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Patients with Hyper Immunoglobulin E Syndrome are predisposed to infections with nontuberculous mycobacteria (NTM) as bronchiectasis develops. Pulmonary NTM infection should be aggressively looked for and treated in these patients.
Nontuberculous mycobacteria (NTM) are commonly isolated from patients with airway clearance defects such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) and from asthenic postmenopausal women with scoliosis, pectus abnormalities, and mitral valve prolapse1–3. Autosomal dominant signal transducer and activator of transcription 3 (STAT3) deficiency (hyper immunoglobulin E, HIES or Job’s) patients develop recurrent pyogenic respiratory infections, frequently with pneumatoceles and bronchiectasis. Once pneumatoceles and/or bronchiectasis are present, the predominant infections change from Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae to Pseudomonas aeruginosa and Aspergillus fumigatus4, 5. NTM have not been considered typical pathogens in HIES. We reviewed NTM infections in a large cohort of HIES patients.
Patients diagnosed with HIES based on clinical scores and expert opinion of the investigators and confirmed by STAT3 sequencing were followed in an IRB approved study 6.
Microbiology records from April 1977 to November 2007 were queried for lower respiratory tract specimen mycobacterial smear and culture results. Mycobacteriology was recorded with other respiratory organisms and specimen source. We identified three groups: NTM culture positive and met the American Thoracic Society (ATS) disease criteria [NTM+/ATS (+)], NTM culture positive but did not meet the ATS criteria [NTM+/ATS (−)] and culture negative [NTM-/ATS (−)] 7. We reviewed age, pulmonary function tests (PFT) and chest CT scans (at or nearest to time of first positive culture for NTM positive; last available for NTM negative) for each patient. Thoraco-lumbar X-rays (not available for one) determined the degree of scoliosis. Each CT scan was scored for bronchiectasis, pneumatoceles or cysts (combined), nodules, and alveolar infiltrates. Sputum was processed with N-acetyl-L-cysteine sodium hydroxide, concentrated by centrifugation for smear staining with Auramine-Rhodamine, and cultured on solid and liquid media. Accuprobe (GenProbe, San Diego, CA), molecular analysis (16S, hsp65, secA sequencing), or (prior to 2005) HPLC and biochemical testing identified organisms3.
Summary statistics are presented as mean ± standard deviation. Continuous variables were compared using one-way ANOVA and frequencies of categorical variables with the Chi Square test.
Of the 62 HIES patients followed, 32 (51%) had at least one specimen submitted for AFB testing [17 females, 15 males, ages 2 – 56 (31±14 years) at the time of culture with an HIES clinical score of 52 to 100 (79±12)]. STAT3 mutation was found in 30 of 32 patients with AFB testing; DNA was unavailable on two deceased patients. Nine of 32 patients (28%) grew NTM on at least one occasion (Table 1). Five NTM positive patients (16%) met ATS criteria for pulmonary disease [NTM+/ATS(+)]: M. avium grew in three, M. kansasii in two, and M. massiliense, M. mucogenicum, and M. intracellulare in one each. More than one species grew from three patients. NTM+/ATS(+) patients had 16±9.5 specimens submitted for mycobacteriology, with 2 to 11 positive cultures (5.6±4.5) each. They grew up to 10 other potential pathogens; Aspergillus fumigatus and Pseudomonas aeruginosa were most common. Four patients did not meet ATS criteria [NTM+/ATS(−)]: two grew M. avium, one M. chelonae, and one M. abscessus. Cultures from NTM+/ATS(−) patients grew Aspergillus fumigatus, Staphylococcus aureus and Haemophilus influenzae in 2 patients each. NTM-/ATS(−) patients had 1 to 46 specimens (7.5±11.8) submitted for mycobacteriology. Up to 17 other organisms grew, with Haemophilus influenzae most frequent (43%). There were proportionately more females in the NTM+/ATS(+) group (80%, p<0.05) than in the NTM+/ATS(−) (none) or the NTM-/ATS(−) groups (57%). All NTM+/ATS(+) patients had at least 10° of scoliosis as did 3/4 NTM+/ATS(−) patients; 63% of NTM-/ATS(−) patients had scoliosis (Table1). Percent predicted FEV1 was the same [NTM+/ATS(+): 54±22; NTM+/ATS(−): 46±25; NTM-/ATS(−): 67±21; p=0.15]. Bronchiectasis and cysts were identified in every patient who grew NTM (Figure 1). Nodules were seen in 4 of 5 NTM+/ATS(+) patients, but only 1 of the 4 NTM+/ATS(−) patients. In NTM negative patients: 4 of 23 (17%) had normal lungs on CT scan; bronchiectasis was found in 10 (43%); cysts and nodules each in eight patients (35%); and alveolar infiltrates in 7 patients (30%). The prevalence of bronchiectasis and cysts was significantly different among the three groups (p<0.05).
Treatment for NTM was initiated in all 5 NTM+/ATS(+) and none of the NTM+/ATS(−) patients. All who were treated showed microbiologic and/or radiologic improvement. Patient 1 successfully cleared MAC and continues on treatment for M. abscessus.
NTM pulmonary infections are common in CF (13%) and PCD (10%), presumably because of impaired mucociliary transport1, 2. Like CF and PCD, HIES is characterized by bronchiectasis, nodules, and cavities5. Once structural damage occurs in HIES, Aspergillus and Pseudomonas become common as they are with other etiologies of bronchiectasis8. Therefore, it is not surprising that NTM infection in HIES occurs in the setting of bronchiectasis and cavities at a similar frequency to that in CF and PCD and is associated with increased radiographic severity of lung disease. While no specific airway clearance defect has been identified in HIES, it is clear that HIES patients have some abnormality making them susceptible to recurrent lung infections in general as well as NTM infection and subsequent disease. NTM+/ATS(+) patients were disproportionately female and had significant scoliosis. While common in Job’s syndrome (63%), this high frequency of scoliosis and the female predominance has been associated with other pulmonary NTM syndromes3, 9.
Although this is a retrospective study without systematic evaluation of the entire cohort of Job’s syndrome, it does suggest NTM are common in HIES patients with structural airway disease. In the absence of predisposing airway changes, NTM infections were not found in HIES patients suggesting that susceptibility to pulmonary NTM in HIES may be more related to airway than immune dysfunction. An alternate explanation is the severity of immune dysfunction, through recurring infections, predisposes both to the severity of the structural lung disease and NTM disease. Since the causes of death in HIES are mostly related to airway infections, NTM infections should be searched for in HIES5. In addition, as the NTM infections suggest that HIES may be associated with abnormal mucociliary clearance, mechanical airway clearance measures should be considered in HIES patients with structural lung disease.
This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD
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