A Novel STK4 Mutation Impairs T Cell Immunity Through Dysregulation of Cytokine-Induced Adhesion and Chemotaxis Genes.

PURPOSE: Human serine/threonine kinase 4 (STK4) deficiency is a rare, autosomal recessive genetic disorder leading to combined immunodeficiency; however, the extent to which immune signaling and host defense are impaired is unclear. We assessed the functional consequences of a novel, homozygous nonsense STK4 mutation (NM_006282.2:c.871C > T, p.Arg291*) identified in a pediatric patient by comparing his innate and adaptive cell-mediated and humoral immune responses with those of three heterozygous relatives and unrelated controls. METHODS: The genetic etiology was verified by whole genome and Sanger sequencing. STK4 gene and protein expression was measured by quantitative RT-PCR and immunoblotting, respectively. Cellular abnormalities were assessed by high-throughput RT-RCR, RNA-Seq, ELISA, and flow cytometry. Antibody responses were assessed by ELISA and phage immunoprecipitation-sequencing. RESULTS: The patient exhibited partial loss of STK4 expression and complete loss of STK4 function combined with recurrent viral and bacterial infections, notably persistent Epstein-Barr virus viremia and pulmonary tuberculosis. Cellular and molecular analyses revealed abnormal fractions of T cell subsets, plasmacytoid dendritic cells, and NK cells. The transcriptional responses of the patient's whole blood and PBMC samples indicated dysregulated interferon signaling, impaired T cell immunity, and increased T cell apoptosis as well as impaired regulation of cytokine-induced adhesion and leukocyte chemotaxis genes. Nonetheless, the patient had detectable vaccine-specific antibodies and IgG responses to various pathogens, consistent with a normal CD19 + B cell fraction, albeit with a distinctive antibody repertoire, largely driven by herpes virus antigens. CONCLUSION: Patients with STK4 deficiency can exhibit broad impairment of immune function extending beyond lymphoid cells.

COVID-19 related multisystem inflammatory syndrome in children (MIS-C): a case series from a tertiary care pediatric hospital in Qatar.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of coronavirus disease 2019 (COVID-19) in children, which is increasingly being reported worldwide. Here we report the first case series of 7 children diagnosed with MIS-C in Qatar. METHODS: Clinical features and outcomes of COVID-19 positive patients admitted to Sidra Medicine, Qatar from June to October 2020, who met the WHO case definition for MIS-C were reviewed. RESULTS: The mean age in our case series was 5.6 years, of which 71.4% were males. All patients were previously healthy but had a history of COVID-19 infection. Fever, rash, vomiting and abdominal pain were the most common symptoms (70-100%). The average hospitalization was 12.9 days with no case fatalities. Laboratory findings included lymphopenia and thrombocytopenia in most patients, as well as evidence of coagulopathy and elevated inflammatory markers such as C-reactive protein, ferritin and procalcitonin. Many patients (71.4%) required inotropic support in intensive care, while only one required respiratory support. Although all patients had elevated cardiac biomarkers, cardiovascular involvement was observed in 42.9% of patients with one patient developing a giant coronary aneurysm. All patients received intravenous immunoglobulin (IVIG) and 86% of patients received corticosteroids, with two patients requiring treatment with IL-1 inhibitors. CONCLUSIONS: Our report is one of the first reports on MIS-C from Asia. Although clinical features and outcomes are not significantly different from those reported elsewhere, lack of case fatalities in our cohort may indicate that early recognition and prompt medical attention is necessary for a favorable outcome in MIS-C.

Unusual accumulation of a wide array of antimicrobial resistance mechanisms in a patient with cytomegalovirus-associated hemophagocytic lymphohistiocytosis: a case report.

BACKGROUND: Infections with multidrug-resistant organisms (MDRO) pose a serious threat to patients with dysregulated immunity such as in hemophagocytic lymphohistiocytosis (HLH), but such infections have rarely been comprehensively characterized. Here, we present a fatal case of HLH secondary to cytomegalovirus (CMV) infection complicated by both anti-viral drug resistance and sepsis from multiple MDROs including pandrug-resistant superbug bacteria. CASE PRESENTATION: A previously healthy, six-year-old boy presented with a 45-day history of fever prior to a diagnosis of hemophagocytic lymphohistiocytosis and hemorrhagic colitis, both associated with CMV. On hospital admission, the patient was found to be colonized with multiple, multidrug-resistant (MDR) bacteria including vancomycin-resistant enterococci (VRE) and carbapenamase-producing organisms (CPO). He eventually developed respiratory, urine and bloodstream infections with highly drug-resistant, including pandrug-resistant bacteria, which could not be controlled by antibiotic treatment. Antiviral therapy also failed to contain his CMV infection and the patient succumbed to overwhelming bacterial and viral infection. Whole genome sequencing (WGS) of the MDR bacteria and metagenomic analysis of his blood sample revealed an unusual accumulation of a wide range of antimicrobial resistance mechanisms in a single patient, including antiviral resistance to ganciclovir, and resistance mechanisms to all currently available antibiotics. CONCLUSIONS: The case highlights both the risk of acquiring MDR superbugs and the severity of these infections in HLH patients.

Peritoneal Dialysis-Associated Peritonitis Caused by Mycobacterium abscessus in Children-A Case Report.

Peritoneal dialysis (PD)-associated peritonitis constitutes a major complication associated with the procedure. PD-associated peritonitis caused by nontuberculous mycobacteria, usually as a result of an infection related to the PD catheter, has been reported in adults and is associated with significant complications and poor outcome. The management of PD-associated peritonitis caused by Mycobacterium abscessus is particularly challenging because this species is resistant to many antimicrobials commonly used to treat mycobacterial species. We present here the second reported case of PD-associated peritonitis caused by M. abscessus in children. Our patient was a 9-year-old boy with end-stage renal disease (ESRD) who presented with suspected peritonitis, and his PD fluid cultures eventually grew M. abscessus. The patient received a 3-week course of triple therapy with clarithromycin, amikacin, and meropenem in addition to PD catheter removal. The infection completely resolved even though a susceptibility report at the end of treatment revealed that the isolate was resistant to clarithromycin and had decreased susceptibility to carbapenems. Our observations suggest that PD catheter removal is important in PD-associated peritonitis caused by M. abscessus in children and that more studies are needed to define the optimal length of treatment.

A metagenomics-based diagnostic approach for central nervous system infections in hospital acute care setting.

The etiology of central nervous system (CNS) infections such as meningitis and encephalitis remains unknown in a large proportion of cases partly because the diversity of pathogens that may cause CNS infections greatly outnumber available test methods. We developed a metagenomic next generation sequencing (mNGS)-based approach for broad-range detection of pathogens associated with CNS infections suitable for application in the acute care hospital setting. The analytical sensitivity of mNGS performed on an Illumina MiSeq was assessed using simulated cerebrospinal fluid (CSF) specimens (n = 9). mNGS data were then used as a training dataset to optimize a bioinformatics workflow based on the IDseq pipeline. For clinical validation, residual CSF specimens (n = 74) from patients with suspected CNS infections previously tested by culture and/or PCR, were analyzed by mNGS. In simulated specimens, the NGS reads aligned to pathogen genomes in IDseq were correlated to qPCR CT values for the respective pathogens (R = 0.96; p < 0.0001), and the results were highly specific for the spiked pathogens. In clinical samples, the diagnostic accuracy, sensitivity and specificity of the mNGS with reference to conventional methods were 100%, 95% and 96%, respectively. The clinical application of mNGS holds promise to benefit patients with CNS infections of unknown etiology.

Epidemiology of neonatal meningitis in Qatar.

OBJECTIVE: Neonatal meningitis is responsible for thousands of neonatal deaths annually all over the world. Our study was conducted to determine the epidemiology, management and best preventive measures for neonatal meningitis in Qatar. METHODS: A retrospective study reviewed the records of bacterial meningitis patients under the age of one month. The study was carried out at Hamad Medical Hospital, the only hospital that provides health care at Qatar and the study period was between January 1998 to December 2000. RESULTS: Thirteen patients were included. Sixty percent of patients had early onset meningitis. Causative organisms were group B Streptococcus pneumoniae, Klebsiella pneumonia, Pseudomonas species, Neisseria meningitidis, Staphylococcus epidermidis and Flavibacterium meningococcus septicum. A bacterial resistance to the usual combination of ampicillin and gentamicin were noticed (as initial treatment before culture sensitivity results), which affected negatively on some patients. Complications of cerebral palsy, mental retardation and epilepsy occurred in 3 patients (23%). None of the patients died during the study period. CONCLUSION: Emphasis is placed on the importance of correct early diagnosis and appropriate antibiotic therapy. It is suggested that the identification and appropriate treatment of any maternal bacterial infection is an important measure in preventing neonatal sepsis and meningitis.

Clinical presentation of acute bacterial meningitis in Qatar.

OBJECTIVE: To study the changes in the epidemiology of bacterial meningitis in the era of the Hemophilus influenzae (H. influenzae) type b vaccine and pneumoccous resistance. METHODS: Retrospective study which included patients admitted to Hamad Medical Corporation, Doha, Qatar between January 1998 through to December 2000 with positive cerebrospinal fluid culture. RESULTS: Thirty-seven patients with culture proven bacterial meningitis were described. Streptococcus pneumoniae (S. pneumoniae) and H. influenzae were the most common organisms, accounting for 30% and 24% of cases. Fever, neck stiffness, vomiting, and bulging fontanel were the most frequent presenting features. Fifty four percent of S. pneumoniae isolates were resistant to penicillin, and 22% of H. influenzae were resistant to ampicillin, but both were sensitive to ceftriaxone. No cases of Listeria monocytogenes meningitis were diagnosed. Morbidity was 32%, and mortality 5%. Poor outcome was associated with altered mental status on admission. CONCLUSION: Bacterial meningitis is a serious illness in our community with significant morbidity and mortality. Streptococcus pneumoniae and H. influenzae are the most frequent pathogens causing meningitis in our community. As there is no bacterial resistance (S. pneumoniae and H. influenzae) reported against ceftrixone, we recommend ceftriaxone alone as empiric therapy for patients with no comorbid conditions presenting with community acquired bacterial meningitis. A continuous surveillance for changes in the microbiology of organisms causing bacterial meningitis or their sensitivity in our community is essential to update these recommendations.

Epidemiology of neonatal meningitis in Qatar.

OBJECTIVE: Neonatal meningitis is responsible for thousands of neonatal deaths annually all over the world. Our study was conducted to determine the epidemiology, management and best preventive measures for neonatal meningitis in Qatar. METHODS: A retrospective study reviewed the records of bacterial meningitis patients under the age of one month. The study was carried out at Hamad Medical Hospital, the only hospital that provides health care at Qatar and the study period was between January 1998 to December 2000. RESULTS: Thirteen patients were included. Sixty percent of patients had early onset meningitis. Causative organisms were group B Streptococcus pneumoniae, Klebsiella pneumonia, Pseudomonas species, Neisseria meningitidis, Staphylococcus epidermidis and Flavibacterium meningococcus septicum. A bacterial resistance to the usual combination of ampicillin and gentamicin were noticed (as initial treatment before culture sensitivity results), which affected negatively on some patients. Complications of cerebral palsy, mental retardation and epilepsy occurred in 3 patients (23%). None of the patients died during the study period. CONCLUSION: Emphasis is placed on the importance of correct early diagnosis and appropriate antibiotic therapy. It is suggested that the identification and appropriate treatment of any maternal bacterial infection is an important measure in preventing neonatal sepsis and meningitis.