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.

The first case of Raoultella planticola infective endocarditis in a 4 year old child: A case report and review of literature.

Infective endocarditis is a complication of bacteremia that can lead to serious morbidity and even mortality if not appropriately treated, well known organisms commonly lead to this condition in many repeated scenarios so they are usually recognized and treated, but if it was caused by other organisms its detection and treatment can be harder. Raoultella planticola, a low virulent organism used to be part of the Klebsiella species, has been found in many reports to cause multiple human conditions. In this article, a novel case of R. planticola is reported, and the organism was reviewed in many aspects for clinician to be able to recognize this infection and manage it in a more effective way.

A child with complicated Mycobacterium tuberculosis.

Tuberculosis (TB) is one of the leading causes of morbidity and mortality worldwide, with ever increasing resistance to commonly used antituberculous drugs. Drug-resistant TB was recognized shortly after the introduction of an effective therapy in the late 1940s, the use of streptomycin, which was the first widely used antituberculosis drug. Patients who received this drug usually had marked and rapid clinical improvement, but treatment failures were common after the first three months of therapy. Most children are infected by household contacts who have TB, particularly parents or other caretakers. Common symptoms of pulmonary TB in children include cough (chronic, without improvement for more than three weeks), fever (higher than 38 °C for more than two weeks), and weight loss or failure to thrive. Findings on a physical exam may suggest the presence of a lower respiratory infection, whereas the clinical presentation of extra pulmonary TB depends on the site of disease. The most common forms of extra pulmonary disease in children are TB of the lymph nodes and of the central nervous system. The role of inadequate treatment and poor compliance in the emergence of resistance highlights the importance of the DOT (Direct Observation Therapy) method in improving treatment outcomes and to control the spread of resistance.

Consensus recommendation for meningococcal disease prevention in children and adolescents in the Middle East region.

Facing the availability of the new generation of quadrivalent meningococcal conjugate vaccines (Menveo®, Menactra® and others pending for license) and their recent implementation in Saudi Arabia, experts from 11 countries of the Middle East region met at a "Meningococcal Leadership Forum" (MLF), which took place in May 2010 in Dubai. The participants of the conference discussed the importance of introducing the concept of conjugate vaccines - especially for children and adolescents - and elaborated a consensus recommendation to support healthcare professionals and decision makers with their expertise. In experts' opinion, conjugate vaccines are the best choice for the prevention of meningococcal disease caused by serogroups A, C, W-135 and Y. As quadrivalent meningococcal conjugate vaccines are registered and available in the Middle East region, they should replace plain polysaccharide vaccines and be integrated in pediatric and adolescent vaccination schedules, including infant vaccination concomitantly with basic EPI vaccines when licensed.

Ceftriaxone treatment failure of meningitis due to penicillin and ceftriaxone resistant streptococcus pneumonia.

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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.

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.