Case Report: Nontuberculous mycobacterial infections in children with complete DiGeorge anomaly

Abstract

Children with complete DiGeorge anomaly (cDGA) have congenital athymia, resulting in severe T cell immunodeficiency and susceptibility to a broad range of infections. We report the clinical course, immunologic phenotypes, treatment, and outcomes of three cases of disseminated nontuberculous mycobacterial infections (NTM) in patients with cDGA who underwent cultured thymus tissue implantation (CTTI). Two patients were diagnosed with Mycobacterium avium complex (MAC) and one patient with Mycobacterium kansasii. All three patients required protracted therapy with multiple antimycobacterial agents. One patient, who was treated with steroids due to concern for immune reconstitution inflammatory syndrome (IRIS), died due to MAC infection. Two patients have completed therapy and are alive and well. T cell counts and cultured thymus tissue biopsies demonstrated good thymic function and thymopoiesis despite NTM infection. Based on our experience with these three patients, we recommend that providers strongly consider macrolide prophylaxis upon diagnosis of cDGA. We obtain mycobacterial blood cultures when cDGA patients have fevers without a localizing source. In cDGA patients with disseminated NTM, treatment should consist of at least two antimycobacterial medications and be provided in close consultation with an infectious diseases subspecialist. Therapy should be continued until T cell reconstitution is achieved.

Keywords: DiGeorge anomaly; Mycobacterium avium complex; Mycobacterium kansasii; athymia; complete DiGeorge syndrome; nontuberculous mycobacteria; primary immunodeficiency; thymus transplantation.

Figure 1

T cell counts. The tenth percentile of the normal CD3⁺ range for age is shown as a dashed line (4). (A) In patient 1, the CD3⁺ count increased to 3,710 cells/mm³ ten months prior to implantation, when the patient developed atypical cDGA. Naïve CD4⁺ T cells appeared at 5.7 months post-CTTI and increased steadily over the next several months. (B) Patient 2 had low, but detectable, naive T cells with 7 naïve CD4⁺ T cells/mm³ three months after transplant. The large increase in CD4⁺ T cells seen at day 105 post CTTI was concerning for development of immune reconstitution inflammatory syndrome. (C) In Patient 3, naïve T cells appeared 6.8 months after CTTI, and have persisted for over six years. The large increase in CD8⁺ cells at month 48 was due to acute Epstein-Barr virus infection.

Figure 2

Cultured thymus tissue biopsy of patient 1. (A, B) Immunohistochemistry with anti-cytokeratin AE1/AE3 antibody shows thymic epithelial cells. (C, D) Anti-CD1a staining shows presence of thymocytes. (E, F) Staining for Ki-67, an intracellular marker for proliferating cells, show that these thymocytes are proliferating.

Figure 3

Patient 2 imaging and autopsy findings. (A) Abdominal MRI with lymphadenopathy surrounding mesenteric vessels. (B) H&E staining of a lymph node showing a caseating granuloma and giant cells. (C) Acid-fast staining of lymph node tissue showing presence of mycobacteria (arrows). (D) Cultured thymus tissue at time of autopsy. H&E staining shows intact Hassall bodies (arrow) surrounded by numerous thymocytes. The cultured thymus tissue graft was implanted in the quadriceps muscles. Muscle tissue is visible adjacent to the cultured thymus tissue.