Immunology and Host Response

When a Nontuberculous Mycobacterial Infection Reveals

an Error of Immunity
A Single Center’s Experience
Alessia Morreale, MD,* Laura Dotta, MD,† Donatella Vairo, PhD,‡ Tullia Bazzana, MD,§
Vassilios Lougaris, MD,¶ Annarosa Soresina, MD,‖ Alessandro Plebani, MD, PhD,¶ Silvia Clara Giliani, PhD,**
Fulvio Porta, MD,†† Alberto Matteelli, MD,‡‡ Luca Oscar Redaelli De Zinis, MD,§§
and Raffaele Badolato, MD, PhD¶

Abstract: We present an algorithm that may be applied in case of a diag- and the Mendelian Susceptibility to Mycobacterial Diseases
nosis of pediatric nontuberculous mycobacterial disease to identify the (MSMD-IEI), a group of continuously emerging and allelic heter-
patients who may require an immunologic assessment to discover a possi- ogenous genetic defects that impair interferon (IFN)-γ immunity.4–12
ble underlying immune system defect predisposing to their nontuberculous However, pediatric physicians may frequently observe NTM
mycobacterial infections. infections in otherwise healthy children. An important question is
if it should be suitable to test every child who experiences a NTM
Key Words: mycobacteria, nontuberculous mycobacterial infection, immu-
infection for a primary immunodeficiency.
nodeficiency, inborn errors of immunity
This study of a cohort of patients with NTM infections led
(Pediatr Infect Dis J 2022;41:427–429) us to elaborate an algorithm that can be applied in case of diagnosis
of NTM disease in the pediatric population to define the patients for
whom an immunologic assessment should be conducted.

T he nontuberculous mycobacterial (NTM) infection is a rare

condition caused by more than 160 ubiquitous, environmental
bacteria, with the species belonging to the Mycobacterium avium
METHODS
We retrospectively collected data of 46 patients under 18 years
complex—particularly M. avium and M. intracellulare—as the most old who were admitted to our tertiary care Children’s Hospital from
frequently reported in humans. The diagnosis of the early-stage January 2004 to December 2018 with a diagnosis of NTM infection.
infection and its treatment may represent a challenge for clinicians.1–3 Our study population includes all patients that had been hospitalized
Notably, inherited immunodeficiencies predisposing to NTM or had been evaluated in the outpatient clinics of the general pediatrics,
infection may include inborn errors of immunity (IEI), that is, severe pediatric oncohematology and pediatric otolaryngology departments.
combined immunodeficiencies, combined immunodeficiencies, The patients were included who had a discharge-diagnosis code of (1)
hyper-IgE syndromes, chronic granulomatous disease, nuclear fac- mycobacteriosis, (2) mycobacterial infection, (3) lymphadenopathy,
tor-kappa B essential modulator deficiency, hyper-IgM syndromes (4) lymphadenomegaly. The study was approved by the Ethical Com-
mittee of the Spedali Civili of Brescia. We excluded children with a
previous confirmed diagnosis of IEI, or with a condition of immuno-
Accepted for publication December 19, 2021 deficiency secondary to immunosuppressive medications, or Human
From the *Department of Pediatrics, ASST Spedali Civili of Brescia, University
of Brescia, †Department of Pediatrics, Institute for Molecular Medicine A. Immunodeficiency Virus infection, or children with cystic fibrosis.
Nocivelli, ASST Spedali Civili of Brescia, ‡Department of Molecular and Statistical analyses were performed using GraphPad Prism
Translational Medicine, Institute for Molecular Medicine A. Nocivelli, Uni- Version 8.0 (GraphPad Software, San Diego, CA), with the Mann-
versity of Brescia, §Department of Pediatric Otorhinolaryngology, ASST Whitney U and Fisher exact tests (P < 0.05 was considered statisti-
Spedali Civili of Brescia, ¶Department of Pediatrics, Institute for Molecular
Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, cally significant).
University of Brescia and ASST Spedali Civili of Brescia, ‖Department of
Pediatrics, ASST Spedali Civili of Brescia, **Institute for Molecular Medi-
cine A. Nocivelli, Department of Pathology, Laboratory of Genetic Disorders RESULTS
of Childhood, Department of Molecular and Translational Medicine, Univer- In the study cohort, 5 patients were revealed to suffer from an
sity of Brescia, ASST Spedali Civili of Brescia, ††Department of Pediatric
Onco-Hematology and BMT, ASST Spedali Civili of Brescia, ‡‡Department
IEI. Specifically, 1 patient received a final diagnosis of F-BAR domain
of Infectious and Tropical Diseases, WHO Collaborating Centre for TB/ only proteins 1 (FCHO1) deficiency (a novel form of combined immu-
human immunodeficiency virus and TB Elimination, University of Bres- nodeficiency with impaired T-cell proliferation, increased activation-
cia and ASST Spedali Civili of Brescia, and §§Department of Medical and induced T-cell death and defective clathrin-mediated endocytosis).8
Surgical Specialties, Radiological Sciences and Public Health, Section of
Head and Neck Surgery, University of Brescia, Pediatric Otorhinolaryngol-
One patient received a diagnosis of myelodysplastic syn-
ogy Head Neck Surgery Division, Children Hospital, ASST Spedali Civili of drome and acute myeloid leukemia in monocytopenia and myco-
Brescia, Brescia, Italy. bacterial infection syndrome and the other 3 patients received a
The authors have no funding or conflicts of interest to disclose. definitive diagnosis of MSMD, that is, signal transducer and activa-
Address for correspondence: Alessia Morreale, MD, Department of Pediatrics,
ASST Spedali Civili of Brescia, Piazzale Spedali Civili 1, 25123 Brescia,
tor of transcription 1 (STAT1) deficiency (an autosomal recessive
Italy. E-mail: [email protected]. partial form of STAT1 deficiency that presented with severe but
Supplemental digital content is available for this article. Direct URL citations curable intracellular bacterial and viral diseases, reduced but not
appear in the printed text and are provided in the HTML and PDF versions of abolished responses to both IFN-γ and IFN-α and weaker STAT1
this article on the journal’s website (www.pidj.com).
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
DNA-binding activity), IFN-γR2 deficiency and IFN-γR1 defi-
ISSN: 0891-3668/22/4105-0427 ciency (both defects resulting in impaired IFN-γ -mediated immu-
DOI: 10.1097/INF.0000000000003461 nity due to a defect of the response to IFN-γ).9,10

The Pediatric Infectious Disease Journal • Volume 41, Number 5, May 2022 www.pidj.com | 427

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Morreale et al The Pediatric Infectious Disease Journal • Volume 41, Number 5, May 2022

Consequently, we divided the patients into 2 groups: idi-

opathic (IDPTH) and immunodeficient (ID) patients; the second
group was furtherly divided into 2 subgroups: patients with IEI and
patients with MSMD-IEI. We therefore analyzed and compared the
characteristics of NTM infections (see Table, Supplemental Digital
Content 1, http://links.lww.com/INF/E655).
Our results showed that ID patients were more likely to
present consanguinity and/or infant deaths in their familiar clini-
cal history (P < 0.01) and a past medical history characterized by
severe and/or systemic/opportunistic infections (particularly, we
observed lower respiratory tract infections, sepsis, persistent oral
and diaper candidiasis, aspergillosis infection) (P < 0.05).
Systemic symptoms at the onset of the disease were charac-
teristic of ID patients (P < 0.01), with fever being more frequent in
MSMD-IEI patients compared with idiopathic patients (P < 0.05).
ID forms presented with the NTM infection in sites other than
head and neck such as abdomen or lungs (P < 0.01). M. avium was
more frequently isolated in idiopathic patients than in IEI patients
(P < 0.05). In MSMD-IEI patients, the same M. avium was the
more frequently isolated mycobacterium. We also analyzed blood
tests and found that IEI patients presented with abnormal lympho-
cytes subpopulation (P < 0.01). P42 with mutation of FCHO1 gene
had severe CD3 T lymphopenia (<10 cells/mmc) and hypogam-
maglobulinemia. P43 presented severe defect of CD14+CD16—
monocytes, of dendritic cells and of recent bone marrow emigrants
lymphocytes B associated to mild defect of natural killer cells.
In patients with clinical suspicion of MSMD, the functional
tests using cytofluorometry (ie, analysis of STAT1 phosphorylation
in response to IFN-γ on monocytes/macrophages) could support
the genetic diagnosis (P < 0.01).
Finally, we observed that 38 patients (37 IDPTH + 1 IEI)
underwent surgery. All patients with ID and 1 patient with IDPTH
(with lungs and mediastinal involvement) were treated with anti-
mycobacterial drugs. All patients with IEI and 2 patients with
MSMD-IEI underwent stem cell transplantation.
Using our results, we have elaborated an algorithm that
should be applied in case of diagnosis of NTM disease in children
to allow the identification of an underlying condition (Fig. 1).

FIGURE 1. Nontuberculous mycobacterial disease—algorithm.

DISCUSSION CGD, chronic granulomatous disease; IFNg indicates interferon
Pediatric patients presenting with a NTM infection should gamma; IL-12, interleukin-12; NEMO, nuclear factor-kappa
be carefully evaluated to identify the features that may be sugges- B essential modulator; RTEs, recent thymic emigrants; STAT1,
tive for an underlying immunodeficiency, in particular MSMD. Our signal transducer and activator of transcription 1.
study was limited by a small sample size due to the rarity of the
condition. However, our Hospital is an Italian Center of reference ACKNOWLEDGMENTS
for pediatric immunology, and this may affect the epidemiologic The Italian Society of Pediatrics rewarded this project with a
distribution of the NTM infection. scholarship to Alessia Morreale in memory of Professor Luigi Maiuri.
Many defects of the innate immune system, particularly
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