To show how newer methods might complement culture, this article briefly reviews how current CF respiratory cultures are performed, and how information is generated and used to direct treatment.
Current methods rely on synthetic laboratory growth media that, together with incubation conditions (generally aerobic and at body temperature for CF microbiology), have been chosen to select for the microbes customarily associated with lung disease pathogenesis. In addition, current protocols usually involve selecting a small number of isolates of those traditional pathogens from those cultures to test susceptibilities and to inform treatment.
However, conventional culture methods can introduce bias or have other shortcomings. For example, it is now known that CF airway mucus has anaerobic niches that alter microbial metabolism and that are not accurately modeled by these laboratory methods. In line with this finding, both advanced culture-based and culture-independent (sequencing) techniques have identified diverse microbes, including anaerobes and other otherwise undetected bacteria together with traditionally cultured pathogens, in respiratory samples from many patients with CF. Microscopic and biochemical investigations suggest that microbes infecting CF airways may commonly exist in biofilms, which are gel-encased communities of cells that are resistant to killing compared with the liquid-suspended, dispersed microbial cells usually studied in the laboratory. In-depth studies of traditional CF pathogens (such as P aeruginosa and S aureus ) have also revealed that they evolve and diversify over time, meaning that 1 or a few isolates do not accurately reflect the behaviors of an entire, chronically infecting population of those bacteria. In addition, studies of the microbes in different specimen types (such as swabs, sputum, and lavages) collected concurrently from individual patients with CF indicate that each may sample different anatomic sites, raising the question of which sample is best for informing treatment or prognosis.
These new findings highlight the constantly evolving and controversial nature of CF microbiology, which has largely been, and continues to be, informed by the results of standard cultures. Accordingly, the focus here is on what is known from conventional CF microbiology, with a later discussion about how recent developments may change clinical practice.
Traditional Cystic Fibrosis Respiratory Pathogens: Epidemiology
The 2 graphs in Fig. 1 show that CF airway infections have 3 key features:
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They are diverse.
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They are frequently polymicrobial.
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They are constantly evolving.
Fig. 1 A shows the US prevalence in 2013 by patient age of the bacteria cultured most commonly from respiratory cultures (as recorded in the Cystic Fibrosis Foundation Patient Registry ). This graph shows that S aureus was particularly common among young children, whereas P aeruginosa was most common in adults. The S aureus subtype methicillin-resistant S aureus (MRSA) had peak CF age prevalence in the midteens to early 20s. P aeruginosa resistant to multiple antibiotics (multidrug-resistant P aeruginosa [MDR-PA]) was uncommon but followed the same age distribution as P aeruginosa in general. A brief consideration of these data reveals that, for each age group, many patients must have had more than 1 of these bacteria during the year.
Fig. 1 B provides a slightly different perspective of the 2013 data. For example, consider how the prevalences of S aureus and P aeruginosa have changed in the United States since 1988. S aureus prevalence has dramatically increased, whereas that of P aeruginosa has decreased. Therefore, even considering just these 6 commonly cultured bacterial species, the diverse, polymicrobial, and constantly evolving nature of CF lung infections can be appreciated. Further, some pathogens that can be cultured (such as nontuberculous mycobacteria [NTM]) are not included on these graphs. This article briefly discuss each of these species later, paying particular attention to S aureus and P aeruginosa , given their high prevalence and clinical associations. For brevity, key points are provided for less common CF respiratory microbes. Clinically relevant variants of common pathogens (such as MRSA and MDR-PA) are also discussed, as well as emerging pathogens such as NTM, with attention to their epidemiology, associations with disease, and treatment.
Staphylococcus aureus
Epidemiology and clinical associations
As described earlier, this gram-positive organism was the bacterium first identified as an important CF respiratory pathogen. The earliest CF antibiotic treatments targeted S aureus , and early proponents of these treatments described the substantial clinical improvements that resulted. However, the role of S aureus in driving CF lung disease, and the appropriate clinical response to its detection, are matters of ongoing debate. A review of published observations regarding the association between S aureus and lung disease clarifies the basis for this controversy.
In addition to the high prevalence of S aureus among children, pediatric CF studies have provided further cause for concern: S aureus has been associated with higher airway inflammation, lower lung function, and even higher subsequent mortality when detected together with P aeruginosa . Further, these associations were for all S aureus ; as described later, specific subtypes of S aureus (such as MRSA and small-colony variants of S aureus [SCVs]) may be associated with even worse outcomes than other S aureus .
However, when considering all S aureus in adults with CF, the picture becomes less clear. Studies of adults found S aureus to be associated with a lower risk of mortality, better lung function, and a lower risk of exacerbations. Therefore, S aureus pathogenesis may either be context dependent (that is, perhaps it is more pathogenic either in children or in the absence of P aeruginosa , or it adapts over time to become less pathogenic). Alternatively, pathogenesis may be higher for specific subtypes of S aureus (such as MRSA or SCVs), or S aureus may not be universally pathogenic but rather serves as a marker of early (as with children) or mild (as with adults) disease.
Answering these questions is particularly pressing because of the recent increase in S aureus prevalence shown in Fig. 1 B. Recent studies showed similar trends in parts of Europe and Australia by the mid-2000s. However, S aureus prevalence has remained comparatively low in the United Kingdom, perhaps related to differences in antibiotic use (discussed later). Importantly, both longevity and lung function have continued to improve in the general CF population, including in the age groups with the highest S aureus prevalences. These combined observations make it difficult to predict the best approach to infection with S aureus .
Subtypes
As suggested earlier, 2 subtypes of S aureus are of particular significance for CF lung disease and treatment: MRSA and SCVs.
MRSA (or oxacillin-resistant S aureus [ORSA]) is usually identified either by its resistance to these β-lactams or by carriage of the mecA gene, which encodes this resistance. MRSA prevalence in CF has increased in the past 2 decades (see Fig. 1 B) in parallel with all S aureus and methicillin-susceptible S aureus (MSSA). MRSA acquisition in CF is strongly associated with exposure to hospitals and to antibiotics, as it is in the general population, which also experienced a parallel increase in MRSA prevalence in the United States. The increase seen in the US CF population has not occurred as dramatically elsewhere, suggesting that environmental, treatment, or other factors unique to specific locations are responsible for this epidemiologic change.
The relationship between MRSA and CF lung disease outcomes is complex. Although several studies have shown an association between MRSA infection and lower lung function in patients with CF, some studies indicated that patients with MRSA had faster lung function decline before MRSA detection, suggesting that MRSA may be a marker for severe disease rather than the cause. However, other studies found MRSA to be an independent risk factor for failure to recover lung function during treatment of respiratory exacerbations and for increased mortality.
S aureus SCVs are slow-growing, antibiotic-resistant variants that are difficult to detect with conventional cultures. Small studies of both European and US CF populations have identified SCVs among 8% to 30% of patients using special laboratory methods. These studies have also found SCVs to be associated with lower lung function, faster lung function decline, and higher rates of preceding treatment with antibiotics known to select for SCVs, including aminoglycosides and sulfonamides, in addition to higher rates of coinfection with P aeruginosa , which may also select for SCVs.
The similarities between MRSA and S aureus SCVs, particularly their relationships with clinical outcomes, antibiotic treatment, and resistance, are instructive. Each of these bacterial types is associated with:
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Preceding antibiotic treatment
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Subsequent antibiotic resistance
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Higher lung disease severity
However, these findings are largely from observational studies, and whether MRSA and SCVs cause worse outcomes, whether they reflect patients with worse preexisting disease and resulting higher antibiotic treatment burdens, or both, remains to be seen. Additional observational and interventional studies may resolve these questions of causality. Until then, the best therapeutic approaches to each subtype remain to be defined.
Treatment
Determining the best approach to S aureus infection in CF is a controversial subject. Some countries provide continuous antistaphylococcal prophylaxis during childhood; this practice has been associated in some trials with earlier detection of P aeruginosa , which, given its association with worse lung disease, led many countries to not adopt this approach. Differences in study outcomes may have resulted from different antibiotic choices. Some centers provide antistaphylococcal antibiotics designed to eradicate S aureus on first detection, and strategies and attitudes differ for MRSA versus MSSA; evidence supports the microbiological efficacy of this strategy, but clinical benefits for eradication of either MRSA and MSSA remain to be determined. By comparison, for patients with S aureus and no other detected pathogens who have an exacerbation, there is consensus that antistaphylococcal antibiotics should be used. The drugs used most often in this case have been reviewed.
Pseudomonas aeruginosa
Epidemiology and clinical associations
With the advent of effective antistaphylococcal therapy, the gram-negative bacterium P aeruginosa emerged as a common and important pathogen in CF lung disease (reviewed in Ref. ). P aeruginosa infection has been associated with :
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Worse lung function outcomes
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Greater respiratory tract inflammation
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A greater risk of respiratory exacerbations
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Higher risk of mortality
Although chronic P aeruginosa infection usually cannot be eradicated, current evidence indicates that initial P aeruginosa detection presents an opportunity for eradication with antibiotics. There is also good evidence that suppressing P aeruginosa can improve measures of lung disease. For CF exacerbations among people with P aeruginosa , antipseudomonal antibiotics have been shown to improve outcomes. However, whether early eradication provides similar clinical benefits is still under investigation.
As shown in Fig. 1 A, P aeruginosa prevalence tends to be higher in adults than in children; its overall prevalence has decreased slightly in the past few decades (see Fig. 1 B), perhaps related to new eradication approaches on initial detection. Longitudinal analyses indicate that P aeruginosa tends to exclude other microbes that were previously detected in the respiratory tract, and that it is frequently the predominant, and often the only, bacterium identified in CF lungs during end-stage disease. These aggregate findings have earned P aeruginosa the reputation as the most important CF respiratory pathogen.
P aeruginosa has a very large genome, encoding numerous potential toxins controlled by a complex array of regulatory elements. During chronic CF infections, P aeruginosa undergoes diverse adaptive changes, including inactivation of many of these so-called virulence factors and their regulators. One of the most common phenotypic changes observed for P aeruginosa is the exuberant production of alginate, resulting in a mucoid colony appearance in vitro. Mucoidy has been associated with both persistence and duration of infection; however, it was not associated with failure of early eradication in recent studies. Those studies also identified mucoid isolates on initial detection of P aeruginosa . Because mucoidy has traditionally been thought to represent adaptation to the airway, these results may indicate that current detection methods are not perfectly sensitive for earliest infection.
Epidemiologic evidence has identified genetically related isolates of P aeruginosa (referred to as epidemic strains) among CF populations in several countries (reviewed in Ref. ). In some cases, these isolates were associated with worse outcomes than nonepidemic P aeruginosa , including higher risks of death and need for lung transplant. Similarly, P aeruginosa resistant to multiple antibiotics has been found to be associated with worse lung disease by several measures, but, as with MRSA and S aureus SCVs, whether these resistant P aeruginosa identify patients with higher antibiotic exposures, or whether they are more pathogenic than other P aeruginosa , remains to be determined.
Treatment
Prophylaxis for P aeruginosa is not recommended. However, treatment with antibiotics on initial detection, with the goal of eradication, has proved to be microbiologically effective and to decrease the risk of subsequent exacerbations. Inhaled antibiotics, such as tobramycin and more recently aztreonam, form the basis of the current guidelines for eradication, with no benefit found by adding an oral drug of another class (ciprofloxacin). Similarly, inhaled antibiotics are recommended as chronic maintenance medications for patients with CF with persistent P aeruginosa . For exacerbation treatment in patients chronically infected with P aeruginosa , limited evidence indicates that treatment with 2 classes of antipseudomonal antibiotics leads to longer periods of clinical stability than does a single class. Treatments for P aeruginosa in CF have been the subject of recent reviews and guidelines.
Burkholderia cepacia Complex
Epidemiology and clinical associations
The Burkholderia cepacia complex (BCC) group of gram-negative bacteria comprises at least 18 distinct species (a related species, Burkholderia gladioli , is often discussed with BCC because it can cause similar infections). Of these, 2 species are among the most common and most associated with CF lung infections and disease:
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Burkholderia cenocepacia
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Burkholderia multivorans
By comparison, other BCC species are less common and their clinical associations less well defined (as is the case for B gladioli ). As shown in Fig. 1 , Burkholderia species have infected between 3% and 4% of patients with CF in the United States for many years, primarily affecting adolescents and adults. B multivorans prevalence was highest, followed by B cenocepacia and B gladioli .
Burkholderia CF infections are notorious for several characteristics:
They are associated with more severe lung disease
These associations are more pronounced for some Burkholderia species than others; some small studies have shown B cenocepacia to be associated with more rapid lung function decline than B multivorans , and a recent Canadian study found the strongest association with subsequent mortality to be with B cenocepacia , followed by B multivorans .
They can be transmissible between persons with cystic fibrosis
Epidemic strains of B cenocepacia have been shown to infect patients with CF after interpatient contact at camps and clinics and have even been shown to replace B multivorans after transmission. This transmissibility was one important driving force behind the institution of stringent infection control measures, which evidence suggests have been highly infective for controlling spread of these strains.
Clinical outcomes of Burkholderia cepacia complex infections are unpredictable
Associated outcomes often range from clinical quiescence to rapidly progressive, necrotizing pneumonia and fatal septic disease (so-called “ cepacia syndrome”).
Treatment
At present, the practice of antibiotic treatment for eradication on detection is controversial, and the utility of this practice is not yet clear. Burkholderia species are also notorious for their antibiotic resistance, both intrinsic and acquired, and therapy is usually limited to specific antibiotics as needed. Systematic reviews have recently been published.
Considerations for the following microbes in CF infections are presented briefly.
Stenotrophomonas maltophilia
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Gram-negative
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Increased US CF prevalence in recent years
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Particularly common among adolescents and young adults
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Conflicting data regarding clinical associations
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Both intrinsically and adaptively resistant to many antibiotics
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Inadequate evidence for the clinical impact of therapy; a Cochrane Review of current approaches recently became available
Haemophilus influenzae
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Gram-negative
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Often the first organism detected in CF respiratory cultures; prevalent in children, less common in adults
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Association with CF clinical outcomes is controversial, but associated with adverse outcomes in other chronic respiratory diseases: non-CF bronchiectasis and chronic obstructive pulmonary disease
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Difficult to culture, requiring specific conditions for detection
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Since the introduction in the United States of the H influenzae type B vaccine, most isolates are nontypeable and unencapsulated
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Can produce β-lactamase; therefore, treatments usually include a β-lactamase inhibitor (eg, amoxicillin-clavulanate)
Achromobacter xylosoxidans
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Gram-negative bacterium similar to P aeruginosa
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Increased recent US prevalence, but remains low (<10% of patients with CF; see Fig. 1 )
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Associated with worse radiographic and spirometric measures of lung disease
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Similar to P aeruginosa and BCC, Achromobacter xylosoxidans can be the dominant, and sometimes only, bacterium isolated from patients with CF at end stage
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Notorious for resistance to many antibiotics, limiting treatment options
Nontuberculous mycobacteria
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Estimated CF prevalence 6% to 30%
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Two groups of mycobacteria, accounting for 6 species, are currently considered important CF pathogens:
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Mycobacterium avium complex (MAC)
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Mycobacterium abscessus complex
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NTM treatment approaches usually involve 2 phases:
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Multiple intravenous (IV) antibiotics for weeks to months
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Multiple inhaled and oral antibiotics for months to years
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Side effects and toxicities are common and can be troublesome
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Guidelines for NTM infection diagnosis and treatment from a joint committee based in both the United States and Europe were recently published.
Fungi and Viruses
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Numerous fungi are frequently isolated from patients with CF, including:
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Yeasts (particularly Candida spp)
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Filamentous fungi (including Aspergillus spp)
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Whether detection of fungi requires treatment is a matter of current debate.
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Allergic bronchopulmonary aspergillosis (ABPA): patients with CF and other chronic airway diseases can develop an immunoglobulin E–mediated allergic airway disease known as ABPA, the treatment of which primarily involves steroids, although the addition of an antifungal (such as itraconazole) may allow lower doses of steroids
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Human respiratory viruses are not thought to chronically infect the CF airway, but they have been shown to be both important and common triggers of CF respiratory exacerbations
The Cystic Fibrosis Airway Microbiome and Future Directions
The application of DNA-based microbiological techniques to CF respiratory samples has afforded a different view of their microbiota. To date, dozens of such studies using a variety of methods have been performed. This collective work provides evidence for dynamic, diverse, and highly resilient CF respiratory microbial communities (reviewed in Ref. ). In general, these respiratory microbiota tend to be more diverse, with more microbial species and not dominated by any individual microbe, in patients with CF who are younger, have better lung function, and/or have had fewer courses of antibiotics. In contrast, this diversity tends to be lower in patients who are older, who have more severe lung disease, and who have been treated with more antibiotics. The microbiota in lungs from patients with end-stage CF disease tend to be dominated by 1 or very few species, most often P aeruginosa , BCC, or A xylosoxidans . However, these associations between age, disease severity, microbial diversity, and antibiotic burden make it difficult to sort out cause and effect; it is not clear yet whether the decrease in diversity drives disease severity, or whether patients with worse preexisting disease receive more antibiotics that “prune” the microbiota to select for the most adaptable and resistant microbes. It is hoped that ongoing and future studies will better define the causal relationships between infection dynamics, therapy, and disease progression.
Cystic Fibrosis Microbiology: Summary
There have been remarkable changes and developments since the first descriptions of CF lung infections in the 1930s and 1940s. Antibiotics have played a central role in improving lung disease outcomes and overall longevity. However, findings over the past 70 years from both culture-based, classical microbiological methods, and those from newer culture-independent techniques, repeatedly show the resilient and dynamic nature of chronic CF lung infections. These findings warrant ongoing vigilance and innovation, and they highlight the many questions that have arisen in this rapidly moving field. In the years to come, there are certain to be new revelations regarding the mechanisms of infection and the microbial determinants of both CF lung disease and response to treatment, which will lead to new recommendations for therapy and infection control. However, the many controversies discussed earlier regarding the relationships between airway microbes and clinical outcomes underscore the importance of host response in driving CF lung disease. These inflammatory mechanisms are discussed later.
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