Empowering the Caregiver: The Challenges, Discoveries, and Rewards

Bronchiectasis is a chronic inflammatory disease of the airways that is often marked by paroxysmal coughing with the expectoration of mucopurulent matter. From a pathological perspective, bronchiectasis involves purulent necrotizing microbial infection leading to persistent inflammation of the airway and the release of immune mediators and microbial toxins that induce further tissue damage and abnormal dilation of the airway. The damaged airway, in turn, is susceptible to subsequent infection, leading to a vicious cycle of adding injury to injury in a progressive and usually irreversible manner. Cumulative bronchiolar damage may eventually be fatal. Genetic research indicates that there is substantial genotypic and phenotypic heterogeneity in bronchiectasis populations, and that these variations may influence response to treatment. It is thought, nevertheless, that prevention of serial infections may spare the bronchioles. Currently, clinical trials on treatment alternatives center on inhalation techniques, which are capable of delivering high concentrations of antibiotics to mucus-filled airways without the risks of systemic toxicity. 

This program was supported by an unrestricted educational grant from Chiron Corporation.

Aerosolized Antibiotics for the Treatment of Bronchiectasis

The concept of inhaled antibiotics for the treatment of pulmonary diseases has a half-century history, though until the late 1980s most of the literature on the subject was anecdotal or consisted of case reports. 

The appeal of this delivery system is based on long-term observation that respiratory tract infections may respond poorly to systemic antibiotic therapy because of poor penetration of bronchial secretions, the impairment of the antibiotic activity by purulent secretions, or altered pharmacokinetic disposition of certain classes of antimicrobials. Theoretically, if an appropriate antibiotic can be formulated into a particle of the proper size (0.5 to 5.0 mass median aerodynamic diameter) and delivered directly to the airway by an inhalation device, these problems can be surmounted with the added benefit of minimizing systemic exposure. Table 1 captures the successful demonstration of this theory in studies of tobramycin solution for inhalation, an aerosolized aminoglycoside. 

Most of the experience with aerosolized antibiotics has been in young cystic fibrosis (CF) populations. In a 2-year extension open-label trial of aerosolized tobramycin for treating Pseudomonas aeruginosa in CF, for example, lung function (FEV₁) increased from baseline by a mean of 4.7 percent after 92 weeks. There was a 62 percent reduction in hospitalizations in the fall season, and a 33 percent reduction in the need for intravenous anti-pseudomonal treatment per patient. 

Based on this demonstration of efficacy, said Stanley Fiel, MD, FCCP (MCP Hahnemann University Hospital), investigators became interested in the potential value of aerosolized tobramycin in other airway diseases characterized by P. aeruginosa colonization. In non-CF bronchiectasis, for example, there is no standardized treatment, and some drugs (e.g., dornase alfa) that are effective in bronchiectasis associated with CF have not shown promise in non-CF bronchiectasis where the patient population is older and more heterogeneous, and has more concomitant diseases. In a proof-of-concept trial, 74 patients with non-CF-related bronchiectasis with P. aeruginosa infection were randomized in equal numbers to placebo or aerosolized tobramycin 300 mg twice daily for 28 days and followed for 14 days (Barker AF et al. Am J Respir Crit Care Med. 2000;162(2Pt1):481). Patients in the tobramycin trial arm experienced a significant reduction in sputum colony-forming units per gram (CFU/g) of P. aeruginosa in 14 days compared with placebo. The improvement was sustained through day 28 (p=<0.001). Infection remained eradicated in 32 percent of patients 2 weeks after discontinuation of therapy. Almost two-thirds of patients in the treatment arm reported improvement in their condition, a fraction that jumped to 92 percent among patients whose infections had been eradicated or partly eradicated. However, treatment did not improve lung function, and patients treated with aerosolized tobramycin had a higher incidence of adverse effects such as dyspnea, non-cardiac chest pain, and wheezing than did patients given placebo. 

The outcome of this trial led to additional investigations of aerosolized tobramycin in non-CF bronchiectasis. For example, in an open-label trial that was just ending at the time of the ACCP conference, patients with severe bronchiectasis who had had a course of intravenous antibiotics or who had failed a course of oral antibiotics were treated with nebulized tobramycin 300 mg twice daily for three cycles of 2 weeks on and 2 weeks off treatment. After 2 weeks the mean sputum density was almost as low as it was after 4 weeks. Future studies that will evaluate the safety and efficacy of aerosolized tobramycin are being 
considered.  
 

Early Diagnosis and Management of Bronchiectasis: A European Perspective

As reported by Peter Cole, MD (Royal Brompton Hospital, London), the current trend in Europe is to consider patients who produce sputum daily as having chronic bronchial suppuration until they have had a high-resolution CT scan. The goal of this approach is to prevent the premature and inaccurate diagnosis of chronic bronchitis. Between 10 and 50 percent of patients who have CT-confirmed non-CF bronchiectasis will have P. aeruginosa infection, but so will some patients who do not have non-CF bronchiectasis on CT scan. Consequently, daily sputum production and sputum cultures positive for P. aeruginosa cannot be relied on for an accurate diagnosis of bronchiectasis. 

Early diagnosis of bronchiectasis is essential, because small airway obstruction resulting from bronchiolar damage is irreversible and may be fatal. The index of suspicion has lessened for bronchiectasis because misconceptions about its frequency since the introduction of vaccines and antibiotics, and because the gross suppurative type associated with finger clubbing has decreased. But there has been an increase in the diffuse, insidious cylindrical type of bronchiectasis that is often associated with sinusitis. Failure to recognize this leads to underdiagnosis. In a review of patients diagnosed as having either chronic obstructive pulmonary disease (COPD) or chronic bronchitis referred either by COPD clinics or primary-care physicians, there was a very high prevalence of bronchiectasis among patients previously diagnosed as having chronic bronchitis. Most of them had never smoked tobacco. 

Because of the frequency with which bronchiectasis is missed, European specialists have adopted a sequential strategy in which all patients producing daily purulent or mucopurulent sputum undergo high-resolution CT scans unless contraindicated. These include expiratory scans to detect the distribution of small airway obstruction. (Chest X-ray is notoriously insensitive for showing bronchiectasis.) Once a diagnosis of bronchiectasis is established, blood and sputum are taken and nasal nitric oxide and a sweat test are performed to find the cause. Then the patient is monitored for disease progress by respiratory function testing, particularly of the small airways since they most accurately indicate progression. C-reactive protein and 
other markers for inflammation are also followed as they are related to inflammatory disease progression. 

The preceding strategy revealed that of the 155 patients with non-CF bronchiectasis who were seen in 1999, 86 percent had disease that was widespread, and only 2 percent had localized bronchiectasis. There was a female preponderance, and although the age range was broad, the median age was 36 years. In the main, patients had never smoked. One-third of patients had associated purulent rhinosinusitis, and a very high proportion had associated nasal symptoms. 

Two studies in the UK have attempted to identify the causes of non-CF bronchiectasis. In one, a high proportion of cases was attributed to prior infection, but that may be an unwarranted assumption unless a good history of a damaging event is followed by infection. Bronchiectasis may be associated with immune deficiency, primary ciliary dyskinesia, ulcerative colitis, or gastroesophageal acid reflux. The majority of cases, however, have no identifiable cause, perhaps suggesting that some individuals may be genetically predisposed to this disease. Most patients have a few exacerbations per year with a winter preponderance. Fewer patients have less stable disease marked by more frequent and more severe exacerbations of longer duration that interfere significantly with the quality of life. Only 5 to 10 percent of patients have rapidly progressing bronchiectasis that fails to respond to therapy. 

The European non-CF bronchiectasis population differs from that of the United States. Based on the patient characteristics of the US aerosolized tobramycin study, the median age of American patients is approximately 65 years compared with 36 years in published series from Europe. A high percentage of American patients smoke or have smoked. In European patients, the FEV₁ is generally much better preserved. European patients are encouraged to practice chest physiotherapy, whereas in the United States few patients are taught it. This strongly suggests that patients were recruited from COPD clinics for this study, whereas in Europe they attend special bronchiectasis clinics.

The infrastructure of treatment for non-CF bronchiectasis in Europe consists of physiotherapy, immunization, treatment of the upper respiratory tract and of acid reflux, and consideration of surgical resection of any localized bronchiectasis. Patients are then given bronchodilators with or without corticosteroids by inhalation. In non-responders, the algorithm for antibiotic usage is a 2-week course of oral antibiotics to clear the patient’s airways of purulent sputum. Those who fail to clear are given intravenous antibiotics for 2 weeks. Most patients who respond to either oral or intravenous antibiotics remain stable until their next virus exacerbation. Patients who have unacceptably frequent and severe exacerbations may require rotating oral antibiotics or continuous nebulized antibiotics. Failure of these alternatives requires elective intravenous antibiotics at regular intervals to reduce the colonizing microbial load. 

 

The Role of Genetics in the Diagnosis of Bronchiectasis

Bronchiectasis is associated with a wide variety of diseases. Most prominent among them is CF, but others are alpha₁-antitrypsin deficiency, hypogammaglobulinemia, dysmotile cilia syndromes, allergic bronchopulmonary mycosis, several neutrophil and complement deficiencies, Marfan and Ehlers-Danlos syndromes, and yellow nail syndrome. Because of this heterogeneous spectrum, bronchiectasis should no longer be thought of as an autosomal recessive or codominant process as it has traditionally. Gwen Huitt, MD, MS (National Jewish Medical and Research Center), who conducts research on the possible genetic basis of sinopulmonary infections, used this observation as a platform for discussing the role of genetics in diagnosing bronchiectasis and for commenting on the wide variations to treatment observed in bronchiectasis patients. 

Dr. Huitt presented a case of a woman of Asian descent who had bronchiectasis, a cavitary lesion in her right upper lobe, and a rapidly growing mycobacterial infection. Genetic screening identified her as a heterozygote for alpha₁-antitryptin deficiency with an MS phenotype and a double heterozygote for CF. 

The correlation of her genetic profile to her clinical condition illustrates that bronchiectasis patients with underlying heterozygosity handle sinopulmonary infections poorly. They are more prone to infection than previously thought, and their treatment outcomes are generally poorer than those of other bronchiectasis patients. She noted, however, that although previous trials have shown no benefit from dornase or pulmozyme, heterozygous subsets of populations may benefit from a 3-day trial of pulmozyme along with appropriate antibiotics to help clear secretions. 

Dr. Huitt also presented a case involving an SZ phenotype diagnosed with CF in her late 60s, a non-smoker with two children, both Z heterozygotes with chronic bronchitis. Finally, she presented the case of a 55-year-old non-smoking male with chronic sinopulmonary infection who is a classic ZZ. Dr. Huitt concluded that in all suspected cases of alpha₁-antitrypsin deficiency, establishment of the patient’s phenotype is as important as establishing the antitrypsin level. 

Until genetic screening became available for diagnostic purposes, CF was known as a chromosome 7 abnormality and thought to be a classic autosomal recessive disorder. Now, however, at least 700 mutations have been identified, four of which are observed most frequently. Standard testing currently involves isolation of 86 mutations, but most laboratories test for only 13. As a result, 20 percent or more of mutations are not picked up during screening. Sweat chloride testing and nasal potential testing may also assist in diagnosing CF. However, with genetic screening available for patients who consent to it, sweat chloride testing in adults, once the diagnostic gold standard, should no longer be the primary initial testing procedure. Until there is a firm diagnosis of CF, Medicare and most private insurance carriers will not cover the cost of inhaled aminoglycosides. 

Alpha₁-antitrypsin deficiency is a chromosome 14 disease. Before it can be treated, one needs to know if the patient lacks sufficient enzyme, has dysfunctional enzyme, or both. Four types of testing are available for making this determination: immunoassay measures the serum concentration of alpha₁-antitrypsin (ATT); phenotyping identifies ATT isoforms; genotyping identifies DNA abnormalities by polymerase chain reaction (PCR); and the function quality of existing ATT is measured by inhibition of leukocyte elastase by the proteinase. Genotyping is very accurate and specific, but it is very expensive. As the technique becomes less expensive and generally available, it will evolve as the most important diagnostic test in this generation of technology. 
 

Challenges in Bronchiectasis Trial Design

FDA approval of aerosolized tobramycin with a single indication in CF with Pseudomonas infection led to interest in the potential application of aerosolized antibiotics in non-CF bronchiectasis. Investigators were faced with six critical questions. First, is bronchiectasis the adult equivalent of CF? Second, do CF study results with aerosolized antibiotics apply to bronchiectasis and to COPD with chronic infection? Third, if they do, are the same doses and regimens appropriate? Fourth, if they do not, why not? Fifth, what are the pharmacoeconomic implications of using aerosolized antibiotics in non-CF bronchiectasis? And sixth, what are the goals of bronchiectasis therapy as pertains to aerosolized antibiotics? Paul Scheinberg, MD of the Atlanta Pulmonary Group discussed these issues pertinent to trial design. 

The study by Barker et al (see Dr. Fiel’s summary and full citation above) used a regimen of aerosolized tobramycin similar to that used in the pivotal CF study. It demonstrated a significant reduction of bacterial load in 2 weeks that correlated with a significant improvement in general health status even though lung function was not improved. There was sustained eradication of organisms up to 2 weeks following discontinuation of therapy. However, there was a higher incidence of adverse effects in treated patients than in those patients taking placebo. 

The 2-week suppression of bacterial infection following discontinuation of treatment led to the next study. It was designed to determine if patients with severe bronchiectasis would benefit from extended treatment with aerosolized tobramycin given in a regimen of 2 weeks on and 2 weeks off for three cycles totaling 12 weeks. Although the data are still being tabulated, anecdotal evidence from patients suggests that the results will be positive. 

The next steps are to determine if aerosolized antibiotic therapy is more efficacious as a primary intervention or as an adjunctive measure and if it is efficacious in preventing infection in patients with bronchiectasis. Also of interest is whether or not inhalation antibiotics are effective against respiratory pathogens other than P. aeruginosa — including Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Staphylococcus aureus, Streptococcus pneumoniae, nontuberculous Mycobacteria of the M. avium complex, and Acinetobacter species. 

The design of the next study entails several challenges. Because it is intended to be a trans-Atlantic study, it must take into account the differences in the bronchiectasis populations in the United Kingdom and the United States. There is also no established standard for diagnosing this disease, as it is not known for certain if CT confirmation is required. There is no diagnostic standard as to what constitutes an exacerbation, yet studying the effect of drugs on the frequency, severity, and duration of exacerbations is of major importance. 

Currently it appears that the trans-Atlantic trial will involve patients with acute infection because it is likely to recruit more subjects than a study of chronic disease and because it will be easier to define useful endpoints such as microbiologic tests of cure. The trial will be a double-blind and randomized multicenter study to evaluate the safety and efficacy of aerosolized tobramycin in the treatment of acute exacerbations. Because there are no separate criteria for safety and efficacy studies in bronchiectasis, the trial will follow the general FDA guidelines for acute bacterial exacerbations of chronic bronchitis. The probable endpoints will be the safety and tolerance of aerosolized tobramycin, the resolution of symptoms, the microbiologic outcome of treatment, treatment-related quality of life changes, pharmacoeconomic implications. 

Another study is currently in progress. It is a retrospective outcomes review of patients receiving aerosolized tobramycin off-label for bronchiectasis. The objectives of this study are to extract variables for further study, to guide development of subsequent trial design, and to gain insight into the clinical efficacy of this agent.

Although early studies in bronchiectasis suggest a role for aerosolized aminoglycosides, particularly tobramycin, in bronchiectasis, larger randomized trials are required to define its role conclusively. 

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