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. 2022 Sep 12;32(4):495–504. doi: 10.1684/ejd.2022.4281

Manifestations of cutaneous mycobacterial infections in patients with inborn errors of IL-12/IL-23-IFNγ immunity

Karolina Dolezalova 1, Tomas Strachan 2, Radoslav Matej 3, Dita Ricna 4, Marketa Bloomfield 5,✉
PMCID: PMC9465665  PMID: 36069176

Abstract

Background

Inborn errors of IL-12/IL-23-IFNγ immunity underlie Mendelian susceptibility to mycobacterial diseases (MSMD), a group of immunodeficiencies characterized by a highly selective susceptibility to weakly virulent strains of mycobacteria, such as non-tuberculous mycobacteria (NTM) and bacillus Calmette-Guérin (BCG). Cutaneous mycobacterial infections are common in MSMD and may represent a red flag for this immunodeficiency.

Objectives

We present a case series of four paediatric patients with MSMD, specifically with IFNγR1 and STAT1 deficiencies, and cutaneous NtM/BCG infections to increase awareness of this immunodeficiency, which may, in some cases, be intercepted by the dermatologist and thus timely referred to the immunologist.

Materials & Methods

Clinical, laboratory and genetic investigations of the four paediatric patients with MSMD are presented.

Results

All four presented patients experienced early complications after BCG vaccination. Two patients suffered recurrent mycobacteriosis, one patient experienced delayed BCG reactivation, and one patient died of disseminated avian mycobacteriosis. The dermatological manifestation in these patients included destructive nasal ulcerations, scrofuloderma of various sites and lupus vulgaris. All patients had a normal basic immune phenotype.

Conclusion

The presented cases demonstrate that NTM/BCG infections in otherwise seemingly immunocompetent patients should raise suspicion of MSMD. This is of utmost importance as specific therapeutic approaches, such as IFNγ treatment or haematopoietic stem cell transplantation, may be employed to improve the disease outcome.

Key words: MSMD, mendelian susceptibility to mycobacterial diseases, IFNγR1, STAT1, inborn error of immunity, non-tuberculous mycobacteria, BCG, necrotizing granulomas, antituberculotics

Acknowledgements

We gratefully thank our patients and their families for placing their trust in us and giving their consent to publish. We thank Irena Hejcmannova MD (Dermatology, Derma Plus, Tábor, Czech Republic) for clinical expertise and collaboration, Nada Mallatova MD and Marie Mikulasova MD (both from Laboratory for Clinical Microbiology and Parasitology, Hospital Ceske Budejovice, Czech Republic) for valuable microbiology consultations and for figures of mycobacterial cultures, Marek Grega MD (Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic) for P1 histopathology images, Blanka Rosova MD (Department of Pathology and Molecular Medicine Characteristics, 3rd Faculty of Medicine, Thomayer University Hospital, Prague, Czech Republic) for P2 histopathology images, Dr. Zuzana Parackova (Department of Immunology, 2nd Faculty of Medicine, University Hospital Motol, Prague, Czech Republic) for performing functional assays to evaluate aspects of IL-12/IL-23-IFNγ immunity, prof. Tomas Freiberger MD, Hana Grombirikova MSc, (Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic) and prof. Jacinta Bustamante MD (Laboratoire de Génétique Humaine des Maladies Infectieuses, Institut National de la Santé et de la Recherche Médicale et Université Paris Descartes, France) for the genetic evaluation of the patients.

Funding

This work was supported by grant NV18-05—00162 from the Ministry of Health of the Czech Republic.

Footnotes

Conflicts of interest

None.

References

  • 1.Bustamante J. Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum Genet. 2020;139:993–1000. doi: 10.1007/s00439-020-02120-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-γ immunity. Semin Immunol. 2014;26:454. doi: 10.1016/j.smim.2014.09.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Taur PD, Gowri V, Pandrowala AA, et al. Clinical and molecular findings in mendelian susceptibility to mycobacterial diseases: experience from India. Front Immunol. 2021;12:426. doi: 10.3389/fimmu.2021.631298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Escalonilla P, Esteban J, Soriano ML, et al. Cutaneous manifestations of infection by nontuberculous mycobacteria. Clin Exp Dermatol. 1998;23:214–21. doi: 10.1046/j.1365-2230.1998.00359.x. [DOI] [PubMed] [Google Scholar]
  • 5.Franco-Paredes C, Marcos LA, Henao-Martínez AF, et al. Cutaneous mycobacterial infections. Clin Microbiol Rev. 2018;32(1):e00069–18. doi: 10.1128/CMR.00069-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Alcaide F, Esteban J. Cutaneous and soft skin infections due to non-tuberculous mycobacteria. Enferm Infecc Microbiol Clin. 2010;28:46–50. doi: 10.1016/S0213-005X(10)70008-2. [DOI] [PubMed] [Google Scholar]
  • 7.Kumar SN, Prasad TS, Narayan PA, Muruganandhan J. Granuloma with langhans giant cells: an overview. J Oral Maxillofac Pathol. 2013;17(3):420. doi: 10.4103/0973-029X.125211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Radomski N, Cambau E, Moulin L, Haenn S, Moilleron R, Lucas FS. Comparison of culture methods for isolation of nontuberculous mycobacteria from surface waters. Appl Environ Microbiol. 2010;76:3514. doi: 10.1128/AEM.02659-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Fonseca L, Moore D, Durier N. MTB culture and phenotypic drug susceptibility testing-methods inventory inventory of methods for mycobacterial culture and Phenotypic Drug Susceptibility Testing (DST) from the culture and phenotypic DST sub-group of the STOP TB Partnership New Diagnostics Working Group Main Tests at a glance solid media liquid media Egg-based Agar-based Automated Manual LJ Ogawa 7H107H11 1 BACTE C 460 MBBacT ALERT MGIT ESP II MGIT CRI MODS NRA Culture [Internet]. https://www.merck.com, 2011. [Accessed on 11/12/2021].
  • 10.Mi Wi Y. Treatment of extrapulmonary nontuberculous mycobacterial diseases. Infect Chemother. 2019;51:245. doi: 10.3947/ic.2019.51.3.245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Henkle E, Winthrop KL. Nontuberculous mycobacteria infections in immunosuppressed hosts. Clin Chest Med. 2015;36:91. doi: 10.1016/j.ccm.2014.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Döffinger R, Helbert MR, Barcenas-Morales G, et al. Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clinical Infec Dis. 2004;38:e10–4. doi: 10.1086/380453. [DOI] [PubMed] [Google Scholar]
  • 13.Lee WI, Huang JL, Yeh KW, et al. Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs) J Formos Med Assoc. 2011;110:750–8. doi: 10.1016/j.jfma.2011.11.004. [DOI] [PubMed] [Google Scholar]
  • 14.Hermansen TS, Thomsen V, Lillebaek T, Ravn P. Non-tuberculous mycobacteria and the performance of interferon gamma release assays in Denmark. PLoS One. 2014;9:e93986. doi: 10.1371/journal.pone.0093986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Casanova JL. Severe infectious diseases of childhood as monogenic inborn errors of immunity. Proc Natl Acad Sci U S A. 2015;112:E7128–37. doi: 10.1073/pnas.1521651112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Tovo PA, Garazzino S, Saglio F, et al. Successful hematopoietic stem cell transplantation in a patient with complete IFN-γ receptor 2 deficiency: a case report and literature review. J Clin Immunol. 2020;40:1191–5. doi: 10.1007/s10875-020-00855-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Falkinham JO. Ecology of nontuberculous mycobacteria. Microorganisms. 2021;9:2262. doi: 10.3390/microorganisms9112262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Wentworth AB, Drage LA, Wengenack NL, Wilson JW, Lohse CM. Increased incidence of cutaneous nontuberculous mycobacterial infection, 1980 to 2009: a population-based study. Mayo Clin Proc. 2013;88:38. doi: 10.1016/j.mayocp.2012.06.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Dolezalova K, Maly M, Wallenfels J, Gopfertova D. Nontuberculous mycobacterial infections in children in the Czech Republic in the period 2003–2018. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2021;165:277–82. doi: 10.5507/bp.2020.025. [DOI] [PubMed] [Google Scholar]
  • 20.Elston D. Nontuberculous mycobacterial skin infections: recognition and management. Am J Clin Dermatol. 2009;10:281–5. doi: 10.2165/00128071-200910050-00001. [DOI] [PubMed] [Google Scholar]
  • 21.Li JJ, Beresford R, Fyfe J, Henderson C. Clinical and histopathological features of cutaneous nontuberculous mycobacterial infection: a review of 13 cases. J Cutan Pathol. 2017;44:433–43. doi: 10.1111/cup.12903. [DOI] [PubMed] [Google Scholar]
  • 22.Bruijnesteijn Van Coppenraet ES, Lindeboom JA, Prins JM, Peeters MF, Claas ECJ, Kuijper EJ. Real-time PCR assay using fine-needle aspirates and tissue biopsy specimens for rapid diagnosis of mycobacterial lymphadenitis in children. J Clin Microbiol. 2004;42:2644. doi: 10.1128/JCM.42.6.2644-2650.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Kim YN, Kim KM, Choi HN, et al. Clinical usefulness of PCR for differential diagnosis of tuberculosis and nontuberculous mycobacterial infection in paraffin-embedded lung tissues. J Mol Diagn. 2015;17:597–604. doi: 10.1016/j.jmoldx.2015.04.005. [DOI] [PubMed] [Google Scholar]
  • 24.Lindeboom JA, Kuijper EJ, Prins JM, Bruijnesteijn Van Coppenraet ES, Lindeboom R. Tuberculin skin testing is useful in the screening for nontuberculous mycobacterial cervicofacial lymphadenitis in children. Clin Infect Dis. 2006;43:1547–51. doi: 10.1086/509326. [DOI] [PubMed] [Google Scholar]

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