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Respiratory infections in patients with cystic fibrosis
Respirator.y Infections in Patients With Cystic Fibrosis Marian G. Michaels, MD, MPH, and Magdalen Gondor,MD Cystic fibrosis remains one of the most frequent and serious genetic disorders in children. Great strides have been made in understanding the defects in cystic fibrosis. In addition, aggressive treatment has led to improved survival so that many individuals with cystic fibrosis now live into adulthood. However, respiratory infections in children with cystic fibrosis continue to be the leading cause of hospitalization, morbidity, and mortality. This article reviews the risk factors for acquiring respiratory pathogens in children with cystic fibrosis, the types of organisms that cause infection, and treatment options. Copyright 9 1998 by W.B. Saunders Company
Ystic fibrosis (CF) is the most common severe genetic disorder among Caucasian populations, with an incidence of 1 in 2,500 to 3,500 live births in the United States. 1,2 Great strides have been made in the care of these children since 1938, when Andersen2,3first described infants with CF. Whereas most children with CF did not survive early childhood in the 1950s, by 1996 aggressive treatment of pulmonary infections and prevention of malnutrition had led to a median survival of 31 years, with many adults living beyond their third decade. !,4 Also, information about the genetics and cellular physiology of CF has been learned during the last two decades. In 1989, the CF gene was localized to chromosome 7.5,6It was recognized as encoding the CF transmembrane conductance regulator (CYFR) protein, which functions as a cyclic adenosine monophosphate-mediated apical chloride channel.7,8 Mutations of CFFR lead to high concentrations of sodium and chloride in sweat and relative dehydration ofintraluminal secretions. Clinically, CF manifests as a multiorgan disease, affecting the respiratory, gastrointestinal, and reproductive systems, as well as the sweat glands. Although much progress has been made in understanding the defects in CF, children and young adults with this disorder still suffer from progressive destruction of the airways. Endobronchial infections and the inflammatory responses elicited by these bacteria remain among the most important factors leading to morbidity and early mortality. 2,4,8-12 This article reviews the importance of respiratory infections in CF, detailing microbial agents, their epidemiology, pathogenesis, and current therapeutic strategies.
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From the Universi~ of Pittsburgh School of Medicine, Division of Allergy, Immunology, Infectious Diseases and the Division of Pulmonology, Children's Hospital ofPittsburgh, Pittsburgh, PA. Address correspondenceto Marian G. Michaels, MD, MPH, University of Pittsburgh, School of Medicine, Division of Allergy, Immunology, Infectious Diseases, Children'sHospital ofPittsburgh, 3705Fifth Ave, Pittsburgh, PA 15213. Copyright 9 1998 by W.B. Saunders Company 1045-1870/98/0903-001058.00/0 234
Risk for Infection Individuals with CF do not have a detectable immune deftciency; rather, altered electrolyte and water content of airway secretions lead to colonization with specific bacteria that are unlikely to colonize the respiratory tract of a healthy person. 1~-15 The composition of normal respiratory secretions is dependent on CFTR channel activity; although the precise mechanism is not understood fully, abnormalities in ion transport across the epithelial cells of persons with CF promote an endobronchial milieu that favors infections.7,a Once infection is established, bronchial mucus becomes thick, tenacious, and difficult to clear. The characteristic thick "CF mucus" results from breakdown products of invading organisms and neutrophils, including actin myofibrils and deoxyribonucleic acid. In addition, neurrophils in the airway fluid of children with CF produce an excess of elastase, 16which causes nonspecific damage of elastin fibers in the airway, stimulates mucus secretion, and interferes with the opsonization and killing of pseudomonads. These local host factors are complicated by bacterial endoproducts, such as proteases and exotoxin A, which allow for chronic colonization.17 Hence, a vicious cycle is created; altered mucus production potentiates plugging of the small airways, favoring infection and inflammation. These factors contribute to further airway obstruction, ultimately resulting in bronchiectasis and irreversible lung disease.
Pulmonary Colonization and Exacerbations Children with CF acquire bacterial colonization of their airways in an orderly fashion. During infancy, Staphylococcus aureus is the predominant organism, and it was the major cause of death in children with CF in the first half of the 20th century.3 During early childhood, nontypeable Hemophilus influenzae is common, and by adolescence most individuals with CF are colonized with Pseudomonus aemginosa. 2,9,14Recent studies in which bronchoalveolar lavage (BAL) were performed have shown an earlier colonization with pseudomonas than previously recognized, is,19 Pseudomonas and, more recently, Burkholderia cepacia (formerly
Seminars in Pediatric Infectious Diseases, Vol 9, No 3 (Ju~), 1998.'pp 234-242
Respiratory Infections in Cystic Fibrosis Pseudomonas cepacia) are the predominant causes of morbidity and mortality in patients with CF.8-12,2~ Other organisms, such as Alcaligenes xylosoxidans and Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia), are found commonly colonizing the lungs of patients with CF; however, their role(s) in production of disease is less clear. 2,9-11Likewise, the roles of respiratory viruses, Mycoplasma species, Chlamydia pneumoniae, and nontubercutous mycobacteria are debated.2 Fungi, particularly Aspergillus species, have been implicated as a cause of symptomatic disease (eg, allergic bronchopulmonary disease) in individuals with CF.2,10,22 Antimicrobialagents are used to treat infections, but they do not eradicate the organisms from patients with CF.9-12 The clinical course of a patient with CF usually is characterized by periods of general well-being punctuated by intercurrent periods of acute deterioration. Patients with CF are a heterogenous population, and multiple factors must be considered when deciding whether or not to treat changes in respiratory symptoms. Pulmonary exacerbations are characterized by increased frequency and intensity of cough and a change in the volume, color, or consistency of the sputum.2,9 Myalgias, anorexia, and weight loss are frequent occurrences, whereas fevers are noted in only a minority of patients.9 In addition, an exacerbation can be manifest by increased respiratory rate, dyspnea, or shortness of breath. Physical examination may show use of accessory muscles and retractions, along with new auscultatory findings, such as crackles or wheezing. Attempts to add more objective criteria to define pulmonary exacerbations sometimes include evidence of radiographic changes and a decrease in oxyhemoglobin saturation. Serial pulmonary function tests to measure airway obstruction are used, as wellJ 2 These studies require cooperation and coordination from the patient and usually cannot be accomplished before the patient reaches 5 years of age. The most reliable measurements are forced vital capacity and forced expiratory volume at 1 second (FEVI). Consensus among clinicians who treat patients with CF is that decline in forced vital capacity and/or FEV1 of 10 to 15 percent from baseline or a continued decline over time is a marker of deterioration. Although no universal criteria that define pulmonary exacerbation exists, these features help to determine when an individual requires therapeutic intervention. Accordingly, it is important for patients with CF to have consistent care at a CF center with health care providers who are familiar with their clinical status and problems. Cultures of sputum are used to help guide choices of antibiotics. Centers caring for children and adults with CF must have reliable microbiology laboratories that are experienced in isolating, identifying, and performing susceptibility tests on pathogens found in the airway of patients with CF.9,1~ The reliability of cultures of the sputum has been borne out by comparison with cultures obtained from thoracotomy specimens.23 In children who are too young to produce sputum, cultures obtained from the oropharynx have been used in an attempt to identify possible pathogens. However, prospective comparison of cultures obtained from the oropharynx with those obtained from the BAL of infants with CF followed over time showed that oropharyngeal cultures did not reliably predict lower respiratory tract pathogens. 18 The positive predictive
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value of a pathogenic bacteria in the oropharynx also being found in the BAL was only 41 percent. In addition, molecular studies of organisms cultured from both the BAL and upper airway showed that they were often of different strains. Accordingly, oropharyngeal cultures obtained from children with CF who cannot produce sputum must be interpreted with care; the need to obtain a culture of BAL fluid must be assessed periodically.
Specific Microorganisms S aureus S aureus was recognized as a major cause of death in children with CF in the preantibiotic era 3 and was the most frequent organism isolated from patients with CF in the 1960s.24 Data from the 1990 United States CF registry showed it to be the most common bacteria isolated from children younger than 1 year of age; it was common in all age groups, and it accounted for 28 percent of isolates. 1In addition, a large prospective study of infants with CF who underwent serial BALs for surveillance found S aureus in the lower respiratory secretions of 27 percent of children less than 1 year of age. 19 Concurrent oropharyngeal cultures identified S aureus in 61 percent of the children. The common finding of upper airway colonization in infants with S aureus may account for the higher prevalence ofS aureus reported in studies in which BAL was not performed in children who did not produce sputum but had oropharyngeal cultures obtained. A smaller study from three CF centers in the United States of children who underwent BALs annually reported S aureus colonization in 23, 32, and 32 percent at 1, 2, and 3 years, respectively.25 Literature from as recently as 1991 states that methicillinresistant S aureus (MRSA) does not play a substantial role in patients with CF. 2'26 The organism was rarely isolated before 1985, but it is found increasingly as resistance patterns change in hospitals. For example, antimicrobial susceptibility testing at The Children's Hospital of Pittsburgh found only a 4 percent prevalence of MRSA in 1990 from specimens obtained from children with CF, but by 1996, MRSA had increased to account for 19 percent ofS aureus isolated from these patients. In general, when only S aureus is found in the sputum of a patient with CF who is experiencing a mild exacerbation of pulmonary symptoms, treatment is initiated with oral antimicrobial agents such as first-generation cephalosporins, dicloxacillin, clindamycin, macrolides, or tlouroquinolones. When patients are compromised more severely or are not responsive to this therapy, intravenous antistaphylococcal penicillins such as oxacillin, nafcillin or methicillin may be required. Vancomycin should be initiated to treat patients with infection caused by MRSA. P aeruginosa Up to 90 percent of patients with CF eventually acquire colonization with P aeruginosa. It rarely is found before patients reach 6 months of age, but as many as 30 percent of patients already are colonized with this organism by 3 to 5 years of age. 1,25 A study attempting to correlate clinical deterioration with acquisition of pseudomonas noted that the organism was acquired before detection of pulmonary dysfunction37 Risk
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factors for the acquisition of colonization with pseudomonas species have been debated. Acquisition of colonization tends to be more common in winter months, concurrent with respiratory viral infections, suggesting that infections with viruses may facilitate colonization with pseudomonas. 14,28A study evaluating the use of inhaled steroids was halted prematurely when patients on steroids acquired colonization with P aeruginosa more often than did patients receiving placebo, intimating a potential causal relationship. 29 Epidemiological evidence shows that siblings with CF often are colonized with the same strain o f P aeruginosa.14,3~ This observation, however, does not distinguish between person-toperson spread and cross-infection from a common environmental source. Concern for nosocomial transmission within hospitals and CF centers has led to debate regarding the need for and best method of control of cross-transmission among patients with CF. Whereas many investigationshave shown that patients with CF do not spread P aeruginosa outside of households, 3~ epidemiological studies performed with molecular techniques show that nosocomial transmission can occur.33,34 Cheng and colleagues 34 documented the spread of a [3-1actam-resistant strain ofP aeruginosa among a large proportion of their patients observed at the same CF center. Taken together, these studies show that although nosocomial spread ofP aeruginosa is possible, it is relatively unusual9,35 Virulence Factors. P ao~ginosa have developed multiple mechanisms to cause tissue injury and evade the immune system, including production of elastase, alkaline protease, exotoxin A, exoenz)ane S, hemolysins, polymorphonuclear inhibitors, and mucoid exopolysaccharide (MEP).2,17 An intricate, complicated interplay of these mechanisms and the specific interaction of receptors on apical epithelial surfaces of patients with CF help to establish infection of the lungs with P aeruginosa. 17Some of these virulence factors are explored here. Saiman and colleagues 17,36noted increased adherence of P aeruginosa to the epithelial cells obtained from patients with CF compared with normal controls. Further work noted a significantly increased number of asialoGM 1 residues on the epithelial cells of individuals with CF compared with normal epithelial cells; these residues are responsible for bindingP aeruginosa.37-39 Unlike pseudomonads in individuals without CF, this bacteria often has a unique mucoid morphoty-pe in patients with CF. 2'14'17This morphotype occurs because of the production of a capsular MEP and has been found even in nonmucoidappearing strains isolated from sputa of individuals with CF.4~ Of interest, mucoid strains of other types of gram-negative rods have been found in patients with CF, suggesting that something in the lung of the patient with CF is conducive to the production o f MEP. 17,41 Longitudinal studies show that the airways of patients with CF initially are colonized with nonmucoid strains of pseudomonas; mucoid strains arise subsequently. 2,25,42 The mechanisms leading to the production of mucoid strains are not understood completely. Microcolonies of mucoid strains may be enhanced in part by the local production ofproteases that cause the release of mucins from the host respiratory epithelium.2 Once present, mucoid strains have a selective advantage in that MEP has antiphagocytic properties. 2,17,43Likewise, in the presence of calcium ions, MEP forms a highly viscous gel that further evades ciliary clearance. 2
P aeruginosa may cause direct damage to the lungs, by production and local release of virulence factors such as alkaline protease, elastase, and exotoxin A, and indirect damage, by eliciting a host-immune response leading to a release of endogenous proteases and elastase. 2,17In addition, the accumulation of immune complexes has been associated with severe pulmonary disease in patients with CF. 2'17'44 Supporting the role of immune complexes in damage to the lungs is the finding that patients with hypogammaglobulinemia are relatively spared this destruction.45 Susceptibility Testing. The mainstay of treatment of P aeruginosa is the administration of antibiotics, even though eradication of organisms usually is not possible.46,47Controversy exists regarding the optimal method of performing susceptibility testing, the ideal antimicrobial regimen, and the best method of delivering antibiotics. Respiratory specimens from patients with CF should be processed promptly to avoid difficulties in recovering organisms. The high viscosity of CF sputum has led some researchers to recommend using quantitative or semiquantitative cultures. 1~ Special media and identification methods are critical to avoiding misidentification of potential pathogensJ ~ Patients often have more than one strain of pseudomonas, with varying susceptibility patterns, in their sputum.48 One approach is to isolate each morphotype and perform separate susceptibility testing on each. An alternate approach is to test all morphotypes together in a single susceptibility assay. The latter method, although much less timeconsuming and expensive, may obscure valuable information regarding the development of patterns of resistance and the potential for combination therapies. A consensus conference on the microbiology of infections in patients with CF noted difficulties with standard methods for testing susceptibility of specimens from patients with CF because of slow growth or lack of data. l~ Another controversial area of susceptibility testing involves defining breakpoints for resistance. 49 Standard in vitro susceptibility data are based on serum concentrations of drugs that are achievable without undue toxicity. The site of infection is assumed to be perfused with this concentration of blood. However, the site of infection in patients with CF is an inflamed airway with purulent secretions. The concentration of antibiotics in the infected compartment may be considerably lower than in the serum. Alternatively, the standard breakpoints may underestimate substantiallysusceptibility of an organism to an antibiotic if an aerosolized delivery system is used, which can safely achieve concentrations of antibiotic in the sputum in excess of 1000/~g/mL.9'49Prospective treatment trials that incorporate studies that examine levels of drug in sputa and measure minimal inhibitory concentrations higher than those currently regarded as standard will help to determine clinically relevant susceptibility testing methods. Treatment. Ideally, antipseudomonal antibiotics would be administered easily (either aerosolized or by the oral route) with little toxicity and without promoting the emergence of resistance. Two major approaches to treatment can be identified: chronic suppression or treatment of acute pulmonary exacerbations. Chronic suppression or prophylactic strategies have been implemented in some centers to attempt to prolong the periods of general wellnessJ 1 In 1983, Szaff and colleagues 5~ reported significant improve-
Respiratory Infections in CysticFibrosis ment in pulmonary function and survival in Danish patients who received a 24-day course of intravenous antimicrobial therapy against P aeruginosa every 3 months, regardless of clinical findings. However, their comparison group was historical controls. A more recent study from a Danish center evaluated an aggressive preemptive treatment strategy initiated after the first isolation o f P aeruginosa and before development of disease or chronic infection.51 In this study, a combination of inhaled colistin and oral ciprofloxacin was administered for 3 weeks when pseudomonas first were isolated. This regimen was repeated if the organism was found a second time; if found a third time within a 6-month period, therapy was extended for 3 months. The authors concluded that, compared with historic controls, this regimen delayed the onset of chronic infection caused by P aeruginosa.51 The other management strategy is to treat acute exacerbations aggressively with an antibiotic regimen based upon culture and susceptibility testing.9,37,4GTherapeutic regimens, in general, are composed of two antimicrobial agents that may provide synergism and slow the rates of emergence of drug resistance, l~ Ideally, antibiotic combinations include those that have different mechanisms of action, such as an aminoglycoside plus an anti-pseudomonal [Mactam antibiotic (eg, ceftazadime, azlocillin, mezlocillin, ticarcillin, piperacillin, imipenim, meropenem, or aztreonam). Flouroquinolones, in particular, ciprofloxacin, norfloxacin, and ofloxacin, are attractive antipseudomonal drugs because of their oral bioavailability,but they are not approved by the Food and Drug Administration for use in children younger than 18 years of age because of concerns regarding joint toxicity. However, a growing number of studies has shown this drug to be safe and efficacious in children with CF. 52,53 The pharmacokinetics and metabolism of many drugs, including antibiotics, are altered in individuals with CF, compared with healthy populations. Individualized dosing of antimicrobials is necessary because CF patients show an increased volume of distribution and clearance of drugs, 54,55which may be related, in part, to the disease process (eg, pancreatic insufficiency); one hypothesis is that the CFTR may affect cellular processing in the liver and kidney, thereby necessitating increased dosing of drugs. 56 Toxicity, particularly of intravenous aminoglycosides, must be considered. Measurements of peak and trough levels are recommended, along with periodic evaluation of renal and auditory function.55 The route of administration of drugs also has been questioned in treating pseudomonas infections in children with CF. In vitro data generated by Levy and colleagues57 showed that, compared with serum dialysates, aminoglycosides had decreased bioactivity against P aeruginosa in the sputum of CF patients. This observation led to the clinical investigation of aerosolized aminoglycosides in an attempt at the site of infection to achieve high levels of antibiotics which cannot be safely achieved by intravenous administration to overcome this antagonism.5s Aerosolization of 600 mg of tobramycin through an ultrasonic nebulizer, three times daily for 3 months, was found to be safe, although some systemic absorption did occur.5a Efficacy has been implied by clinical improvement and stabilization or improvement of serial pulmonary function tests in short-term studies. Long-term, multicentered studies are ongoing.
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B cepacia This gram-negative, nonspore-forming, motile, nonfermentative, aerobic bacillus was classified as a Pseudornonasspecies until 1992, when it was reclassified as B cepacia. In the past two decades, it has been recognized as an important pathogen within the CF population.TM 1,20,21In the mid-1980s, several CF centers reported severe deterioration and bacteremia in patients colonized with B cepacia.2,11,2~ In general, these patients followed one of three clinical courses (1) long-term colonization without adverse effect, (2) slow decline of lung function, or (3) acute fulminant lung infection leading to death within weeks to months. 2~ Not all of the virulence factors for B cepacia are understood; however, this bacteria is known to be more resistant to antibiotics than is P aeruginosa, and resistance develops rapidly. Risk factors for acquiring B cepacia include having severe pulmonary disease, use of aminoglycosides, and having a sibling with CF who is colonized with B cepacia.21 Epidemiology. In contrast to the epidemiology of P aeruginosa, growing evidence points to person-to-person transmission as a major factor in the spread ofB cepacia.59~4 The apparent ability of these bacteria to spread from one colonized individual, either directly or indirectly from the contaminated environment, to other individuals with CF, along with its severe consequences, led to the institution of restrictive isolation practices in clinics, hospitals, and even social events designed for people with CF. 59'64'65 Although these infection-control policies have in some instances decreased spread, they may be unnecessarily restrictive for some individuals. Not all strains are equally transmissible. Steinbach and colleagues66 found that patients from different CF centers coming for lung transplantation maintained the same B cepacia strain before and after transplantation and did not transmit it to others. Studies by LiPuma and colleagues62 stress the need for continued vigilance because transmission may not be apparent for prolonged periods of time. However, more recent identification of specific properties associated with high-transmission rates may help explain the variability observed in different centers. 67 Treatment. Treatment of B cepacia has been frustrated by intrinsic resistance to aminoglycosides and the rapid emergence of resistance to [3-1actams by inducible [Mactamases and altered penicillin-binding proteins. 2 Treatment with a combination of antibiotics based on susceptibility and synergy testing performed at reference laboratories may be helpful in preventing the emergence of resistance and treating severe disease.
Other Bacterial Organisms Other bacteria can be isolated from the sputa of patients with CF, but their role(s) in lung disease is not dear. H inJluenzae, usually nontypeable, has been recovered often from the respiratory cultures of young children with CF. 1,2,18Data from the 1990 United States CF Registry recorded nontypeable Hinj'luenzae in 5.5 percent of all reported cultures, with a peak prevalence of 7.8 percent in children aged 2 to 5 years. 1 Microbiological data comparing 150 concurrent BAL and oropharyngeal cultures of young children with CF found a greater prevalence of H inj'luenzae in cultures from the upper respiratory tract (15%)
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compared with BAL (8%), suggesting that oropharyngeal cultures in children who do not produce sputum may be misleading. 18 Increasing attention is being given to other noufermentative gram-negative rods, such as S maltophilia and A xylosoxidans, in patients with CF.68"71While their pathogenic role is still being defined, evolving resistance patterns make them a concern. In addition, epidemiological studies suggest correlation between their presence and exacerbation of pulmonary symptoms. 6s,7l Invasive disease with S maltophiliahas been reported in hospitalized patients, particularly ones with compromised immune systems. 7~ Trimethoprim-sulfamethoxazole and ticarcillinclavulanic acid seem to have the best activity against these organisms in vitro, whereas resistance to [Mactam antibiotics, in particular imipenem, aminoglycosides, and ciprofloxacin, is common.68,7~ Molecular epidemiological typing of S maltophiha and A xylosoxidans isolates within two hospitals failed to show relatedness between these organisms and patients.69,71 Nontuberculous mycobacteria (NTM) have been isolated from the sputum of relatively large numbers of patients with CF, compared with healthy individuals. 73"75 Preliminary data from a prospective study of 21 CF centers in the United States identified NTM in 102 of 849 (12%) patients sampled. 74Distinguishing airway colonization from infection, which might benefit from treatment, is difficult in the patient with CF. Criteria set forth by the American Thoracic Society to make the distinction in the normal host include (1) finding NTM on at least two sputum samples, (2) inability to clear NTM with pulmonary toilet, and (3) finding radiographic abnormalities not attributable to other infections. 73 The third criterion is difficult to apply to patients with CF, who often have radiologic abnormalities from other infectious processes. Epidemiologically, patients with CF who are found to be colonized with NTM compared with those who are not colonized are older and have more severe lung disease. 73-75 Pinto-Powell and colleagues TM performed specific skin tests forMycobacteriaavium on 51 patients with CF from two centers and found that 16 percent had reactions over 10 mm. All patients with a positive skin test had positive cultures in the sputum. However, one patient with histological evidence of disease was anergic, and four others with positive cultures had negative specific response to this skin antigen.76 The authors concluded that the finding of delayed type hypersensitivity against NTM represents true infection rather than colonization. Clinical correlations still are needed to help guide decisions on treatment. Autopsies of patients with CF were examined and comparisons were made between those who had positive cultures for N'I~I before death and those who did not have a prior history of positive cultures for NTM. 77 Six patients had more than one sputum positive for NTM, whereas 12 others had a single culture positive; 18 patients had no previous history of NTM. Three patients had clinically significant NTM disease before death; two were found on autopsy to have necrotizing granulomas. Patients with either only one or no positive cultures had no evidence of disease on autopsy. 77Data from multicenter trials will help in determining whether treatment of NTM in patients with CF is effective. Meanwhile, treatment may be
reserved for individuals with worsening clinical status and/or histopathologic evidence of NTM disease. Organisms that cause respiratory disease in healthy individuals can trigger pulmonary exacerbations in patients with CF as well. C pneumoniae was isolated from 4 of 32 patients with CF admitted with acute pulmonary exacerbations, but not from any of 24 clinically stable patients observed at one CF center. 78
Viruses The role of respiratory viruses in disease progression, particularly in young children with CF, remains controversial. 2Abman and colleagnes 79 prospectively followed 48 infants diagnosed with CF. Thirty-eight percent of infants younger than 1 year of age required hospitalization on 30 occasions because of acute respiratory symptoms. Respiratory syncytial virus (RSV) accounted for seven (23%) of these admissions. The children hospitalized with RSV tended to have prolonged hospital stays (mean of 22 days), and three required mechanical ventilation. In addition, these seven children were more likely to develop chronic respiratory disease than were those in whom no virus was isolated or in whom another virus was found. 79Multicenter trials that should yield information on the role of RSV in progression of disease in infants with CF have begun. A large study from Liverpool investigated the presence of respiratory viruses in patients admitted with pulmonary exacerbations during a 1-year period. 8~ Viruses were identified by serology, culture, or polymerase chain reaction of respiratory secretions in 44 of 157 episodes of pulmonary exacerbation. Rhinovirus was identified in 25 of these samples by polymerase chain reaction. Parainfluenza and influenza were each identified in five patients by serology; four of the patients also had parainfluenza identified by culture.
Funsal Infections Candida and aspergillus commonly are isolated from the respiratory secretions of patients with CF. Most candidal infections are related to extensive antibiotic use or as a side effect of inhaled steroid therapy localized to the oropharynx. These infections rarely are invasive. Aspergillusfumigatus is the species of aspergillus most commonly isolated, al-8~The most common disease manifestation is allergic bronchopulmonary aspergillosis, which is estimated to affect 6 to 10 percent of patients with CF.22,82-84The disease is suspected on clinical grounds when episodic wheezing, accompanied by transient pulmonaryinfiltrates, occurs in the presence of aspergillus in the sputum culture.82-84Additional criteria include eosinophils in the blood and sputum, IgE greater than 400 IU/mL, elevated serum IgE and IgG specifically directed against A~pergillus, immediate skin test reactivity to specific aspergillus antigen, and, ultimately, central bronchiectasis. 22,8v84Systemic steroids are used to treat patients with a positive cfinical history and laboratory data suggestive of allergic bronchopulmonary aspergillosis.82~4 Oral corticosteroids reduce clinical symptoms and decrease allergic markers (such as peripheral eosinophilia and serum IgE levels), but they have potential detrimental long-term side effects. Itraconazole, an oral azole with activity against aspergillus, has been used as adjunctive therapy for patients who do not respond to steroids alone and can lead to a decrease in the dose of steroids used. 8183
Respiratory Infections in Cystic Fibrosis
New and Ongoing Research Approaches to combatting pulmonary disease in patients with CF include using gene therapy to replace the defective protein, augmenting epithelial cell chloride secretion, preventing specific infections with immunizations, developing new treatment strategies, and, finally, considering replacement of the endstage lungs by transplantation. The aim of gene therapy is to transfer a normal copy of the CFTR gene into airway epithelial cells, which has been accomplished successfully in vitro and in animal models. 85 Human trials have used normal CFI'R cDNA within recombinant adenovirus vectors. 86 Difficulties encountered have included poor transfection efficiency, localized inflammato12r responses to the vectors, and only transient gene expression when transfection does occur. 87An estimated 5 to 10 percent of the airway epithelial cells will need to be corrected to modify the lung disease. 87 Pharmacological manipulations of CFTR also are being investigated with the goal of increasing chloride secretion through CFTR. As noted previously, respiratory virus infections in infants with CF, particularly RSV, have been implicated in the subsequent colonization of their airways with P aeruginosa.79 Accordingly, passive immunization with RSV-intravenous immunoglobulin might offer a strategy for improving the clinical outcome of these children. Epidemiological studies currently are being conducted to determine if this strategy has merit. Since the mid-1980s, double-lung (or heart-lung) transplantation has been used in more than 700 children with end-stage lung disease from CF. 8a,89 Three-year survival rates range between 46 and 55 percent, 8s with most deaths caused by infections or chronic rejection (bronchiolitis obliterans). In general, patients with a predicted survival of 12 to 24 months and severe lower ai~vcay obstruction with a FEVI of less than 35 percent predicted are evaluated. 88,89 Relative contraindications to transplantation include colonization with B cepacia or multiple resistant P aeruginosa, tracheotomy, need for mechanical ventilation, and previous thoracotomy or pleurodesis. 88,9~ In addition, it is imperative to optimize nutrition and compliance with other medications before transplantation. Patients undergoing transplantation require a multidisciplinary approach to care. Immunosuppression can predispose patients to infections not ordinarily a particular problem in patients with CF (before transplantation), such as c3rtomegalovirus and Epstein-Barr virus. 92 Patients with CF are unique in that their sinuses and trachea may remain colonized with the same bacteria found before transplantation. These areas may subsequently reinfect the new lungs. Studies evaluating prophylactic sinus surgery are in progress.
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41. 42.
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46. 47. 48.
49. 50.
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pseudomonads increased by" use of inhaled corticosteroids? Unexpected results from a double blind placebo controlled study. Pediatr Pulmonology 14:293-294, 1997 (abstr 318, suppl) Thomassen MJ, Demko CA, Doershuk CF, et al: Pseudomonas aeruginosa isolates: Comparisons of isolates from campers and fi'om sibling pairs with cystic fibrosis. Pediatr Pulmonol 1:41-46, 1985 Grothues D, Kopman U, vonder Hardt H, et al: Genome fingerprinting ofPseudomonas aemginosa indicates colonization of cystic fibrosis siblings with closely related strains. J Clin Microbiol 26:1973-1977, 1988 Speert DP, Lawton D, Damn S: Communicability of Pseudomonas aeruginosa in a cystic fibrosis summer camp.J Pediatr 101:227-229, 1982 Tummler B, Kooperman U, Grothues D, et al: Nosocomial acquisition of Pseudomonas aeruginosa by cystic fibrosis patients. J Clin Microbio129:1265-1267, 1991 Cheng K, Smyth RL, Govan JRW, et al: Spread of 13-1actamresistant Pseudomoncu" aeruginosa in a cystic fibrosis clinic. Lancet 348:639-642, 1996 Doring G, Jansem S, Noll H, et al: Distribution and transmission of Pseudomonas aeruginosa and Burkholderia cepacia in a hospital ward. Pediatr Pulmono121:90-100, 1996 Saiman L, Cacalano G, Gruenert D, et al: Comparison of adherence of Pseudomonas aeruginosa to respiratory epithelial cells from cystic fibrosis patients and healthy subjects. Infect Immun 60:2808-2814, 1992 Saiman L, Prince A: Pseudomonas aeruginosa pili bind to asialoGM1 which is increased on the surface of cystic fibrosis epithelial cells.J Clin Invest 92:1875-1880, 1993 Krivan HC, Roberts DD, Ginsburg V: Many pulmonary pathogenic bacteria bind specifically to carbohydrate sequence GalNAcl314Gal found in some glycolipids. Proc Natl Acad Sci 85:6157-6161, I988 Imundo L, BaraschJ, Prince A, et al: Cystic fibrosis epithelial cells have a receptor for pathogenic bacteria on their apical surface. Proc Natl Acad Sci 92:3019-3023, 1995 Pier GB, Desjardins D, Aguilar T, et al: Polysaccharide surface antigens expressed by nonmucoid isolates ofP. aeruginosa from cystic fibrosis patients.J Clin Microbio124:189-196, 1986 Macone AB, Pier GB, PenningtonJE, et al: MucoidEscherichia coli in cystic fibrosis. N EnglJ Med 304:1445-1449, 1981 Pier GB, Matthews WJJr, Eardley DD: Immunochemical characterization of the mucoid exopolysaccharide ofP. aeruginosa.J Infect Dis 147:494-503, 1983 Cabral DA, Loh BA, Speert DP: Pseudornonas aeruginosa resists nonopsonic phagocytosis by human neutrophils and macrophages. Pediatr Res 22:429-431, 1987 Mcfarlane H, Holzel A, Brenchley P, et al: Immune complexes in cystic fibrosis. Br MedJ 1:423-428, 1975 Matthews WJ, Williams M, Oliphint B, et al: Hypogammaglobulinemia in patients with cystic fibrosis. N EnglJ Med 302:245-249, 1980 Boxerbaum B: The art and science of the use of antibiotics in cystic fibrosis. Pediatr Infect Dis 6:381-383, 1982 Smith AL: Antibiotic therapy in cystic fibrosis: Evaluation of clinical trials.J Pediatr 108:866-870, 1986 Thomassen MJ, Demko CA, Boxerbaum B, et al: Multiple isolates of Pseudomonas aeruginosa with differing antimicrobial susceptibility patterns from patients with cystic fibrosis.J Infect Dis 140:873-880, 1987 Burns JL: Clinical definition of susceptibility and resistance to tobramycin. Pediatr Pulmonol 14:139-140, S10.4, 1997 (suppl) Szaff M, Hoiby N, Flensborg EW: Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronicPseudomonas aeruginosa infection. Acta Paediatr Scand 72:651-657, 1983
51. Frederikscn B, Koch C, Hoiby N: Antibiotic treatment of initial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmono123:330-335, 1997 52. Orenstein DM, Pattishall EN, Noyes BE, et al: Safety of ciprofloxacin in children with cystic fibrosis. Clin Pediatr 32:504-506, 1993 53. Grenier B: Use of the new quinolones in cystic fibrosis. Rev Infect Dis 11 :S 1245-252, 1987 (suppl) 54. Hsu MC, Gauila HA, Schmidt VL, et al: Individualization of tobramycin dosage in patients with cystic fibrosis. Pediatr Infect Dis 3:526-529, 1984 55. Hendeles L, Iafrate RP, Stillwell PC, et al: Individualizing gentamicin dosage in patients with cystic fibrosis: Limitations to pharmacokinetic approach.J Pediatr 110:303-310, 1987 56. Kavanaugh RE, Unadkat JD, Smith AL: Drug disposition in cystic fibrosis, in Davis PB (ed): Cystic Fibrosis, vol 64. New York, NY, Marcel Dekker Inc, 1993, chapter 4, pp 91-136 57. Levy.], Smith AL, Kenny MA, et al: Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: Comparison with activity in serum.J Infect Dis 148:1069-1076, 1983 58. Smith AL, Ramsey BW, Hedges DL, et al: Safety of aerosol tobramycin administration for 3 months to patients with cystic fibrosis. Pediatr Pulmonol 7:265-271, 1989 59. Pegues DA, Carson LA, Tablan OC: Acquisition of Pseudornonas cepacia at summer camps for patients with cystic fibrosis. J Pediatr 124:694-702, 1994 60. LiPumaJJ, Dasen SE, Nielson DW, et al: Person-to-person transmission of Pseudomonas cepacia between patients with cystic fibrosis. Lancet 336:1094-1096, 1990 61. GovanJRW, Brown PH, MaddisonJ, et al: Evidence for transmission ofPseudornonas cepacia by social contact in cystic fibrosis. Lancet 342:15-19, 1993 62. LiPuma JJ, Marks-Austin KA, Holsclaw DS Jr, et al: Inapparent transmission of Pseudomonas (Burkholderia) cepacia among patients with cystic fibrosis. Pediatr Infect DisJ 13:716-719, 1994 63. John M, Ecclestone E, Huner E, et al: Epidemiology of Pseudornonas cepacia colonization among patients with cystic fibrosis. Pediatr Pulmonol 18:108-113, 1994 64. Thomassen MJ, Demko CA, Doershuk CF, et al: Pseudomonas cepacir Decrease in colonization in patients with cystic fibrosis. Am Rev Respir Dis 134:669-671, 1986 65. Humphreys H, Peckham D, Patel P, et al: Airborne dissemination of Burkholderia (Pseudomonas) cepacia from adult patients with cystic fibrosis. Thorax 49:1157-1159, 1994 66. Steinbach S, Sun L, Jiang R, et al: Transmissibility of Pseudornonas cepacia infection in clinic patients and lung-transplant recipients with cystic fibrosis. N EnglJ Med 331:981-987, 1994 67. Sun L, Jian R-Z, Steinbach S, et al: The emergence of a highly transmissible lineage of cbl Pseudomonas (Burkholderia) cepacia causing CF centre epidemics in North America and Britain. Nature Med 1:661-666, 1995 68. Wrist J, Frei R, Gfinthard H, et al: Analysis of restriction fragment length polymo@ism and ribotyping of multiresistant Stenotrophomonas maltophilia isolated from persisting lung infection in a cystic fibrosis patient. ScandJ Infect Dis 27:499-502, 1995 69. Vu-Thien H, Moissenet D, Valcin M, et al: Molecular epidemiology of Burkholderia cepacia, Stenotrophomonas maltophilia, and Alca[igenes xylosoxidans in a cystic fibrosis center. EurJ Clin Microbiol Infect Dis 15:876-879, 1996 70. Spencer RC: The emergence of epidemic, multiple-antibioticresistant Stenotrophomonas (Xanthomonas) maltophilia and Burkholderia (Pseudomonas) cepacia.J Hosp Infect 30:453-464, 1995 (snppl) 71. Dunne WM, Maisch S: Epidemiological investigation of infections due toAIcaligenes species in children and patients with cystic fibrosis:
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Use of repetitive-element-sequence polymerase chain reaction. Clin Infect Dis 20:836-841, 1995 Muder RR, Harris AP, Muller S, et al: Bacteremia due to Stenotrophomonas (Xanthomonas)maltophiliw A prospective, multicenter study of 91 episodes. Clin Infect Dis 22:508-512, 1996 Aitken ML, Burke W, McDonald G, et al: Nontuberculous mycobact erial disease in adult cystic fibrosis patients. Chest 103:1096-1099, 1993 Olivier K, Faiz A, Jones B, et al: Prevalence of nontuberculous mycobacteria in US CD centers. Pediatr Pulmono1287, 1997 (abstr 292, suppl) Boxerbaum B: Isolation of rapidly growing mycobacteria in patients with cystic fibrosis.J Pediatr 96:689-691, 1980 Pinto-Powell R, Olivier KN, Marsh BJ, et al: Skin testing with Mycobacterium avium sensitin to identify infection with M avium complex in patients with cystic fibrosis. Clin Infect Dis 22:560-562, 1996 Tomashefski JF Jr, Stern RC, Demko CA, et al: Nontuberculous mycobacteria in cystic fibrosis; an autopsy study. AmerJ Resp Crit Care Med 154(2 ptl):523-528, 1996 Emre U, Bernius M, Roblin PM, et al: Chlamydiapneumonic~infection in patients with cystic fibrosis. Clin Infect Dis 22:819-823, 1996 Abman SH, OgleJW, Bulter-Simon CM, et al: Role of Respiratory syncytial virus in early hospitalizations for respiratory distress of young infants with cystic fibrosis.J Pediatrics 113:826-830, 1988 Smyth AR, Smuth RL, Tong CYW, et al: Effect of respiratory virus infections including rhinovirus on clinical status in cystic fibrosis. Arch Dis Child 73:117-120, 1995 EI-Dahr JM, Fink R, Selden R, et al: Development of immune responses to aspergillus at an early age in children with cystic fibrosis. AmJ Respir Crit Care Med 150:1513-1518, 1994
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82. Denning DW, vanWye JE, Lewiston NJ, et al: Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole. Chest 100:813-819, 1991 83. Mannes GPM, van der Heide S, van Aalderen WMC, et al: Itraconazole and allergic bronchopulmonary aspergillosis in twin brothers with cystic fibrosis. Lancet 341:492, 1993 84. Mroueh S, Spock A: Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. Chest 105:32-36, 1994 85. Rosenfeld MA, Yoshimura K, Trapnell BC, et al: In vitro transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68:143-155, 1992 86. Wilson JM: Cystic fibrosis: Strategies for gene therapy. Semin Respir Crit Care Med 15:439-445, 1994 87. Crystal RG: Gene therapy for cystic fibrosis: Where have we been and where are we going? Pediatr Pulmonol 14:73, 1997 (suppl) 88. Cystic Fibrosis Foundation: Lung transplantation in cystic fibrosis: Consensus conference statement. 7 (section 2): 1-19, 1996 89. Mallory GB, Spray TL: Lung transplantation for cystic fibrosis in children, in Franco KL (ed): Pediatric Cardiopulmonary Transplantation, Armonk, NY, Futura, 1997, chap 14, pp 277-299 90. Noyes BE, Michaels MG, Kurland G, et al: Pseudomonas cepacia empyema necessitates after lung transplantation in two patients with cystic fibrosis. Chest 105:1888-1891, 1994 91. Aris RM, Gilligan PH, Neuringer IP: The effects of panresistant pseudomonas in cystic fibrosis patients on lung transplant outcome. AmJ Respir Crit Care Med 155:1699-1704, 1997 92. Michaels MG, Green M: Infectious complications of heart and lung transplantation in children, in Franco KL (ed): Pediatric Cardiopulmonary Transplantation, Armonk, NY, Futura, 1997, pp 27-46
ERRATUM Please note the following correction in the article entitled "Mycoplasma pneumoniae Infection in Pediatrics," which appeared in the April 1998 issue of Seminars in Pediatric Infectious Diseases (Vol 9, No 2, pp 112-119). The correct Figure 1 is shown below.
F i g u r e 1. A 10-year-old girl with Mycoplasma pneumoniae pneumonia. (Reprinted with permission from McMillian JA: Mycoplasma pneumonia, in Long, Pickering, Prober (eds): Principles and Practice of Pediatric Infectious Diseases. Philadelphia, PA, Churchill Livingstone, 1997, p 1106.)
Ystic fibrosis (CF) is the most common severe genetic disorder among Caucasian populations, with an incidence of 1 in 2,500 to 3,500 live births in the United States. 1,2 Great strides have been made in the care of these children since 1938, when Andersen2,3first described infants with CF. Whereas most children with CF did not survive early childhood in the 1950s, by 1996 aggressive treatment of pulmonary infections and prevention of malnutrition had led to a median survival of 31 years, with many adults living beyond their third decade. !,4 Also, information about the genetics and cellular physiology of CF has been learned during the last two decades. In 1989, the CF gene was localized to chromosome 7.5,6It was recognized as encoding the CF transmembrane conductance regulator (CYFR) protein, which functions as a cyclic adenosine monophosphate-mediated apical chloride channel.7,8 Mutations of CFFR lead to high concentrations of sodium and chloride in sweat and relative dehydration ofintraluminal secretions. Clinically, CF manifests as a multiorgan disease, affecting the respiratory, gastrointestinal, and reproductive systems, as well as the sweat glands. Although much progress has been made in understanding the defects in CF, children and young adults with this disorder still suffer from progressive destruction of the airways. Endobronchial infections and the inflammatory responses elicited by these bacteria remain among the most important factors leading to morbidity and early mortality. 2,4,8-12 This article reviews the importance of respiratory infections in CF, detailing microbial agents, their epidemiology, pathogenesis, and current therapeutic strategies.
C
From the Universi~ of Pittsburgh School of Medicine, Division of Allergy, Immunology, Infectious Diseases and the Division of Pulmonology, Children's Hospital ofPittsburgh, Pittsburgh, PA. Address correspondenceto Marian G. Michaels, MD, MPH, University of Pittsburgh, School of Medicine, Division of Allergy, Immunology, Infectious Diseases, Children'sHospital ofPittsburgh, 3705Fifth Ave, Pittsburgh, PA 15213. Copyright 9 1998 by W.B. Saunders Company 1045-1870/98/0903-001058.00/0 234
Risk for Infection Individuals with CF do not have a detectable immune deftciency; rather, altered electrolyte and water content of airway secretions lead to colonization with specific bacteria that are unlikely to colonize the respiratory tract of a healthy person. 1~-15 The composition of normal respiratory secretions is dependent on CFTR channel activity; although the precise mechanism is not understood fully, abnormalities in ion transport across the epithelial cells of persons with CF promote an endobronchial milieu that favors infections.7,a Once infection is established, bronchial mucus becomes thick, tenacious, and difficult to clear. The characteristic thick "CF mucus" results from breakdown products of invading organisms and neutrophils, including actin myofibrils and deoxyribonucleic acid. In addition, neurrophils in the airway fluid of children with CF produce an excess of elastase, 16which causes nonspecific damage of elastin fibers in the airway, stimulates mucus secretion, and interferes with the opsonization and killing of pseudomonads. These local host factors are complicated by bacterial endoproducts, such as proteases and exotoxin A, which allow for chronic colonization.17 Hence, a vicious cycle is created; altered mucus production potentiates plugging of the small airways, favoring infection and inflammation. These factors contribute to further airway obstruction, ultimately resulting in bronchiectasis and irreversible lung disease.
Pulmonary Colonization and Exacerbations Children with CF acquire bacterial colonization of their airways in an orderly fashion. During infancy, Staphylococcus aureus is the predominant organism, and it was the major cause of death in children with CF in the first half of the 20th century.3 During early childhood, nontypeable Hemophilus influenzae is common, and by adolescence most individuals with CF are colonized with Pseudomonus aemginosa. 2,9,14Recent studies in which bronchoalveolar lavage (BAL) were performed have shown an earlier colonization with pseudomonas than previously recognized, is,19 Pseudomonas and, more recently, Burkholderia cepacia (formerly
Seminars in Pediatric Infectious Diseases, Vol 9, No 3 (Ju~), 1998.'pp 234-242
Respiratory Infections in Cystic Fibrosis Pseudomonas cepacia) are the predominant causes of morbidity and mortality in patients with CF.8-12,2~ Other organisms, such as Alcaligenes xylosoxidans and Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia), are found commonly colonizing the lungs of patients with CF; however, their role(s) in production of disease is less clear. 2,9-11Likewise, the roles of respiratory viruses, Mycoplasma species, Chlamydia pneumoniae, and nontubercutous mycobacteria are debated.2 Fungi, particularly Aspergillus species, have been implicated as a cause of symptomatic disease (eg, allergic bronchopulmonary disease) in individuals with CF.2,10,22 Antimicrobialagents are used to treat infections, but they do not eradicate the organisms from patients with CF.9-12 The clinical course of a patient with CF usually is characterized by periods of general well-being punctuated by intercurrent periods of acute deterioration. Patients with CF are a heterogenous population, and multiple factors must be considered when deciding whether or not to treat changes in respiratory symptoms. Pulmonary exacerbations are characterized by increased frequency and intensity of cough and a change in the volume, color, or consistency of the sputum.2,9 Myalgias, anorexia, and weight loss are frequent occurrences, whereas fevers are noted in only a minority of patients.9 In addition, an exacerbation can be manifest by increased respiratory rate, dyspnea, or shortness of breath. Physical examination may show use of accessory muscles and retractions, along with new auscultatory findings, such as crackles or wheezing. Attempts to add more objective criteria to define pulmonary exacerbations sometimes include evidence of radiographic changes and a decrease in oxyhemoglobin saturation. Serial pulmonary function tests to measure airway obstruction are used, as wellJ 2 These studies require cooperation and coordination from the patient and usually cannot be accomplished before the patient reaches 5 years of age. The most reliable measurements are forced vital capacity and forced expiratory volume at 1 second (FEVI). Consensus among clinicians who treat patients with CF is that decline in forced vital capacity and/or FEV1 of 10 to 15 percent from baseline or a continued decline over time is a marker of deterioration. Although no universal criteria that define pulmonary exacerbation exists, these features help to determine when an individual requires therapeutic intervention. Accordingly, it is important for patients with CF to have consistent care at a CF center with health care providers who are familiar with their clinical status and problems. Cultures of sputum are used to help guide choices of antibiotics. Centers caring for children and adults with CF must have reliable microbiology laboratories that are experienced in isolating, identifying, and performing susceptibility tests on pathogens found in the airway of patients with CF.9,1~ The reliability of cultures of the sputum has been borne out by comparison with cultures obtained from thoracotomy specimens.23 In children who are too young to produce sputum, cultures obtained from the oropharynx have been used in an attempt to identify possible pathogens. However, prospective comparison of cultures obtained from the oropharynx with those obtained from the BAL of infants with CF followed over time showed that oropharyngeal cultures did not reliably predict lower respiratory tract pathogens. 18 The positive predictive
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value of a pathogenic bacteria in the oropharynx also being found in the BAL was only 41 percent. In addition, molecular studies of organisms cultured from both the BAL and upper airway showed that they were often of different strains. Accordingly, oropharyngeal cultures obtained from children with CF who cannot produce sputum must be interpreted with care; the need to obtain a culture of BAL fluid must be assessed periodically.
Specific Microorganisms S aureus S aureus was recognized as a major cause of death in children with CF in the preantibiotic era 3 and was the most frequent organism isolated from patients with CF in the 1960s.24 Data from the 1990 United States CF registry showed it to be the most common bacteria isolated from children younger than 1 year of age; it was common in all age groups, and it accounted for 28 percent of isolates. 1In addition, a large prospective study of infants with CF who underwent serial BALs for surveillance found S aureus in the lower respiratory secretions of 27 percent of children less than 1 year of age. 19 Concurrent oropharyngeal cultures identified S aureus in 61 percent of the children. The common finding of upper airway colonization in infants with S aureus may account for the higher prevalence ofS aureus reported in studies in which BAL was not performed in children who did not produce sputum but had oropharyngeal cultures obtained. A smaller study from three CF centers in the United States of children who underwent BALs annually reported S aureus colonization in 23, 32, and 32 percent at 1, 2, and 3 years, respectively.25 Literature from as recently as 1991 states that methicillinresistant S aureus (MRSA) does not play a substantial role in patients with CF. 2'26 The organism was rarely isolated before 1985, but it is found increasingly as resistance patterns change in hospitals. For example, antimicrobial susceptibility testing at The Children's Hospital of Pittsburgh found only a 4 percent prevalence of MRSA in 1990 from specimens obtained from children with CF, but by 1996, MRSA had increased to account for 19 percent ofS aureus isolated from these patients. In general, when only S aureus is found in the sputum of a patient with CF who is experiencing a mild exacerbation of pulmonary symptoms, treatment is initiated with oral antimicrobial agents such as first-generation cephalosporins, dicloxacillin, clindamycin, macrolides, or tlouroquinolones. When patients are compromised more severely or are not responsive to this therapy, intravenous antistaphylococcal penicillins such as oxacillin, nafcillin or methicillin may be required. Vancomycin should be initiated to treat patients with infection caused by MRSA. P aeruginosa Up to 90 percent of patients with CF eventually acquire colonization with P aeruginosa. It rarely is found before patients reach 6 months of age, but as many as 30 percent of patients already are colonized with this organism by 3 to 5 years of age. 1,25 A study attempting to correlate clinical deterioration with acquisition of pseudomonas noted that the organism was acquired before detection of pulmonary dysfunction37 Risk
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factors for the acquisition of colonization with pseudomonas species have been debated. Acquisition of colonization tends to be more common in winter months, concurrent with respiratory viral infections, suggesting that infections with viruses may facilitate colonization with pseudomonas. 14,28A study evaluating the use of inhaled steroids was halted prematurely when patients on steroids acquired colonization with P aeruginosa more often than did patients receiving placebo, intimating a potential causal relationship. 29 Epidemiological evidence shows that siblings with CF often are colonized with the same strain o f P aeruginosa.14,3~ This observation, however, does not distinguish between person-toperson spread and cross-infection from a common environmental source. Concern for nosocomial transmission within hospitals and CF centers has led to debate regarding the need for and best method of control of cross-transmission among patients with CF. Whereas many investigationshave shown that patients with CF do not spread P aeruginosa outside of households, 3~ epidemiological studies performed with molecular techniques show that nosocomial transmission can occur.33,34 Cheng and colleagues 34 documented the spread of a [3-1actam-resistant strain ofP aeruginosa among a large proportion of their patients observed at the same CF center. Taken together, these studies show that although nosocomial spread ofP aeruginosa is possible, it is relatively unusual9,35 Virulence Factors. P ao~ginosa have developed multiple mechanisms to cause tissue injury and evade the immune system, including production of elastase, alkaline protease, exotoxin A, exoenz)ane S, hemolysins, polymorphonuclear inhibitors, and mucoid exopolysaccharide (MEP).2,17 An intricate, complicated interplay of these mechanisms and the specific interaction of receptors on apical epithelial surfaces of patients with CF help to establish infection of the lungs with P aeruginosa. 17Some of these virulence factors are explored here. Saiman and colleagues 17,36noted increased adherence of P aeruginosa to the epithelial cells obtained from patients with CF compared with normal controls. Further work noted a significantly increased number of asialoGM 1 residues on the epithelial cells of individuals with CF compared with normal epithelial cells; these residues are responsible for bindingP aeruginosa.37-39 Unlike pseudomonads in individuals without CF, this bacteria often has a unique mucoid morphoty-pe in patients with CF. 2'14'17This morphotype occurs because of the production of a capsular MEP and has been found even in nonmucoidappearing strains isolated from sputa of individuals with CF.4~ Of interest, mucoid strains of other types of gram-negative rods have been found in patients with CF, suggesting that something in the lung of the patient with CF is conducive to the production o f MEP. 17,41 Longitudinal studies show that the airways of patients with CF initially are colonized with nonmucoid strains of pseudomonas; mucoid strains arise subsequently. 2,25,42 The mechanisms leading to the production of mucoid strains are not understood completely. Microcolonies of mucoid strains may be enhanced in part by the local production ofproteases that cause the release of mucins from the host respiratory epithelium.2 Once present, mucoid strains have a selective advantage in that MEP has antiphagocytic properties. 2,17,43Likewise, in the presence of calcium ions, MEP forms a highly viscous gel that further evades ciliary clearance. 2
P aeruginosa may cause direct damage to the lungs, by production and local release of virulence factors such as alkaline protease, elastase, and exotoxin A, and indirect damage, by eliciting a host-immune response leading to a release of endogenous proteases and elastase. 2,17In addition, the accumulation of immune complexes has been associated with severe pulmonary disease in patients with CF. 2'17'44 Supporting the role of immune complexes in damage to the lungs is the finding that patients with hypogammaglobulinemia are relatively spared this destruction.45 Susceptibility Testing. The mainstay of treatment of P aeruginosa is the administration of antibiotics, even though eradication of organisms usually is not possible.46,47Controversy exists regarding the optimal method of performing susceptibility testing, the ideal antimicrobial regimen, and the best method of delivering antibiotics. Respiratory specimens from patients with CF should be processed promptly to avoid difficulties in recovering organisms. The high viscosity of CF sputum has led some researchers to recommend using quantitative or semiquantitative cultures. 1~ Special media and identification methods are critical to avoiding misidentification of potential pathogensJ ~ Patients often have more than one strain of pseudomonas, with varying susceptibility patterns, in their sputum.48 One approach is to isolate each morphotype and perform separate susceptibility testing on each. An alternate approach is to test all morphotypes together in a single susceptibility assay. The latter method, although much less timeconsuming and expensive, may obscure valuable information regarding the development of patterns of resistance and the potential for combination therapies. A consensus conference on the microbiology of infections in patients with CF noted difficulties with standard methods for testing susceptibility of specimens from patients with CF because of slow growth or lack of data. l~ Another controversial area of susceptibility testing involves defining breakpoints for resistance. 49 Standard in vitro susceptibility data are based on serum concentrations of drugs that are achievable without undue toxicity. The site of infection is assumed to be perfused with this concentration of blood. However, the site of infection in patients with CF is an inflamed airway with purulent secretions. The concentration of antibiotics in the infected compartment may be considerably lower than in the serum. Alternatively, the standard breakpoints may underestimate substantiallysusceptibility of an organism to an antibiotic if an aerosolized delivery system is used, which can safely achieve concentrations of antibiotic in the sputum in excess of 1000/~g/mL.9'49Prospective treatment trials that incorporate studies that examine levels of drug in sputa and measure minimal inhibitory concentrations higher than those currently regarded as standard will help to determine clinically relevant susceptibility testing methods. Treatment. Ideally, antipseudomonal antibiotics would be administered easily (either aerosolized or by the oral route) with little toxicity and without promoting the emergence of resistance. Two major approaches to treatment can be identified: chronic suppression or treatment of acute pulmonary exacerbations. Chronic suppression or prophylactic strategies have been implemented in some centers to attempt to prolong the periods of general wellnessJ 1 In 1983, Szaff and colleagues 5~ reported significant improve-
Respiratory Infections in CysticFibrosis ment in pulmonary function and survival in Danish patients who received a 24-day course of intravenous antimicrobial therapy against P aeruginosa every 3 months, regardless of clinical findings. However, their comparison group was historical controls. A more recent study from a Danish center evaluated an aggressive preemptive treatment strategy initiated after the first isolation o f P aeruginosa and before development of disease or chronic infection.51 In this study, a combination of inhaled colistin and oral ciprofloxacin was administered for 3 weeks when pseudomonas first were isolated. This regimen was repeated if the organism was found a second time; if found a third time within a 6-month period, therapy was extended for 3 months. The authors concluded that, compared with historic controls, this regimen delayed the onset of chronic infection caused by P aeruginosa.51 The other management strategy is to treat acute exacerbations aggressively with an antibiotic regimen based upon culture and susceptibility testing.9,37,4GTherapeutic regimens, in general, are composed of two antimicrobial agents that may provide synergism and slow the rates of emergence of drug resistance, l~ Ideally, antibiotic combinations include those that have different mechanisms of action, such as an aminoglycoside plus an anti-pseudomonal [Mactam antibiotic (eg, ceftazadime, azlocillin, mezlocillin, ticarcillin, piperacillin, imipenim, meropenem, or aztreonam). Flouroquinolones, in particular, ciprofloxacin, norfloxacin, and ofloxacin, are attractive antipseudomonal drugs because of their oral bioavailability,but they are not approved by the Food and Drug Administration for use in children younger than 18 years of age because of concerns regarding joint toxicity. However, a growing number of studies has shown this drug to be safe and efficacious in children with CF. 52,53 The pharmacokinetics and metabolism of many drugs, including antibiotics, are altered in individuals with CF, compared with healthy populations. Individualized dosing of antimicrobials is necessary because CF patients show an increased volume of distribution and clearance of drugs, 54,55which may be related, in part, to the disease process (eg, pancreatic insufficiency); one hypothesis is that the CFTR may affect cellular processing in the liver and kidney, thereby necessitating increased dosing of drugs. 56 Toxicity, particularly of intravenous aminoglycosides, must be considered. Measurements of peak and trough levels are recommended, along with periodic evaluation of renal and auditory function.55 The route of administration of drugs also has been questioned in treating pseudomonas infections in children with CF. In vitro data generated by Levy and colleagues57 showed that, compared with serum dialysates, aminoglycosides had decreased bioactivity against P aeruginosa in the sputum of CF patients. This observation led to the clinical investigation of aerosolized aminoglycosides in an attempt at the site of infection to achieve high levels of antibiotics which cannot be safely achieved by intravenous administration to overcome this antagonism.5s Aerosolization of 600 mg of tobramycin through an ultrasonic nebulizer, three times daily for 3 months, was found to be safe, although some systemic absorption did occur.5a Efficacy has been implied by clinical improvement and stabilization or improvement of serial pulmonary function tests in short-term studies. Long-term, multicentered studies are ongoing.
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B cepacia This gram-negative, nonspore-forming, motile, nonfermentative, aerobic bacillus was classified as a Pseudornonasspecies until 1992, when it was reclassified as B cepacia. In the past two decades, it has been recognized as an important pathogen within the CF population.TM 1,20,21In the mid-1980s, several CF centers reported severe deterioration and bacteremia in patients colonized with B cepacia.2,11,2~ In general, these patients followed one of three clinical courses (1) long-term colonization without adverse effect, (2) slow decline of lung function, or (3) acute fulminant lung infection leading to death within weeks to months. 2~ Not all of the virulence factors for B cepacia are understood; however, this bacteria is known to be more resistant to antibiotics than is P aeruginosa, and resistance develops rapidly. Risk factors for acquiring B cepacia include having severe pulmonary disease, use of aminoglycosides, and having a sibling with CF who is colonized with B cepacia.21 Epidemiology. In contrast to the epidemiology of P aeruginosa, growing evidence points to person-to-person transmission as a major factor in the spread ofB cepacia.59~4 The apparent ability of these bacteria to spread from one colonized individual, either directly or indirectly from the contaminated environment, to other individuals with CF, along with its severe consequences, led to the institution of restrictive isolation practices in clinics, hospitals, and even social events designed for people with CF. 59'64'65 Although these infection-control policies have in some instances decreased spread, they may be unnecessarily restrictive for some individuals. Not all strains are equally transmissible. Steinbach and colleagues66 found that patients from different CF centers coming for lung transplantation maintained the same B cepacia strain before and after transplantation and did not transmit it to others. Studies by LiPuma and colleagues62 stress the need for continued vigilance because transmission may not be apparent for prolonged periods of time. However, more recent identification of specific properties associated with high-transmission rates may help explain the variability observed in different centers. 67 Treatment. Treatment of B cepacia has been frustrated by intrinsic resistance to aminoglycosides and the rapid emergence of resistance to [3-1actams by inducible [Mactamases and altered penicillin-binding proteins. 2 Treatment with a combination of antibiotics based on susceptibility and synergy testing performed at reference laboratories may be helpful in preventing the emergence of resistance and treating severe disease.
Other Bacterial Organisms Other bacteria can be isolated from the sputa of patients with CF, but their role(s) in lung disease is not dear. H inJluenzae, usually nontypeable, has been recovered often from the respiratory cultures of young children with CF. 1,2,18Data from the 1990 United States CF Registry recorded nontypeable Hinj'luenzae in 5.5 percent of all reported cultures, with a peak prevalence of 7.8 percent in children aged 2 to 5 years. 1 Microbiological data comparing 150 concurrent BAL and oropharyngeal cultures of young children with CF found a greater prevalence of H inj'luenzae in cultures from the upper respiratory tract (15%)
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compared with BAL (8%), suggesting that oropharyngeal cultures in children who do not produce sputum may be misleading. 18 Increasing attention is being given to other noufermentative gram-negative rods, such as S maltophilia and A xylosoxidans, in patients with CF.68"71While their pathogenic role is still being defined, evolving resistance patterns make them a concern. In addition, epidemiological studies suggest correlation between their presence and exacerbation of pulmonary symptoms. 6s,7l Invasive disease with S maltophiliahas been reported in hospitalized patients, particularly ones with compromised immune systems. 7~ Trimethoprim-sulfamethoxazole and ticarcillinclavulanic acid seem to have the best activity against these organisms in vitro, whereas resistance to [Mactam antibiotics, in particular imipenem, aminoglycosides, and ciprofloxacin, is common.68,7~ Molecular epidemiological typing of S maltophiha and A xylosoxidans isolates within two hospitals failed to show relatedness between these organisms and patients.69,71 Nontuberculous mycobacteria (NTM) have been isolated from the sputum of relatively large numbers of patients with CF, compared with healthy individuals. 73"75 Preliminary data from a prospective study of 21 CF centers in the United States identified NTM in 102 of 849 (12%) patients sampled. 74Distinguishing airway colonization from infection, which might benefit from treatment, is difficult in the patient with CF. Criteria set forth by the American Thoracic Society to make the distinction in the normal host include (1) finding NTM on at least two sputum samples, (2) inability to clear NTM with pulmonary toilet, and (3) finding radiographic abnormalities not attributable to other infections. 73 The third criterion is difficult to apply to patients with CF, who often have radiologic abnormalities from other infectious processes. Epidemiologically, patients with CF who are found to be colonized with NTM compared with those who are not colonized are older and have more severe lung disease. 73-75 Pinto-Powell and colleagues TM performed specific skin tests forMycobacteriaavium on 51 patients with CF from two centers and found that 16 percent had reactions over 10 mm. All patients with a positive skin test had positive cultures in the sputum. However, one patient with histological evidence of disease was anergic, and four others with positive cultures had negative specific response to this skin antigen.76 The authors concluded that the finding of delayed type hypersensitivity against NTM represents true infection rather than colonization. Clinical correlations still are needed to help guide decisions on treatment. Autopsies of patients with CF were examined and comparisons were made between those who had positive cultures for N'I~I before death and those who did not have a prior history of positive cultures for NTM. 77 Six patients had more than one sputum positive for NTM, whereas 12 others had a single culture positive; 18 patients had no previous history of NTM. Three patients had clinically significant NTM disease before death; two were found on autopsy to have necrotizing granulomas. Patients with either only one or no positive cultures had no evidence of disease on autopsy. 77Data from multicenter trials will help in determining whether treatment of NTM in patients with CF is effective. Meanwhile, treatment may be
reserved for individuals with worsening clinical status and/or histopathologic evidence of NTM disease. Organisms that cause respiratory disease in healthy individuals can trigger pulmonary exacerbations in patients with CF as well. C pneumoniae was isolated from 4 of 32 patients with CF admitted with acute pulmonary exacerbations, but not from any of 24 clinically stable patients observed at one CF center. 78
Viruses The role of respiratory viruses in disease progression, particularly in young children with CF, remains controversial. 2Abman and colleagnes 79 prospectively followed 48 infants diagnosed with CF. Thirty-eight percent of infants younger than 1 year of age required hospitalization on 30 occasions because of acute respiratory symptoms. Respiratory syncytial virus (RSV) accounted for seven (23%) of these admissions. The children hospitalized with RSV tended to have prolonged hospital stays (mean of 22 days), and three required mechanical ventilation. In addition, these seven children were more likely to develop chronic respiratory disease than were those in whom no virus was isolated or in whom another virus was found. 79Multicenter trials that should yield information on the role of RSV in progression of disease in infants with CF have begun. A large study from Liverpool investigated the presence of respiratory viruses in patients admitted with pulmonary exacerbations during a 1-year period. 8~ Viruses were identified by serology, culture, or polymerase chain reaction of respiratory secretions in 44 of 157 episodes of pulmonary exacerbation. Rhinovirus was identified in 25 of these samples by polymerase chain reaction. Parainfluenza and influenza were each identified in five patients by serology; four of the patients also had parainfluenza identified by culture.
Funsal Infections Candida and aspergillus commonly are isolated from the respiratory secretions of patients with CF. Most candidal infections are related to extensive antibiotic use or as a side effect of inhaled steroid therapy localized to the oropharynx. These infections rarely are invasive. Aspergillusfumigatus is the species of aspergillus most commonly isolated, al-8~The most common disease manifestation is allergic bronchopulmonary aspergillosis, which is estimated to affect 6 to 10 percent of patients with CF.22,82-84The disease is suspected on clinical grounds when episodic wheezing, accompanied by transient pulmonaryinfiltrates, occurs in the presence of aspergillus in the sputum culture.82-84Additional criteria include eosinophils in the blood and sputum, IgE greater than 400 IU/mL, elevated serum IgE and IgG specifically directed against A~pergillus, immediate skin test reactivity to specific aspergillus antigen, and, ultimately, central bronchiectasis. 22,8v84Systemic steroids are used to treat patients with a positive cfinical history and laboratory data suggestive of allergic bronchopulmonary aspergillosis.82~4 Oral corticosteroids reduce clinical symptoms and decrease allergic markers (such as peripheral eosinophilia and serum IgE levels), but they have potential detrimental long-term side effects. Itraconazole, an oral azole with activity against aspergillus, has been used as adjunctive therapy for patients who do not respond to steroids alone and can lead to a decrease in the dose of steroids used. 8183
Respiratory Infections in Cystic Fibrosis
New and Ongoing Research Approaches to combatting pulmonary disease in patients with CF include using gene therapy to replace the defective protein, augmenting epithelial cell chloride secretion, preventing specific infections with immunizations, developing new treatment strategies, and, finally, considering replacement of the endstage lungs by transplantation. The aim of gene therapy is to transfer a normal copy of the CFTR gene into airway epithelial cells, which has been accomplished successfully in vitro and in animal models. 85 Human trials have used normal CFI'R cDNA within recombinant adenovirus vectors. 86 Difficulties encountered have included poor transfection efficiency, localized inflammato12r responses to the vectors, and only transient gene expression when transfection does occur. 87An estimated 5 to 10 percent of the airway epithelial cells will need to be corrected to modify the lung disease. 87 Pharmacological manipulations of CFTR also are being investigated with the goal of increasing chloride secretion through CFTR. As noted previously, respiratory virus infections in infants with CF, particularly RSV, have been implicated in the subsequent colonization of their airways with P aeruginosa.79 Accordingly, passive immunization with RSV-intravenous immunoglobulin might offer a strategy for improving the clinical outcome of these children. Epidemiological studies currently are being conducted to determine if this strategy has merit. Since the mid-1980s, double-lung (or heart-lung) transplantation has been used in more than 700 children with end-stage lung disease from CF. 8a,89 Three-year survival rates range between 46 and 55 percent, 8s with most deaths caused by infections or chronic rejection (bronchiolitis obliterans). In general, patients with a predicted survival of 12 to 24 months and severe lower ai~vcay obstruction with a FEVI of less than 35 percent predicted are evaluated. 88,89 Relative contraindications to transplantation include colonization with B cepacia or multiple resistant P aeruginosa, tracheotomy, need for mechanical ventilation, and previous thoracotomy or pleurodesis. 88,9~ In addition, it is imperative to optimize nutrition and compliance with other medications before transplantation. Patients undergoing transplantation require a multidisciplinary approach to care. Immunosuppression can predispose patients to infections not ordinarily a particular problem in patients with CF (before transplantation), such as c3rtomegalovirus and Epstein-Barr virus. 92 Patients with CF are unique in that their sinuses and trachea may remain colonized with the same bacteria found before transplantation. These areas may subsequently reinfect the new lungs. Studies evaluating prophylactic sinus surgery are in progress.
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ERRATUM Please note the following correction in the article entitled "Mycoplasma pneumoniae Infection in Pediatrics," which appeared in the April 1998 issue of Seminars in Pediatric Infectious Diseases (Vol 9, No 2, pp 112-119). The correct Figure 1 is shown below.
F i g u r e 1. A 10-year-old girl with Mycoplasma pneumoniae pneumonia. (Reprinted with permission from McMillian JA: Mycoplasma pneumonia, in Long, Pickering, Prober (eds): Principles and Practice of Pediatric Infectious Diseases. Philadelphia, PA, Churchill Livingstone, 1997, p 1106.)