Variable outcome of experimental interferon-? therapy of disseminated Bacillus Calmette-Guerin infection in two unrelated interleukin-12R?1-deficient Slovakian children

Ulrichs, Timo; Fieschi, Claire; Nevická, Eva; Hahn, Helmut; Brezina, Martin; Kaufmann, Stefan H. E.; Casanova, Jean‐Laurent; Frecerová, Klára

doi:10.1007/s00431-004-1599-2

Cited by 26 publications

(11 citation statements)

References 22 publications

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“…Similarly, an IL-12Rβ1-independent T-cell response to IL-12 has been proposed as a general compensatory mechanism,[66] but this hypothesis was not confirmed in our assays. [8,23,24,48,60,65,PR] In all patients tested, including patients with IL-12Rβ1 expression on the cell surface, no cellular response to IL-12 was detected in our whole-blood assay. [22] Despite the varying clinical presentation as well as substantial genetic heterogeneity, the cellular defect was complete.…”

Section: Discussionmentioning

confidence: 99%

Revisiting Human IL-12Rβ1 Deficiency

et al. 2010

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Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.

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Section: Discussionmentioning

confidence: 99%

Revisiting Human IL-12Rβ1 Deficiency

et al. 2010

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“…There are only two reports of three patients where IFN- γ was tried. The first report includes 2 patients with BCGosis treated with IFN- γ for 18 months in addition to antimycobacterials [11]. One patient survived and the other died.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Disseminated Mycobacterial Infection with High-Dose IFN-γin a Patient with IL-12Rβ1 Deficiency

Alangari

Alzamil

Almazrou

et al. 2011

Clinical and Developmental Immunology

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IFN-γ has been used in the treatment of IL-12Rβ1 deficiency patients with disseminated BCG infection (BCGosis), but the optimal dose to reach efficacy is not clear. We used IFN-γ in the treatment of a 2.7-year-old patient with IL-12Rβ1 deficiency and refractory BCG-osis. IFNγ was started at a dose of 50 μg/m2 3 times per week. The dose was upgraded to 100 mcg/m2 after 3 months, then to 200 mcg/m2 6 months afterwards. Serum mycobactericidal activity and lymphocytes number and function were evaluated throughout the study. There was no clinical response to IFN-γ with 50 or 100 μg/m2 doses. However, there was some response to the 200 μg/m2 dose with no additional adverse effects. The serum mycobactericidal activity was not significantly different during the whole treatment period. Lymphocytes proliferation in response to PHA was significantly higher after 3 months of using the highest dose as compared to the lowest dose. The tuberculin skin test reaction remained persistently negative. We conclude that in a patient with IL-12Rβ1 deficiency, IFN-γ at a dose of 200 μg/m2, but not at lower dosages, was found to have a noticeable clinical effect with no additional adverse effects.

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“…Although MSMD is most frequently a result of complete IL-12Rβ1, IFN-γR1 and IL-12p40 deficiency [2], there are potentially other pathways involved [5]. While patients with deficiencies can be treated, this is not always successful [6]. However, recent gene therapy experiments demonstrating reconstitution of IL-12 responsiveness and IFN-γ production in T cells following gene transfer show some promise for future treatment [7].…”

Section: Importance Of Il-12 In Immunity To Mycobacterial Infection Imentioning

confidence: 99%