A CASE OF INTERLEUKIN-12 RECEPTOR β-1 DEFICIENCY WITH... : The Pediatric Infectious Disease Journal (original) (raw)

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome with predisposition to infectious diseases caused by poorly virulent mycobacteria, such as Mycobacterium bovis BCG vaccine, and nontuberculous environmental mycobacteria (EM), as well as by poorly virulent Salmonella strains.1–7 Occasionally, patients develop infections caused by more virulent Mycobacterium tuberculosis and typhoidal Salmonella serotypes.3,5,6 Unlike patients with classic immunodeficiencies, these patients rarely develop other severe bacterial, viral, fungal or parasitic diseases.8

In MSMD, mutations in 5 proteins (IFN-γR1, IFN-γR2, IL-12Rβ1, IL-12p40 and STAT1), all of which result in impaired IFN-γ mediated immunity, have been described.3,5 Resistance to infections by Leishmania, a protozoal parasite, is associated with the development of _Leishmania_-specific TH1 cells, whereas susceptibility and disease progression are related to a TH2 type response.9 TH1, a functional subset of CD4+ T cell clones, preferentially produces IFN-γ. Interleukin-12, a major cytokine produced by macrophages, is a powerful stimulus for the differentiation of TH1 cells and thereby drives the production of IFN-γ.

Several species of Leishmania are human pathogens and responsible for one of 3 clinical forms of the disease which include cutaneous, mucosal and visceral leishmaniasis (VL). The pathogenicity of the parasite and the cell-mediated immune response of the human host affect the clinical manifestations of infection.9,10 An intriguing feature of leishmaniasis is that not all infected individuals develop disease. VL is generally associated with severe immunodeficiency (acquired immunodeficiency syndrome, organ transplantations, hematopoietic malignancies), and is an important opportunistic infection among individuals infected with human immunodeficiency virus (HIV) in some European countries.10

We report a patient with IL-12Rβ1 deficiency who developed recurrent visceral leishmaniasis. This is the first case with TH1-IL-12 axis defect associated with a Leishmania infection.

CASE REPORT

The patient, a 5-year-old boy, diagnosed to have IL-12Rβ1 defect at the age of 2 years,7 was admitted to hospital with the complaints of malaise, abdominal pain, abdominal distention and enlarged submandibular lymph nodes. Previously, he had experienced recurrent Salmonella infections beginning at the age of 18 months associated with bacteremia and lymph node involvement. He responded to antibacterial therapy for salmonellosis and did well while receiving prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) treatment. Physical examination revealed enlarged submandibular (3 × 1.5 cm) and cervical (1 × 1 cm) lymph nodes, and splenomegaly (spleen was 8 cm palpable below the left costal margin). Of note, the patient did not show a high temperature pattern consistent with an infectious episode either during this admission or at the time of previous Salmonella infections. Complete blood count and C-reactive protein values are shown in Table 1. Serum electrolytes, and liver transaminases were in normal range (ALT and AST, were 15 U/L and 27 U/L, respectively). Serum triglycerides (163 mg/dL) and ferritin (150 ng/mL) values were normal. Epstein-Barr virus (EBV) panel showed positive IgG for Epstein-Barr nuclear antigen (EBNA) (78 U) and viral capsid antigen (VCA) (157 U) compatible with a past EBV infection. IgG antibodies against rubella and cytomegalovirus (CMV) were positive, whereas IgM antibodies against these antigens were negative. Both IgG and IgM antibodies against Toxoplasma gondii were negative. An enzyme-linked immunosorbent assay (ELISA) using k39 antigen was equivocal, and an indirect fluorescence assay for antileishmanial antibodies was positive.

TABLE 1:

Complete Blood Count and C-Reactive Protein Values Before and After Treatment of Visceral Leishmaniasis

Because of newly developed splenomegaly and persistent anemia, bone marrow examination was done. Detection of Leishmania amastigotes in Giemsa-stained bone marrow specimen established the diagnosis of VL (Fig. 1). The bone marrow also showed hemophagocytosis (Fig. 1). Lyposomal amphotericin B 3 mg/kg/d was administered for 21 days. Good clinical response was observed with a remarkable decrease in serum CRP, improvement of cytopenia and regression of splenomegaly after completion of the treatment course. Six months after, a relapse of the infection occurred with the same clinical signs suggestive of a new episode of VL, which was again confirmed with detection of Leishmania amastigotes in the bone marrow smear. During this episode, Salmonella group D was also grown in cultures from peripheral blood and bone marrow. The patient was placed on liposomal amphotericin B (3 mg/kg for 15 days) and ciprofloxacin (15 mg/kg iv). By the end of the treatment course, the symptoms had ameliorated. Full recovery was achieved when treatment with IFN-γ 50 μg/m2 3 times weekly and amikacin was administered.

FIGURE 1.:

Bone marrow smear stained with Giemsa showing numerous Leishmania amastigotes. The arrow indicates the hemophagocytic cell with an intracellular blood cell and amastigotes (magnification ×100).

DISCUSSION

In MSMD, mutations in any of the 5 proteins (IFN-γR1, IFN-γR2, IL-12Rβ1, IL-12p40 and STAT1) of IFN-γ/IL-12 axis result in impaired IFN-γ mediated immunity. Both IL-12Rβ1 and IL-12p40 defects result in otherwise normal cellular responses to IFN-γ, but abnormal IL-12 dependent production of IFN-γ.3,5

Several species of Leishmania capable of infecting man are classified into 2 main groups: Old World: L. major, L. tropica, L. aethiopica and donovani complex (L. donovani, L. infantum) and New World: L. mexicana, L. amazonensis and Viannia complex (eg, L. brasiliensis, L. guyanensis).11 These different species of Leishmania cause different types of infection. However, most of the studies related to immunopathology of Leishmania are carried out with the species that cause cutaneous leishmaniasis, particularly with L. major. For several million years, the Old World species and the New World species have evolved differently in various hosts by developing different survival mechanisms. Therefore, significant differences in immunopathology of Leishmania species would be expected. Although the factors that cause disease progression are varied, protective immune responses in all species depend on TH1 type CD4+ T lymphocytes,.9,12 IL-12, an essential cytokine in the development of a TH1 response, is crucial in the immune response to leishmaniasis. Mouse models mimicking IL-12/IL-12R deficiency have facilitated the investigations on the role of IL-12 in the natural course of leishmaniasis.13–17 In one study with L. donovani, the species that is responsible for visceral leishmaniasis, IL-12p35−/− mice (deficient in IL-12 alone) and IL-12p40−/− mice (deficient in IL-12 and IL-23) have shown increased susceptibility to L. Donovani. IL-12p35−/− mice developed high-level infection although, unlike IL-12p40−/− mice, they have normal IL-23 function. In addition, initial kinetics of parasite replication in IL-12p35−/− mice and IL-12p40−/− mice are also similar suggesting a prime role for IL-12 alone in the early phase of L. donovani infection.17 Furthermore, IL-12 is functional in maintaining an established response against this parasite.9,13,17 Thus, the defect in IFN-γ/IL-12 axis in our patient must have predisposed him to develop recurrent Leishmania infections. This patient, however, responded to anti-Leishmania treatment reasonably well considering the underlying immunologic defect. This favorable response may be due to the fact that there is still some IFN-γ production in patients with IL-12Rβ1 defect,5,9 and/or there are potentially IL-12- or IFN-γ-independent mechanisms in protective immunity against Leishmania.18 This is the first documented case of visceral leishmaniasis in patient with IL-12Rβ1 defect. Two patients with IFN-γR1 deficiency, another defect in the IFN-γ/IL-12 axis, have been found to have a positive antileishmania serology without clinical symptoms.19

The patient presented here did not develop a high body temperature expected in both Salmonella infections and in visceral leishmaniasis or during hemophagocytosis. This is most likely because of decreased production of pyrogenic cytokines secondary to IL-12Rβ1 deficiency. In the light of this observation, it would be prudent not to consider fever a criterion for an infectious disease process in a patient with IL-12Rβ1 deficiency.

The bone marrow aspiration showed evidence of hemophagocytosis. Hemophagocytosis can be seen as primary hemophagocytic lymphohistiocytosis or secondary, associated with neoplasms, congenital or acquired immunodeficiencies, collagen vascular diseases and infections, including leishmaniasis.20 Secondary hemophagocytosis has also been reported in association with disseminated tuberculosis in a patient with IL-12Rβ1 deficiency.6 The common feature is a dysregulation of T lymphocytes and excessive production of cytokines resulting in abnormal macrophage activation. The IL-12Rβ1 defect in this patient might have contributed to development of hemophagocytosis by causing an imbalance in IFN-γ/IL-12 axis and related cytokines.

In conclusion, patients with IL-12Rβ1 defect may experience recurrent Leishmania infections. Because patients who develop Leishmania infection may have an underlying IFN-γ/IL-12 axis defect, we suggest that these patients with Leishmania infection be immunologically evaluated.

Addendum.

As we revise this manuscript, the patient has developed a third episode of visceral leishmaniasis treated with liposomal amphotericin B. Currently, the patient is taking amphotericin B every 3–4 weeks as prophylaxis to prevent recurrent infection.

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Keywords:

Mendelian susceptibility to mycobacterial disease; interleukin-12 receptor beta-1 deficiency; leishmaniasis; salmonella infection