Pulmonary Nontuberculous Mycobacterial Infections in Hyper-IgESyndrome
Elizabeth Melia, B.A.
a,
Alexandra F. Freeman, M.D.
a,
Yvonne R. Shea, M.S.
b,
Amy P. Hsu,B.A.
a,
Steven M. Holland, M.D.
a, and
Kenneth N. Olivier, M.D., M.P.H.
a
a
Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute ofAllergy and Infectious Diseases, National Institutes of Health, US Department of Health and HumanServices, Bethesda, MD 20892, USA
b
Microbiology Service, Department of Laboratory Medicine, Warren Grant Magnuson ClinicalCenter, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD20892, USA
Summary
Patients with Hyper Immunoglobulin E Syndrome are predisposed to infections with nontuberculousmycobacteria (NTM) as bronchiectasis develops. Pulmonary NTM infection should be aggressivelylooked for and treated in these patients.
Keywords
Nontuberculous mycobacteria; Hyper-Immunoglobulin E Syndrome; Job’s Syndrome;
STAT3
Nontuberculous mycobacteria (NTM) are commonly isolated from patients with airwayclearance defects such as cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) and fromasthenic postmenopausal women with scoliosis, pectus abnormalities, and mitral valveprolapse
1
3
. Autosomal dominant signal transducer and activator of transcription 3 (
STAT3
)deficiency (hyper immunoglobulin E, HIES or Job’s) patients develop recurrent pyogenicrespiratory infections, frequently with pneumatoceles and bronchiectasis. Once pneumatocelesand/or bronchiectasis are present, the predominant infections change from
Streptococcus pneumoniae, Staphylococcus aureus
, and
 Haemophilus influenzae
 to
Pseudomonasaeruginosa
 and
 Aspergillus fumigatus
4
,
5
. NTM have not been considered typical pathogensin HIES. We reviewed NTM infections in a large cohort of HIES patients.
Methods
Patients diagnosed with HIES based on clinical scores and expert opinion of the investigatorsand confirmed by
STAT3
 sequencing were followed in an IRB approved study
6
.
© 2009 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.Correspondence to: Kenneth N Olivier, MD, MPH, 10 Center Drive, Room 11N234, Bethesda, MD 20892-1888, 301-496-5673 v,301-496-0773 f, olivierk@niaid.nih.gov.
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Author Manuscript
 J Allergy Clin Immunol
. Author manuscript; available in PMC 2010 September 1.
Published in final edited form as:
 J Allergy Clin Immunol
. 2009 September ; 124(3): 617618. doi:10.1016/j.jaci.2009.07.007.
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Microbiology records from April 1977 to November 2007 were queried for lower respiratorytract specimen mycobacterial smear and culture results. Mycobacteriology was recorded withother respiratory organisms and specimen source. We identified three groups: NTM culturepositive 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 (ator 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 sodiumhydroxide, concentrated by centrifugation for smear staining with Auramine-Rhodamine, andcultured on solid and liquid media. Accuprobe (GenProbe, San Diego, CA), molecular analysis(16S, hsp65, secA sequencing), or (prior to 2005) HPLC and biochemical testing identifiedorganisms
3
.
Summary statistics are presented as mean ± standard deviation. Continuous variables werecompared using one-way ANOVA and frequencies of categorical variables with the Chi Squaretest.
Results
Of the 62 HIES patients followed, 32 (51%) had at least one specimen submitted for AFBtesting [17 females, 15 males, ages 2 – 56 (31±14 years) at the time of culture with an HIESclinical score of 52 to 100 (79±12)].
STAT3
 mutation was found in 30 of 32 patients with AFBtesting; DNA was unavailable on two deceased patients. Nine of 32 patients (28%) grew NTMon at least one occasion (Table 1). Five NTM positive patients (16%) met ATS criteria forpulmonary 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 grewfrom three patients. NTM+/ATS(+) patients had 16±9.5 specimens submitted formycobacteriology, with 2 to 11 positive cultures (5.6±4.5) each. They grew up to 10 otherpotential 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 A
spergillus 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 otherorganisms grew, with
 Haemophilus influenzae
 most frequent (43%). There wereproportionately 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 least10° of scoliosis as did 3/4 NTM+/ATS(
) patients; 63% of NTM-/ATS(
) patients hadscoliosis (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 inevery 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%) hadnormal lungs on CT scan; bronchiectasis was found in 10 (43%); cysts and nodules each ineight 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. Patient1 successfully cleared MAC and continues on treatment for
 M. abscessus
.
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Discussion
NTM pulmonary infections are common in CF (13%) and PCD (10%), presumably becauseof impaired mucociliary transport
1
,
2
. Like CF and PCD, HIES is characterized bybronchiectasis, nodules, and cavities
5
. Once structural damage occurs in HIES,
 Aspergillus
and
Pseudomonas
 become common as they are with other etiologies of bronchiectasis
8
.Therefore, it is not surprising that NTM infection in HIES occurs in the setting of bronchiectasisand cavities at a similar frequency to that in CF and PCD and is associated with increasedradiographic severity of lung disease. While no specific airway clearance defect has beenidentified in HIES, it is clear that HIES patients have some abnormality making themsusceptible to recurrent lung infections in general as well as NTM infection and subsequentdisease. NTM+/ATS(+) patients were disproportionately female and had significant scoliosis.While common in Job’s syndrome (63%), this high frequency of scoliosis and the femalepredominance has been associated with other pulmonary NTM syndromes
3
,
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 airwaydisease. In the absence of predisposing airway changes, NTM infections were not found inHIES patients suggesting that susceptibility to pulmonary NTM in HIES may be more relatedto airway than immune dysfunction. An alternate explanation is the severity of immunedysfunction, through recurring infections, predisposes both to the severity of the structural lungdisease and NTM disease. Since the causes of death in HIES are mostly related to airwayinfections, NTM infections should be searched for in HIES
5
. In addition, as the NTM infectionssuggest that HIES may be associated with abnormal mucociliary clearance, mechanical airwayclearance measures should be considered in HIES patients with structural lung disease.
Acknowledgments
This research was supported by the Division of Intramural Research of the National Institute of Allergy and InfectiousDiseases, NIH, Bethesda, MD
Abbreviations
NTM, nontuberculous mycobacteria; CF, cystic fibrosis; PCD, primary ciliary dyskinesia;
STAT3
, signal transducer and activator of transcription 3; HIES, hyper-immunoglobulin Esyndrome;
 M 
, mycobacterium; NIH, National Institutes of Health; NIAID, National Instituteof Allergy and Infectious Diseases; ATS, American Thoracic Society; CT, computedtomography.
References
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6. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in thehyper-IgE syndrome. N Engl J Med 2007;357:1608–1619. [PubMed: 17881745]7. Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, et al. An official ATS/ IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. AmJ Respir Crit Care Med 2007;175:367–416. [PubMed: 17277290]8. Kunst H, Wickremasinghe M, Wells A, Wilson R. Nontuberculous mycobacterial disease andAspergillus-related lung disease in bronchiectasis. Eur Respir J 2006;28:352–357. [PubMed:16611651]9. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et al. Hyper-IgE syndromewith recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med 1999;340:692–702. [PubMed: 10053178]
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Figure 1.
Radiographic manifestations of NTM in HIES. a) CT image Patient #1 at time of NTMdiagnosis. Arrow notes peripheral nodules. b) CT image after NTM treatment initiated. Arrownotes cyst formation.
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