Evolving Epidemiology of Pediatric Respiratory Syncytial Virus (RSV) Cases Around COVID-19 Pandemic: Impact and Clinical Insights, Retrospective Cohort Study.

BACKGROUND: The burden of respiratory syncytial virus (RSV) in high-risk pediatric patients remains unclear. Therefore, this study aims to characterize pediatric RSV cases from January 2019 to December 2022 and assess the impact of the COVID-19 pandemic on RSV burden and RSV-related outcomes. In addition, examining factors influencing RSV-related hospitalization. METHODS: This is a retrospective study that included pediatric patients (aged 14 and below) who presented at King Faisal Specialist Hospital and Research Centre (KFSHRC) in Riyadh, Saudi Arabia with RSV infection identified using real-time reverse-transcriptase polymerase chain reaction assays. Statistical analyses were performed using STATA. RESULTS: A total of 885 RSV cases were reported; (56.05%) were males and (43.95%) were females with a median age of 24 months [interquartile range (IQR): 11-60]. 534 (60.34%) required hospitalization. As for RSV seasonality, there was a significant increase in RSV prevalence following the COVID-19 pandemic, escalating from 205 cases in 2019 to 425 cases in 2022. The increase in 2022 was evident in January and persisted from September to December, reaching its peak during the months of October (20.70% - 88 cases) and November (32.00% - 136 cases). About (27.12%) of RSV infected children were medically free patients. Symptomatic patients exhibited various clinical manifestations, with ventilation necessary in (13.11%) of cases. Further analysis revealed significant changes in RSV-related outcomes post-COVID-19, including a decrease in hospitalization rates, an increase in medically free patients, and a lower need for ventilation (p < 0.05). Notably, a significant proportion of RSV admissions occurred within the first 6 months of life, with (77.69%) in the age group of 0 to 5 months. In addition, previous RSV infection, prematurity, low birth weight, renal disease, congenital heart disease, endocrine/metabolic disease, neuro/neuromuscular diseases, and genetic disorders were positively associated with hospitalization (P < 0.05). Interestingly, asthma and bone marrow transplantation were negatively associated with hospitalization (P < 0.05). The mortality rate in this study is (2.37%) (21/885). CONCLUSION: This study provides a comprehensive understanding of the demographic and clinical factors influencing RSV outcomes, highlighting the impact of the COVID-19 pandemic and shedding light on potential risk factors for RSV-related hospitalization. The highest prevalence of RSV during (September to January), aligning with global patterns and emphasizing the importance of timing in preventive strategies.

Omicron variants of SARS-CoV-2: Epidemiological and clinical insights from a tertiary care center in Saudi Arabia.

BACKGROUND: The actual burden of the Omicron variants remains unclear. Therefore, this study aims to analyze the epidemiological and clinical features of Omicron-infected patients and investigate factors influencing hospital admission. METHODS: This retrospective single-center study included individuals with positive SARS-CoV-2 infection, specifically the Omicron variants (XBB, EG or JN), identified through real-time reverse-transcriptase polymerase chain reaction assays from January 2022 to December 2023. RESULTS: A total of 305 Omicron-infected patients were included; (53.11 %) were females and (46.89 %) were males, with a median age of 39 years [interquartile range (IQR): 30, 53]. Underlying diseases, including endocrine/metabolic disorders (22.30 %), hypertension (12.79 %), chronic respiratory disease (10.49 %), and malignancy (9.18 %) were prevalent, while (40.98 %) were medically free. The XBB variant was predominant (73.11 %), followed by JN (20.33 %), and EG variant (6.56 %). The seasonality analysis demonstrates XBB variants' domination in 2022, with a surge to 40 cases in December. The trend continued in 2023, peaking at 76 XBB cases in March. May 2023 reported 38 XBB cases and the emergence of 17 EG instances. Notably, in December, only one XBB case was reported, and 62 instances emerged with the JN variant. Overall, 233 out of 305 cases were reported during flu season (September to March) (76.39 %). Moreover, hospitalization occurred in (16.39 %), with a (1.31 %) mortality rate (all deaths in the JN variant). Multivariable analysis confirmed renal disease, chronic respiratory disease, endocrine/metabolism issues, and polymicrobial infection as positive predictors of hospitalization (p < 0.05). While COVID-19 vaccination significantly reduced hospitalization odds (Odds Ratio: 0.20, p = 0.001). CONCLUSIONS: These findings contribute valuable insights into Omicron epidemiology and factors influencing hospitalization. The dynamic fluctuations in Omicron variants, particularly XBB, EG, and JN, over 2022 and 2023, with JN emerging as the dominant circulating variant globally, underscore the need for continuous vigilance and urgency for updated vaccine formulations.

Observational cohort study of perinatal outcomes of women with COVID-19.

BACKGROUND: Understanding the impact of SARS-CoV-2 infection on pregnancy outcomes and of pregnancy on COVID-19 outcomes is critical for ensuring proper prenatal and antenatal care. No similar studies have been published in Saudi Arabia. METHODS: We performed a prospective cohort study of pregnant women with confirmed SARS-CoV-2 infection who presented at King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh, Kingdom of Saudi Arabia. COVID-19 staging was performed, pregnancy-related complications were assessed, and neonatal infection was evaluated. RESULTS: We enrolled 81 patients (mean age 31.75 years, SD 5.25) of which there were 17 cases in the first trimester, 20 in the second trimester, and 34 in the third trimester. The distribution of COVID-19 severity was 40 patients with Stage A, 36 with Stage B, 4 with Stage C, and 1 with Stage D. Complications were pregnancy loss in 2 patients (one in each first and second trimester) and 1 fetal death after 20 weeks of pregnancy, 7 patients with fetal growth restriction, and 8 with pre-term delivery. CONCLUSIONS: We did not observe an unusual frequency of pregnancy-related complications due to SARS-CoV-2 infection in this high-risk obstetric population and there was no evidence of vertical transmission in newborns from women who delivered while positive for the virus.

Stenotrophomonas maltophilia bacteremia in children: risk factors and mortality rate.

PURPOSE: Stenotrophomonas maltophilia (S. maltophilia) is an opportunistic and nosocomial pathogen that can cause an invasive and fatal infection, particularly in hospitalized and immunocompromised patients. However, little is known about the impact of S. maltophilia bacteremia in pediatric patients. Therefore, we aimed to identify risk factors for mortality, antibiotics susceptibility to S. maltophilia, and mortality rates in pediatric patients with S. maltophilia bacteremia. METHODS: We conducted a retrospective cohort study by identifying all S. maltophilia positive blood cultures in the microbiology laboratory database between January 2007 and December 2018 from hospitalized pediatric patients (age 1-14 years). After identifying patients with S. maltophilia bacteremia, medical charts were reviewed for demographics, clinical data, and outcomes within seven days of bacteremia diagnosis. Risk factors associated with mortality in S. maltophilia bacteremia patients were determined using univariate and multivariate analyses. FINDINGS: Sixty-eight pediatric patients with S. maltophilia bacteremia were identified. All infections were nosocomial infections, and (88.2%) bacteremia cases were catheter-related bloodstream infections. On multivariate analysis, ICU admission prior to bacteremia episode and neutropenia were the major risk factors associated with mortality. S. maltophilia was the most susceptible to trimethoprim and sulfamethoxazole (TMP/SMX, 94.1%), followed by levofloxacin (85.7%). The overall mortality rate within seven days of S. maltophilia bacteremia diagnosis was 33.8%. CONCLUSION: S. maltophilia bacteremia is a devastating emerging infection associated with high mortality among hospitalized children. Therefore, early diagnosis and prompt management based on local susceptibility data are crucial. Various risk factors, especially ICU admission prior to bacteremia episode and neutropenia, are associated with S. maltophilia bacteremia mortality.

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.

Approach to recurrent Herpes Simplex Encephalitis in children.

Herpes Simplex Encephalitis (HSE) is one of the commonest viral encephalitis and its recurrence is being increasingly reported were HSE relapse rate came up to 5%. Both herpes simplex virus (HSV) types can lead to encephalitis and it was established that HSV-1 is capable of nervous system invasion, latency, and recurrence. The recurrence of HSE used to be attributed to immunological compromise, but reports show many cases have no obvious immune system impairment. Further investigations revealed genetic predispositions to HSV infection that would explain the host vulnerability to its recurrence. In this review, we discuss the gene mutations that may predispose to recurrent HSE and the importance of early diagnosis and treatment.

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

Guidelines for the secondary prevention of rheumatic heart disease: Endorsed by Saudi Pediatric Infectious Diseases Society (SPIDS).

Rheumatic fever is a rare yet serious condition develop as a consequence of throat infection caused by Streptococcus pyogenes. It is the leading cause for rheumatic heart disease. Rheumatic heart disease is a worldwide public health concern. It is a chronic condition that results in carditis, irreversible valve damage and heart failure in children and young adults living in low-income countries. The age of onset peaks between 5 and 15 years. Approximately, 3% of patients with untreated acute streptococcal sore throats develop rheumatic fever. Rheumatic fever and rheumatic heart disease can be prevented with appropriate antibiotics administration to prevent the progression of valve damage. The current use of primary and secondary prevention antibiotics in Saudi Arabia is not known. Therefore, this clinical practice guideline is developed, based on the best available evidence, to promote appropriate antibiotics secondary prophylaxis use for prevention of rheumatic heart disease.

Guidelines for palivizumab prophylaxis in infants and young children at increased risk for respiratory syncytial virus infection in Saudi Arabia.

Respiratory syncytial virus (RSV) is a leading cause of serious seasonal lower respiratory tract infections (LRTI) in high-risk infants and children, with epidemics occurring annually in Saudi Arabia from October to March. Premature infants born at less than 29 weeks gestation with chronic lung disease or those with significant congenital heart disease who have RSV infection are more likely to be hospitalized and have increased morbidity and mortality. Palivizumab (Synagis®, Medimmune) is a humanized monoclonal antibody for the prevention of severe LRTI by RSV in high-risk children. The current use of Palivizumab in Saudi Arabia is not regulated and does not meet approved standards. This clinical practice policy statement was developed by the Ministry of Health and is supported by the National Immunization Technical Advisory Group (NITAG) in Saudi Arabia. It is based on available national and international data on the use of Palivizumab for the prevention of severe LRTI caused by RSV in high-risk pediatric patients. These guidelines were solicited and endorsed by two Saudi societies: The Neonatology and the Pediatric Infectious Diseases Societies.

13-valent pneumococcal conjugate vaccine (PCV13) is immunogenic and safe in children 6-17 years of age with sickle cell disease previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23): Results of a phase 3 study.

BACKGROUND: A large population of older children with sickle cell disease (SCD) is currently vaccinated with only 23-valent pneumococcal polysaccharide vaccine (PPSV23). In immunocompetent adults, PPSV23 vaccination reduces immune responses to subsequent vaccination with a pneumococcal vaccine. The 13-valent pneumococcal conjugate vaccine (PCV13), which addresses this limitation, may offer an advantage to this population at high risk of pneumococcal disease. PROCEDURE: Children with SCD 6-17 years of age previously vaccinated with PPSV23 at least 6 months before study enrollment received two doses of PCV13 6 months apart. Anti-pneumococcal polysaccharide immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured before, 1 month after each administration, and 1 year after the second administration. RESULTS: Following each PCV13 administration, IgG GMCs and OPA GMTs significantly increased, and antibody levels after doses 1 and 2 were generally comparable. Antibody levels declined over the year following dose 2. At 1 year after the second administration, OPA GMTs for all and IgG GMCs for most serotypes remained above pre-vaccination levels. Most adverse events were due to vaso-occlusive crises, a characteristic of the underlying condition of SCD. CONCLUSIONS: Children with SCD who were previously vaccinated with PPSV23 responded well to 1 PCV13 dose, and a second dose did not increase antibody response. PCV13 antibodies persisted above pre-vaccination levels for all serotypes 1 year after dose 2. Children with SCD may benefit from at least one dose of PCV13.

Middle East respiratory syndrome coronavirus disease in children.

BACKGROUND: In the initial description of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, many affected patients were adults with underlying medical comorbidities. Data on the clinical presentation and outcome of pediatric cases are lacking. We report the clinical presentation and outcome of MERS-CoV infection in 11 pediatric patients. METHODS: The clinical presentation, demographic and laboratory data of pediatric patients with MERS-CoV were analyzed. RESULTS: A total of 11 pediatric cases that tested positive by screening and confirmatory polymerase chain reaction for MERS-CoV were reported from Saudi Arabia. Two patients were symptomatic and the other 9 cases were asymptomatic. The median age of patients was 13 (range 2-16) years. There were 8 females and 3 males (2.7:1 ratio). One symptomatic patient died and the other symptomatic patient recovered. The diagnosis of patients was based on positive nasopharyngeal swabs on 10 patients. CONCLUSIONS: MERS-CoV disease is not limited to adults. Most cases of childhood MERS-CoV infection were asymptomatic and tested positive during contact investigation of older patients. Severe disease can occur in children with underlying conditions.

Spread, circulation, and evolution of the Middle East respiratory syndrome coronavirus.

UNLABELLED: The Middle East respiratory syndrome coronavirus (MERS-CoV) was first documented in the Kingdom of Saudi Arabia (KSA) in 2012 and, to date, has been identified in 180 cases with 43% mortality. In this study, we have determined the MERS-CoV evolutionary rate, documented genetic variants of the virus and their distribution throughout the Arabian peninsula, and identified the genome positions under positive selection, important features for monitoring adaptation of MERS-CoV to human transmission and for identifying the source of infections. Respiratory samples from confirmed KSA MERS cases from May to September 2013 were subjected to whole-genome deep sequencing, and 32 complete or partial sequences (20 were ≥ 99% complete, 7 were 50 to 94% complete, and 5 were 27 to 50% complete) were obtained, bringing the total available MERS-CoV genomic sequences to 65. An evolutionary rate of 1.12 × 10(-3) substitutions per site per year (95% credible interval [95% CI], 8.76 × 10(-4); 1.37 × 10(-3)) was estimated, bringing the time to most recent common ancestor to March 2012 (95% CI, December 2011; June 2012). Only one MERS-CoV codon, spike 1020, located in a domain required for cell entry, is under strong positive selection. Four KSA MERS-CoV phylogenetic clades were found, with 3 clades apparently no longer contributing to current cases. The size of the population infected with MERS-CoV showed a gradual increase to June 2013, followed by a decline, possibly due to increased surveillance and infection control measures combined with a basic reproduction number (R0) for the virus that is less than 1. IMPORTANCE: MERS-CoV adaptation toward higher rates of sustained human-to-human transmission appears not to have occurred yet. While MERS-CoV transmission currently appears weak, careful monitoring of changes in MERS-CoV genomes and of the MERS epidemic should be maintained. The observation of phylogenetically related MERS-CoV in geographically diverse locations must be taken into account in efforts to identify the animal source and transmission of the virus.

Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study.

BACKGROUND: Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin. METHODS: Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85-95%, and four 30-50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done. FINDINGS: Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction. INTERPRETATION: We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed. FUNDING: Saudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre.

Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study.

BACKGROUND: Middle East respiratory syndrome (MERS) is a new human disease caused by a novel coronavirus (CoV). Clinical data on MERS-CoV infections are scarce. We report epidemiological, demographic, clinical, and laboratory characteristics of 47 cases of MERS-CoV infections, identify knowledge gaps, and define research priorities. METHODS: We abstracted and analysed epidemiological, demographic, clinical, and laboratory data from confirmed cases of sporadic, household, community, and health-care-associated MERS-CoV infections reported from Saudi Arabia between Sept 1, 2012, and June 15, 2013. Cases were confirmed as having MERS-CoV by real-time RT-PCR. FINDINGS: 47 individuals (46 adults, one child) with laboratory-confirmed MERS-CoV disease were identified; 36 (77%) were male (male:female ratio 3·3:1). 28 patients died, a 60% case-fatality rate. The case-fatality rate rose with increasing age. Only two of the 47 cases were previously healthy; most patients (45 [96%]) had underlying comorbid medical disorders, including diabetes (32 [68%]), hypertension (16 [34%]), chronic cardiac disease (13 [28%]), and chronic renal disease (23 [49%]). Common symptoms at presentation were fever (46 [98%]), fever with chills or rigors (41 [87%]), cough (39 [83%]), shortness of breath (34 [72%]), and myalgia (15 [32%]). Gastrointestinal symptoms were also frequent, including diarrhoea (12 [26%]), vomiting (ten [21%]), and abdominal pain (eight [17%]). All patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities. Laboratory analyses showed raised concentrations of lactate dehydrogenase (23 [49%]) and aspartate aminotransferase (seven [15%]) and thrombocytopenia (17 [36%]) and lymphopenia (16 [34%]). INTERPRETATION: Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities. Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition. FUNDING: None.

Impact of the revised penicillin susceptibility breakpoints for Streptococcus pneumoniae on antimicrobial resistance rates of meningeal and non-meningeal pneumococcal strains.

BACKGROUND AND OBJECTIVES: In January 2008, the Clinical Laboratory Standard Institute (CLSI) revised the Streptococcus pneumoniae breakpoints for penicillin to define the susceptibility of meningeal and non-meningeal isolates. We studied the impact of these changes. In addition, the pneumococcal resistance rate to other antimicrobial agents was reviewed. DESIGN AND SETTING: Laboratory data on peumococcal isolates collected retrospectively from hospitalized children in tertiary care hospital in Riyadh, Saudi Arabia from January 2006 to March 2012. PATIENTS AND METHODS: Only sterile samples were included from cerebrospinal fluids, blood, sterile body fluids and surgical tissue. Other samples such as sputum and non sterile samples were excluded. We included samples from children 14 years old or younger. The minimum inhibitory concentration (MIC) for penicillin, cefuroxime, ceftriaxone and meropenem were determined by using the E-test, while susceptibility to erythromycin, cotrimoxazole and vancomycin were measured using the disc diffusion methods following the guideline of CLSI. RESULTS: Specimens were analyzed in two different periods: from January 2006 to December 2007 and from January 2008 to March 2012. During the two periods there were 208 samples of which 203 were blood samples. Full penicillin resistance was detected in 6.6% in the first period. There was decrease in penicillin nonmeningeal resistance to 1.5% and an increase in resistance in penicillin meningeal 68.2% in the second period (P=.0001). There was an increase in rate of resistance among S pneumoniae isolates over the two periods to parenteral cefuroxime, erythromycin and cotrimoxazole by 34.6%, 35.5% and 51.9%, respectively. Total meropenem resistance found 4.3% and no vancomycin resistance was detected. CONCLUSIONS: The current study supports the use of the revised CLSI susceptibility breakpoints that promote using penicillin to treat nonmeningeal pneumococcal disease, and might slow the development of resistance to broader-spectrum antibiotics.

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.