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Concise Reviews of Pediatric Infectious Diseases®

Nontuberculous Mycobacteria in Cystic Fibrosis

Razvi, Samiya MD; Saiman, Lisa MD, MPH

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The Pediatric Infectious Disease Journal: March 2007 - Volume 26 - Issue 3 - p 263-264
doi: 10.1097/01.inf.0000256964.30181.df
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Nontuberculous mycobacteria (NTM) are increasingly isolated from patients with cystic fibrosis (CF), although the clinical significance of NTM in this population is not yet entirely understood.1 The incidence of NTM appears to be increasing in all populations potentially due to changes in host susceptibility to NTM, increased NTM virulence, and/ or increased exposure to NTM (eg, showering rather than bathing which increases respiratory exposure to water contaminated by NTM). Thus, CF patients, due to their underlying lung disease, may represent a sentinel population for NTM.

EPIDEMIOLOGY

Isolation of NTM species from CF patients was reported as early as the 1970s.2 The prevalence and predominant species vary by study population. Esther et al found the prevalence to be 6% in children <12 years of age.3 The most common species were Mycobacterium avium complex (MAC) and the rapid grower, M. abscessus. Olivier et al prospectively studied 986 CF patients 10–51 years of age and found the prevalence to be 13%.4 Most isolates were MAC (72%) or M. abscessus (16%). When compared with culture-negative subjects, NTM culture-positive subjects were older, had better lung function, more coinfection with Staphylococcus aureus and less coinfection with Pseudomonas aeruginosa. These data suggested a healthy survivor effect in culture-positive subjects. Pierre-Audigier et al reported a prevalence of 8% with M. abscessus being most common (39%) among 385 CF subjects ≤24 years of age.5 Potential risk factors for NTM in CF include steroid treatment of allergic broncho-pulmonary aspergillosis and use of bronchoscopes or aerosolized medications contaminated with NTM.6,7 Thus far, there is no evidence for patient-to-patient transmission of NTM species in CF.8

INDICATIONS FOR SCREENING FOR NTM

CF patients with increased clinical symptoms (eg, fever, weight loss), worsening lung function, and progressive radiographic findings despite treatment of common CF pathogens (eg, P. aeruginosa), should be evaluated for NTM infection. Long-term azithromycin is increasingly used in CF as it has been shown to improve lung function, reduce pulmonary exacerbations, and reduce antibiotic use.9 Due to concerns about the emergence of azithromycin resistance, patients should have respiratory tract cultures sent for NTM prior to initiating azithromycin and yearly thereafter. While NTM infection is not a contraindication for lung transplantation in CF, disseminated disease can develop following transplantation.10 Thus, transplant candidates should also be routinely screened for NTM prior to transplant. Some clinicians screen patients with CF annually, particularly those with extensive bronchiectasis.

DIAGNOSIS

Bronchiectasis, with demonstrable abnormalities on chest x-rays and high resolution CT scans (HRCT), is the result of the vicious cycle of inflammation and infection that is the hallmark of CF lung disease. As a result, clinical and radiographic diagnostic criteria for NTM pulmonary infection overlap with signs and symptoms of CF. CF clinicians generally rely on the American Thoracic Society (ATS) criteria for NTM disease in HIV-negative patients. However, these criteria which use mycobacteriologic, clinical, and radiographic criteria following exclusion of other diseases,11 may not be entirely applicable to CF.

Mycobacteriology

To appropriately diagnose and treat NTM, it is critical to obtain adequate respiratory tract specimens to improve the sensitivity and specificity of culture results. Supervised collection of spontaneously expectorated sputum is ideal, but saline induction of sputum can be performed. Three sputum specimens (5 mL each) are recommended to avoid false negative results. Specimens should be collected in a double sputum container to reduce contamination and false positive results. Bronchoalveolar lavage sampling may be performed in younger children who do not expectorate sputum, patients presenting as a diagnostic dilemma, or those with localized disease. Laboratory processing for NTM from CF specimens requires an additional decontamination step using N-acetyl cysteine, sodium hydroxide (NALC-NaOH) and 5% oxalic acid to prevent overgrowth with Pseudomonas.12 Some species, eg, M. abscessus when present in low concentration, may be killed by this decontamination step. As in other patient populations, acid-fast bacilli (AFB) smears and cultures remain the gold standard for diagnosis.

Susceptibility testing is recommended for NTM isolates from CF patients because of concerns about increased resistance due to chronic antimicrobial treatment of common CF pathogens.13 For example, CF patients infected with P. aeruginosa can receive long-term azithromycin and aerosolized tobramycin. These therapies may lead to increased resistance in coinfecting NTM and thus, complicate treatment.

Clinical features

Clinical features of NTM in CF patients vary widely; patients may be asymptomatic, have deterioration in pulmonary function, or experience rapid clinical deterioration and death. Olivier et al found that new incident cases of NTM disease, as defined by ATS criteria, had the same rate of mean annual decline in FEV1 % predicted compared with NTM-positive patients who did not met ATS criteria, and NTM-negative patients.14

Radiographic findings

Due to pre-existing lung disease in CF patients, it can be very challenging to evaluate radiographic changes for NTM infection. Esther et al scored HRCT scans from CF children <12 years of age using 4 features: cystic cavitary lesions, parenchymal consolidation, pulmonary nodules, and tree-in-bud opacities.3 Subjects with these radiographic findings were more likely to fulfill ATS criteria. Similar HRCT findings were reported by Olivier et al.14

TREATMENT

Treatment is favored for CF patients with clinical symptoms (eg, fever, weight loss), worsening in lung function, radiographic progression despite treatment of more classic CF pathogens, and >1 positive NTM culture, particularly with pathogenic NTM species such as M. abscessus or MAC. Olivier et al reported that most of the 128 subjects with positive screening cultures had only 1 of 3 positive cultures for NTM; 90 (70%), 21 (16%) and 17 (14%) subjects had 1, 2, or 3 positive cultures.4 These observations suggest that contamination or colonization with NTM is relatively common in CF.

Antimicrobial treatment

Starting antimycobacterial therapy is a commitment to complex and prolonged treatment regimens. As treatment is guided by the NTM species, effective therapy may be delayed until species identification. Depending upon the NTM species and severity of illness, initial parenteral therapy may be indicated for several weeks, followed by prolonged oral regimens as symptoms and AFB smears improve.

Depending on the species, NTM are generally susceptible to aminoglycosides (amikacin, streptomycin), cephalosporins (cefoxitin), macrolides (clarithromycin, azithromycin), rifamycins (rifampin, rifabutin) and imipenem. Newer drugs such as linezolid, tigecycline and γ- interferon are promising agents for NTM treatment. The ATS recommends daily oral treatment of MAC with 3 to 4 drugs including clarithromycin, rifabutin and ethambutol with the addition of parenteral streptomycin for severe disease. M. abscessus is notoriously difficult to treat and parenteral therapy with cefoxitin and amikacin plus an oral macrolide is initiated for several weeks until a clinical response is seen. Macrolide therapy is then continued as therapeutic or suppressive therapy for several months.

Monitoring clinical response to therapy

Monthly follow-up is recommended. Monitoring serum drug levels is useful to ensure therapeutic dosages and limit adverse reactions, particularly as pharmacokinetics are altered in CF patients. Clinical response to treatment is indicated by decreased cough, sputum production, and fever and improved pulmonary function. Monthly AFB smears and cultures can monitor a reduction in organism burden. Stabilization or resolution of radiographic findings may be seen on HRCT performed at 3–6 months intervals or as dictated by the clinical course. The appropriate duration of therapy is unknown. ATS guidelines recommend that treatment be continued until sputum cultures are consecutively negative ≥1 year. However, eradication of NTM, particularly M. abscessus, may be difficult to achieve and thus, intermittent, suppressive therapy guided by the patient’s clinical and mycobacteriologic status is recommended by some. There is very limited experience with serologic markers; among 186 CF patients, anti-A60 IgG was 80–87% sensitive and 91–95% specific compared with culture.15

CONCLUSION

NTM are recognized as emerging pathogens in CF. Increased clinician awareness of NTM and improved laboratory techniques for CF respiratory specimens have contributed to the increased prevalence of NTM in CF. The clinical significance of NTM in CF needs further study as do the long-term benefits of treatment.

REFERENCES

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Keywords:

nontuberculous mycobacteria; cystic fibrosis

© 2007 Lippincott Williams & Wilkins, Inc.