Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia.

PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30). METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain. RESULTS: Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect. CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.

Encephalopathy and Axonal Neuropathy Associated With Mycoplasma Pneumoniae Infection: Response to Intravenous Immunoglobulin Therapy.

Mycoplasma pneumoniae infection frequently presents as a self-limited process, however, severe cases and even fatalities have been reported. The authors present a case of Mycoplasma pneumoniae infection associated with both encephalopathy and peripheral neuropathy that responded to intravenous immunoglobulin therapy. To our knowledge, this is the first documented case of Mycoplasma pneumoniae related to encephalitis and peripheral axonal neuropathy. To date, there is insufficient data on the effect of intravenous immunoglobulin on the course of mycoplasma-associated central nervous system/peripheral nervous system disease. While intravenous immunoglobulin has aided in a variety of autoimmune-mediated disorders, its efficacy in mycoplasma-mediated encephalitis treatment remains unclear. In this patient case, reversal of both central and peripheral nervous system symptoms after treatment with intravenous immunoglobulin suggested a possible therapeutic benefit.

HIV-Care Outcome in Saudi Arabia; a Longitudinal Cohort.

BACKGROUND: Clinical characteristics of HIV-1 infection in people inhabiting Western, Sub-Saharan African, and South-East Asian countries are well recognized. However, very little information is available with regard to HIV-1 infection and treatment outcome in MENA countries including the Gulf Cooperation Council (GCC) states. METHODS: Clinical, demographic and epidemiologic characteristics of 602 HIV-1 infected patients followed in the adult Infectious Diseases Clinic of King Faisal Specialist Hospital and Research Centre, in Riyadh, Kingdom of Saudi Arabia a tertiary referral center were longitudinally collected from 1989 to 2010. RESULTS: Of the 602 HIV-1 infected patients in this observation period, 70% were male. The major mode of HIV-1 transmission was heterosexual contact (55%). At diagnosis, opportunistic infections were found in 49% of patients, most commonly being pneumocysitis. AIDS associated neoplasia was also noted in 6% of patients. A hundred and forty-seven patients (24%) died from the cohort by the end of the observation period. The mortality rate peaked in 1992 at 90 deaths per 1000 person-year, whereas the mortality rate gradually decreased to <1% from 1993-2010. In 2010, 71% of the patients were receiving highly active retroviral therapy. CONCLUSIONS: These data describe the clinical characteristic of HIV-1-infected patients at a major tertiary referral hospital in KSA over a 20-year period. Initiation of antiretroviral therapy resulted in a significant reduction in both morbidity and mortality. Future studies are needed in the design and implementation of targeted treatment and prevention strategies for HIV-1 infection in KSA.

Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor ß1 (IL-12Rß1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Lethal Legionella infection in an immunocompromised child: first reported case in the Middle East.

Legionnaires disease continues to be underreported in the Middle East--a reflection of underdiagnosis, both clinically and by laboratory investigations. We draw the attention to this unusual cause of occasionally fatal, yet severe, pneumonia by reporting an immunocompromised infant who succumbed to Legionella pneumophila pneumonia. The urinary test for Legionella antigen was positive, and this was then confirmed by a bronchoalveolar fluid culture. Moreover we have reviewed the incidence, pathophysiology, association with immunodeficiency, diagnostic tools, and treatment in this case report.

Antiretroviral resistance in HIV-infected Saudi children failing first-line highly active antiretroviral therapy.

BACKGROUND AND OBJECTIVES: The use of a potent combination of antiretroviral (ARV) drugs, so-called highly active ARV therapy (HAART), has dramatically improved the quality of life and overall survival of children with human immunodeficiency virus (HIV) infection. However, these benefits can be compromised by the development of drug resistance. Our objectives were to analyze the prevalence and pattern of HIV-drug resistance among HIV-infected children failing first-line HAART. DESIGN AND SETTING: Retrospective study based on data obtained from July 2006 through January 2009 of prevalence of genotypic resistance estimated in HAART-treated children who experienced virologic failure (HIV RNA > 1000 copies/mL) at a tertiary care center in Riyadh. PATIENTS AND METHODS: The characteristics of the study population and genotype resistance data were analyzed in ARV-treated children who experience virologic failure. RESULTS: Among 22 children who underwent resistance testing, the prevalence of resistance to any drug was 86.4%. Inadequate adherence to ARVs in children with drug resistance was 91%. Twenty-four mutations were detected within the protease coding region and 14 in the reverse transcriptase (RT) coding region. In 80% of isolates piM36I was detected, while rtM184V was detected in 70% of the isolates and was associated with cross-resistance to at least two nucleoside RT inhibitors (NRTI). Clinically significant non-nucleoside RT inhibitors (NNRTI) resistance was conferred by rtK103N. The best ARV susceptibility was to lopinavir in the PI class. ARV resistance was not associated with geographic regions or the CDC classification status. Study children responded satisfactorily to genotype-guided treatment and intensive family counseling. CONCLUSION: ARVs resistance is common among HIV-infected Saudi children who experienced virologic failure to HAART. Inadequate adherence is a common cause for resistance to ARVs in children. Mutations M36I and M184V were more frequent for PIs, NRTIs and NNRTIs. Evaluation of genotype tests should be considered in all children with therapeutic failure to guide future selection of ARV regimens. These data will help improve clinical management of HIV-infected children in Saudi Arabia.

Revisiting human IL-12Rß1 deficiency: a survey of 141 patients from 30 countries.

Interleukin-12 receptor ß1 (IL-12Rß1) 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-12Rß1 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.

Human immunodeficiency virus infection in Saudi Arabian children: transmission, clinical manifestations and outcome.

BACKGROUND: Vertical transmission from mother to infant is the most common mode of transmission of HIV infection in children. Data on pediatric HIV in the Middle East and Gulf region are scarce. We describe the spectrum, characteristics and outcome of HIV infection in Saudi children. METHODS: We collected descriptive data on HIV-infected or exposed children seen at the King Faisal Hospital and Research Centre (KFSH&RC) between 1986 and 2003. RESULTS: Sixty-three children had proven HIV infection. The source of infection was perinatal transmission in 63.5% of cases and contaminated blood or blood products transfusion in 34.5%. Median age at diagnosis was 6 years. In 42 patients for whom complete records were available, 90% were delivered by spontaneous vaginal delivery and 10% by cesarean delivery. Ninety-three percent of infected infants were breastfed throughout infancy. The complete medical records were available for 66% of children; for the remainder, part of the records could not be retrieved. Thirteen percent had an AIDS-defining opportunistic infection, with disseminated cytomegalovirus (CMV) infection being the most common (37.5%). All cases received antiretroviral therapy starting in 1997. Of those who received highly active antiretroviral therapy, 79% were compliant with treatment and had a sustained virologic response below the detectable level. Seventy-five percent of those diagnosed before 1995 died compared with 7.7% diagnosed later. CONCLUSION: Effective preventive measures, such as antiretroviral prophylaxis, cesarean delivery, and abstention from breastfeeding are not being applied. This could be largely due to lack of knowledge among patients and healthcare providers. Physicians must recognize the signs and symptoms of HIV infection, and have a high index of suspicion so that infected children are diagnosed early and referred to a specialized center for treatment and follow-up.

Pyogenic bacterial infections in humans with IRAK-4 deficiency.

Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.

Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency.

The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.

Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds.

Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82_856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82_856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315_316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82_856-854del and g.315_316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.