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.

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.

Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications.

The clinical phenotype of interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rbeta1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rbeta1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.

A role for interleukin-12/23 in the maturation of human natural killer and CD56+ T cells in vivo.

Natural killer (NK) cells have been originally defined by their "naturally occurring" effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-gamma (IFN-gamma) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rbeta1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-gamma production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rbeta1- and IL-12p40-deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56(+) effector memory T cells. The susceptibility of IL-12/23 axis-deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56(+) T cells in the control of these infections in humans.

Three years' experience of dialysis event surveillance.

BACKGROUND: The main study aim was to track infections, evaluate performance, and identify opportunities for improved practice since infections, especially those associated with multidrug-resistant organisms, are the second most common cause of death among end-stage renal disease patients. METHODS: This study describes the establishment of baseline dialysis event surveillance at a large dialysis center. Every month, the dialysis center staff reported the total number of maintenance hemodialysis patients to the department of infection control and hospital epidemiology. The surveillance system for dialysis events included monthly monitoring of hemodialysis patients in outpatient settings for positive blood cultures, intravenous antimicrobial initiation, and local vascular access infections. RESULTS: We calculated the pooled mean rates of positive blood cultures, intravenous antimicrobial initiation, and local vascular access infections during the period from June 1, 2014 to September 30, 2017. Results indicated more dialysis events were attributed to the CVC than any other dialysis vascular access. Regardless of vascular access type, intravenous antimicrobial initiation was the most commonly reported dialysis-associated event. CONCLUSIONS: Dialysis events surveillance can be used to produce a decrease in both morbidity and mortality rates in hemodialysis patients.

Pediatric gastrointestinal basidiobolomycosis.

Basidiobolomycosisis an unusual fungal infection that manifests in the skin and rarely involves other systems including the gastrointestinal tract. We retrospectively reviewed records of six pediatric patients (< or =14 years of age) diagnosed with gastrointestinal basidiobolomycosis from March 2000 to March 2002. Four patients came from the same region, suggesting environmental exposure. Basidiobolomycosis should be considered in the differential diagnosis in pediatric patients presenting with abdominal mass and eosinophilia.

Streptococcus pneumoniae resistance to penicillin and ceftriaxone in a tertiary care center in Saudi Arabia.

OBJECTIVE: The proportion of penicillin and ceftriaxone resistant Streptococcus pneumoniae isolates and associated risk factors varies by geographic areas in the world. We conducted a retrospective study to determine the extent of penicillin and ceftriaxone non-susceptible Streptococcus pneumoniae bacteremia in a tertiary care medical center in the city of Riyadh, Kingdom of Saudi Arabia. METHODS: We reviewed 172 episodes of Streptrococcus pneumoniae bacteremic diseases involving 160 hospitalized patients at King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, over a 5 year period between January 1995 through to December 1999. Patients' characteristics and underlying illnesses of those patients with bacteremias and meningitis caused by Streptococccus pneumoniae as well as antimicrobial susceptibility were examined. RESULTS: The majority of patients affected with Streptococcus pneumoniae bacteremia were children <5 years of age (number=91, 53%). Malignant diseases were the main underlying diagnosis in our patient population affected with pneumoncoccal bacteremia (number=46, 27%). Overall (51%) of the isolates were penicillin non-susceptible; of these (7%) were highly resistant. The overall resistance rate to ceftriaxone was 7%. CONCLUSION: With the high prevalence in Streptococcus pneumoniae antimicrobial resistance to penicillin and ceftriaxone, it is important to continue surveillance of infections caused by Streptococcus pneumoniae, and also we recommend that guidelines for treatment and prevention of pneumococcal infection must be addressed by health care and public health agencies.

Central nervous system and spinal tuberculosis in children at a tertiary care center in Saudi Arabia.

BACKGROUND AND OBJECTIVES: Tuberculosis (TB) remains a global health problem. There is limited data on pediatric central nervous system tuberculosis (CNSTB) in Saudi Arabia on diagnosis and therapy. DESIGN AND SETTING: Retrospective review of health record of pediatric patients < 14 years old who were diagnosed as having CNSTB or spinal TB and admitted to a tertiary care center. PATIENTS AND METHODS: Health records and microbiology data of pediatric patients diagnosed with CNSTB were over 20-year period were reviewed. Data on demographics, clinical presentation, surgical interventions, neuroimaging, mycobacterial cultures and susceptibility and treatment were collected. RESULTS: Thirteen children were diagnosed with CNSTB or spinal TB. Tuberculoma was the most frequent in 8 cases (62%), followed by TB of the spine in 4 cases (31%), and one case of meningitis. Six patients had a history of TB contact (46%) and 8 (62%) patients had a positive tuberculin skin test (TST). Seizure and weakness was the most frequent symptoms (38% each), while fever was less frequently encountered (23%). Tissue cultures (brain tissues/spinal tissues) showed a high yield (92%) of Mycobacterium tuberculosis with positive cultures for 11 surgical specimens out of 12 for whom cultures were done. There were no surgical complications from biopsies. All of MTB isolates were sensitive to first-line agents. CONCLUSIONS: Brain or spinal biopsy is safe and has a high culture yield for MTB so it is advisable to perform a biopsy for any child in whom CNSTB is suspected and when there is no other less risky involved site for biopsy. All MTB isolates in this series were sensitive to first-line anti-tubercular agents.

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.

Chronic recurrent multifocal osteomyelitis: a first report from Saudi Arabia.

BACKGROUND AND OBJECTIVES: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, systemic, aseptic, inflammatory disorder that involves different sites. Pathogenesis of chronic recurrent multifocal osteomyelitis is currently unknown. To our knowledge, there are no reports of CRMO from Saudi Arabia. We describe the clinical and laboratory features and treatment of a cohort of children with CRMO. DESIGN AND SETTING: Retrospective, patients referred to pediatric rheumatology clinic at a tertiary care center in Riyadh, Saudi Arabia. PATIENTS AND METHODS: The diagnosis of CRMO was based on evidence of recurrent osteomyelitis with radiographic evidence of chronic osteomyelitis involving at least two sites in the absence of infectious cause in a child less than 14 years old. RESULTS: Ten patients (9 female, 1 male) with CRMO; 2 patients presented in infancy. The referral diagnosis was inaccurate in all patients. All of them presented with pain and 8 of them had associated swelling and were found to have multifocal lesions. Imaging studies showed findings consistent with chronic osteomyelitis. Histopathological and microbiological examination confirmed the diagnosis in 9 patients. Cyclic pamidronate infusions induced good improvement in 6 patients. CONCLUSION: This report indicates that CRMO may be overlooked in our community. Early diagnosis and treatment are required to avoid potential complications.