Manuka honey activates the aryl hydrocarbon receptor: Implications for skin inflammation.

Manuka honey (MH) is a complex nutritional material with antimicrobial, antioxidant and anti-inflammatory activity. We have previously shown that MH down regulates IL-4-induced CCL26 expression in immortalized keratinocytes. As MH contains potential ligands of the Aryl Hydrocarbon Receptor (AHR), a key regulator of skin homeostasis, we hypothesize that this effect is mediated via AHR activation. Here, we treated HaCaT cell lines, either stable transfected with an empty vector (EV-HaCaT) or in which AHR had been stable silenced (AHR-silenced HaCaT); or primary normal human epithelial keratinocytes (NHEK) with 2% MH for 24 h. This induced a 15.4-fold upregulation of CYP1A1 in EV-HaCaTs, which was significantly reduced in AHR-silenced cells. Pre-treatment with the AHR antagonist CH223191 completely abrogated this effect. Similar findings were observed in NHEK. In vivo treatment of the Cyp1a1Cre x R26ReYFP reporter mice strain's skin with pure MH significantly induced CYP1A1 expression compared with Vaseline. Treatment of HaCaT with 2% MH significantly decreased baseline CYP1 enzymatic activity at 3 and 6 h but increased it after 12 h, suggesting that MH may activate the AHR both through direct and indirect means. Importantly, MH downregulation of IL-4-induced CCL26 mRNA and protein was abrogated in AHR-silenced HaCaTs and by pre-treatment with CH223191. Finally, MH significantly upregulated FLG expression in NHEK in an AHR-dependent manner. In conclusion, MH activates AHR, both in vitro and in vivo, thereby providing a mechanism of its IL4-induced CCL26 downregulation and upregulation of FLG expression. These results have potential clinical implications for atopic diseases and beyond.

Case report: Durable response to ruxolitinib in a child with TREX1-related disorder.

Background: JAK inhibitors are useful in treating interferonopathies, presumably because they downregulate the JAK/STAT signaling. There are limited studies about the safety and effectiveness of using JAK inhibitors in children with TREX1-related disorders. Case presentation: We report an 8-year-old female who presented at five years of age with features suggestive of hemophagocytic lymphohistiocytosis (HLH)-like disorder. The infectious disease workup was negative. Neurological assessment was normal. A brain CT scan was performed because of headache. It showed a faint subcortical calcification at right frontal lobe and almost symmetrical calcification within the basal ganglia. Brain MRI showed bilateral symmetrical globus pallidus, high T1 signal intensities, and a few scattered nonspecific FLAIR hyperintensities in subcortical and deep white matter. IVIG as an immune modulating agent was administered initially which led to the resolution of fever, improvement of blood count parameters, inflammatory markers, and normalization of liver enzymes. The child remained afebrile with no significant events for several months, then had disease flare up. The patient was started on pulse methylprednisolone 30 mg/kg for three days, then continued on 2 mg/kg. Whole exome sequencing revealed a novel heterozygous missense TREX1 mutation NM_016381.3:c.223G > A p.(Glu75Lys). The child was started on ruxolitinib, 5 mg orally twice daily. The child has prolonged, durable remission after initiating ruxolitinib with no adverse effects. Steroids were tapered off and the patient is no longer on IVIG. The patient is still on ruxolitinib for more than two years. Conclusion: This case highlights the potential role of ruxolitinib in the treatment of TREX1-related disorders. A longer follow-up period is required to evaluate the long-term outcome.

Immune dysregulation caused by homozygous mutations in CBLB.

CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient's cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. CblbH257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and CblbH257L mice were resistant to suppression by WT Tregs. Bone marrow-derived mast cells from CblbH257L mice were hyperactivated after FcεRI cross-linking, and CblbH257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.

The burden of asthma among children and adolescents in Saudi Arabia: A national cross-sectional survey.

Background: Asthma disease is one of the most common chronic diseases of childhood. Studies assessing asthma prevalence in Saudi Arabia have been variable and not recently updated. Objectives: We sought to assess asthma prevalence, severity, and related risk factors among children and adolescents in Saudi Arabia. Methods: A national, cross-sectional design was used following the Global Asthma Network phase I design. A total of 3817 children aged 6 to 7 years and 4138 adolescents aged 13 to 14 years were recruited from 137 primary and 140 intermediate schools across 20 regions by using a multistage stratified cluster sampling technique. Standardized written questionnaires were answered by the adolescents and by the parents or guardians of the children. The adolescents also answered a video-based questionnaire. Results: Overall, the prevalences of current wheeze were 10.4% and 13.3% and the prevalences of asthma ever were 13.8% and 15.7%, % in children and adolescents, respectively. Of all the children and adolescents, 5.2% and 5.6% had symptoms of severe asthma, respectively. Among those who reported asthma, 86.0% of the children and 74.8% of the adolescents had their asthma confirmed by a doctor, and 53.0% and 32.4%, respectively, were provided with a written plan to control their asthma. The main risk factors associated with current wheeze included antibiotic use in the first year of life, a history of being diagnosed with pneumonia in children, paracetamol use, and having a cat at home during the past 12 months in adolescents. Conclusions: The prevalence of asthma in children and adolescents in Saudi Arabia is within the average international range and is at a plateau phase.

The Saudi Initiative for Asthma - 2021 Update: Guidelines for the diagnosis and management of asthma in adults and children.

The Saudi Initiative for Asthma 2021 (SINA-2021) is the fifth version of asthma guidelines for the diagnosis and management of asthma for adults and children, which is developed by the SINA group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is aligned for age groups: adults, adolescents, children aged 5-12 years, and children aged less than 5 years. SINA guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with the integration of recommendations related to biologic agents, evidence-based updates on treatment, and the role of immunotherapy in management. Medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and the current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.

Multiple Family Members With Delayed Cord Separtion and Combined Immunodeficiency With Novel Mutation in IKBKB.

Background: Inhibitor of kappa kinase 2 (IKK2) deficiency is a recently described combined immunodeficiency. It undermines the nuclear factor-kappa B (NF-κB) activation pathway. Methods: The clinical and immunological data of four patients diagnosed with combined immunodeficiency (CID) from two related Saudi families were collected. Autozygosity mapping of all available members and whole exome sequencing of the index case were performed to define the genetic etiology. Results: The patients had early onset (2-4 months of age) severe infections caused by viruses, bacteria, mycobacteria, and fungi. They all had hypogammaglobulinemia and low absolute lymphocyte count. Their lymphocytes failed to respond to PHA mitogen stimulation. A novel homozygous non-sense mutation in the IKBKB gene, c.850C>T (p. Arg284*) was identified in the index patient and segregated with the disease in the rest of the family. He underwent hematopoietic stem cell transplantation (HSCT) from a fully matched sibling with no conditioning. The other three patients succumbed to their disease. Interestingly, all patients had delayed umbilical cord separation. Conclusion: IKK2 deficiency causes CID with high mortality. Immune reconstitution with HSCT should be considered as early as possible. Delayed umbilical cord separation in CID patients may be a clue to IKK2 deficiency.

JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency.

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).

The Saudi Initiative for Asthma - 2019 Update: Guidelines for the diagnosis and management of asthma in adults and children.

This is the fourth version of the updated guidelines for the diagnosis and management of asthma, developed by the Saudi Initiative for Asthma (SINA) group, a subsidiary of the Saudi Thoracic Society. The main objective of the SINA is to have guidelines that are up to date, simple to understand, and easy to use by healthcare workers dealing with asthma patients. To facilitate achieving the goals of asthma management, the SINA panel approach is mainly based on the assessment of symptom control and risk for both adults and children. The approach to asthma management is now more aligned for different age groups. The guidelines have focused more on personalized approaches reflecting better understanding of disease heterogeneity with integration of recommendations related to biologic agents, evidence-based updates on treatment, and role of immunotherapy in management. The medication appendix has also been updated with the addition of recent evidence, new indications for existing medication, and new medications. The guidelines are constructed based on the available evidence, local literature, and current situation at national and regional levels. There is also an emphasis on patient-doctor partnership in the management that also includes a self-management plan.

Admission predictability of children with acute asthma.

OBJECTIVES: We aimed to evaluate the seasonal variations of acute asthma presentation in children and the utility of the pediatric asthma score (PAS) and its components in early admission prediction. METHODS: As part of a randomized controlled trial addressing the clinical efficacy of budesonide nebulization in the treatment of acute asthma in children, the PAS was measured at baseline, 1st, 2nd, 3rd, and 4th h from the start of medications. Decision of admission was taken at or beyond the 2nd h. RESULTS: Out of a total 906 emergency department (ED) visits with moderate-to-severe acute asthma, 157 children were admitted. June to September had the lowest number of visits. The admission-to-discharge ratio varied throughout the year. During the ED stay, between baseline and 3rd h, admission predictability of the total score improved progressively with a small difference between the 2nd and 3rd h. The total score remained the strongest predictor of admission at every time point compared to its individual components. The drop of PAS from baseline to the 2nd h was not a good predictor of admission. Oxygen saturation (OS) and respiratory rate (RR) had relatively higher predictability than other components. CONCLUSIONS: Decision of admission could be made to many children with moderate-to-severe acute asthma at the 2nd h of ED stay based on their total PAS. OS and RR should be part of any scoring system to evaluate acute asthma in children.

Hyperglycemia in Children Hospitalized with Acute Asthma.

Hyperglycemia is frequently observed in adults with acute asthma. We aimed to assess the frequency of hyperglycemia and its relation to outcomes in children admitted with acute asthma. In this retrospective study, we reviewed medical records of non-diabetic 166 children (66 girls) with the mean age of 5.4 ± 2.6 years (range of 2-12 years), who were hospitalized with acute asthma between January 2012 through December 2014. Data pertaining to demographics, vital signs, oxygen saturation, serum blood glucose level, electrolytes, blood gases, and admission were collected. Children with other chronic conditions were excluded. The findings were that hyperglycemia (blood glucose ≥ 11.1 mmol/l) was observed in 38.6% of children. The median baseline blood glucose (IQR) was 9.8 mmol/l (7.2-13.3 mmol/l). Blood glucose level was associated with the length of hospitalization, with a median extension of 1.8 days, but was inversely associated with the serum potassium and bicarbonate levels. There were no associations between baseline blood glucose and age, gender, baseline respiratory rate, oxygen saturation, or intensive care admission. Hyperglycemia resolved spontaneously in all affected children. We conclude that hyperglycemia is common in children hospitalized with acute asthma. Hyperglycemia could be considered as a marker of a longer hospital stay.

Honey is potentially effective in the treatment of atopic dermatitis: Clinical and mechanistic studies.

INTRODUCTION: As manuka honey (MH) exhibits immunoregulatory and anti-staphylococcal activities, we aimed to investigate if it could be effective in the treatment of atopic dermatitis (AD). METHODS: Adult volunteers with bilateral AD lesions were asked to apply MH on one site overnight for seven consecutive days and leave the contralateral site untreated as possible. Three Item Severity score was used to evaluate the response. Skin swabs were obtained from both sites before and after treatment to investigate the presence of staphylococci and enterotoxin production. In addition, the ability of MH and its methanolic and hexane extracts to down regulate IL4-induced CCL26 protein release from HaCaT cells was evaluated by enzyme linked immunosorbent assay. Also, the ability of MH to modulate calcium ionophore-induced mast cell degranulation was assessed by enzyme immunoassay. RESULTS: In 14 patients, AD lesions significantly improved post MH treatment versus pre-treatment as compared to control lesions. No significant changes in the skin staphylococci were observed after day 7, irrespective of honey treatment. Consistent with the clinical observation, MH significantly down regulated IL4-induced CCL26 release from HaCaT cells in a dose-dependent manner. This effect was partially lost, though remained significant, when methanolic and hexane extracts of MH were utilized. In addition, mast cell degranulation was significantly inhibited following treatment with MH. CONCLUSIONS: MH is potentially effective in the treatment of AD lesions based on both clinical and cellular studies through different mechanisms. This needs to be confirmed by randomized and controlled clinical trials.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort.

PURPOSE: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. METHODS: Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes. RESULTS: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. CONCLUSION: Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.Genet Med 18 7, 686-695.

The effect of sand storms on acute asthma in Riyadh, Saudi Arabia.

OBJECTIVE: Major sand storms are frequent in the Middle East. This study aims to investigate the role of air particulate matter (PM) level in acute asthma in children in Riyadh, Saudi Arabia. METHODS: An aerosol spectrometer was used to evaluate PM < 10µm in diameter (PM10) and PM < 2.5 µm in diameter (PM2.5) concentrations in the air every 30 minutes throughout February and March 2012 in Riyadh. Data on children 2-12 years of age presenting to the emergency department of a major children's hospital with acute asthma during the same period were collected including their acute asthma severity score. RESULTS: The median with interquartile range (IQR) levels of PM10 and PM2.5 were 454 µg/m(3) (309,864) and 108 µg/m(3) (72,192) respectively. There was no correlation between the average daily PM10 levels and the average number of children presenting with acute asthma per day (r = -0.14, P = 0.45), their daily asthma score (r = 0.014, P = 0.94), or admission rate ( r= -0.08, P = 0.65). This was also true for average daily PM2.5 levels. In addition, there was no difference in these variables between days with PM10 >1000 µg/m(3), representing major sand storms, plus the following 5 days and other days with PM10< 1000 µg/m(3). CONCLUSION: Sand storms, even major ones, had no significant impact on acute asthma exacerbations in children in Riyadh, Saudi Arabia. The very high levels of PM, however, deserve further studying especially of their long-term effects.

Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA.

BACKGROUND: A number of heritable immune dysregulatory diseases result from defects affecting regulatory T (Treg) cell development, function, or both. They include immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which is caused by mutations in forkhead box P3 (FOXP3), and IPEX-like disorders caused by mutations in IL-2 receptor α (IL2RA), signal transducer and activator of transcription 5b (STAT5b), and signal transducer and activator of transcription 1 (STAT1). However, the genetic defects underlying many cases of IPEX-like disorders remain unknown. OBJECTIVE: We sought to identify the genetic abnormalities in patients with idiopathic IPEX-like disorders. METHODS: We performed whole-exome and targeted gene sequencing and phenotypic and functional analyses of Treg cells. RESULTS: A child who presented with an IPEX-like syndrome and severe Treg cell deficiency was found to harbor a nonsense mutation in the gene encoding LPS-responsive beige-like anchor (LRBA), which was previously implicated as a cause of common variable immunodeficiency with autoimmunity. Analysis of subjects with LRBA deficiency revealed marked Treg cell depletion; profoundly decreased expression of canonical Treg cell markers, including FOXP3, CD25, Helios, and cytotoxic T lymphocyte-associated antigen 4; and impaired Treg cell-mediated suppression. There was skewing in favor of memory T cells and intense autoantibody production, with marked expansion of T follicular helper and contraction of T follicular regulatory cells. Whereas the frequency of recent thymic emigrants and the differentiation of induced Treg cells were normal, LRBA-deficient T cells exhibited increased apoptosis and reduced activities of the metabolic sensors mammalian target of rapamycin complexes 1 and 2. CONCLUSION: LRBA deficiency is a novel cause of IPEX-like syndrome and Treg cell deficiency associated with metabolic dysfunction and increased apoptosis of Treg cells.

Corticosteroids in the treatment of acute asthma.

Asthma is a prevalent chronic disease of the respiratory system and acute asthma exacerbations are among the most common causes of presentation to the emergency department (ED) and admission to hospital particularly in children. Bronchial airways inflammation is the most prominent pathological feature of asthma. Inhaled corticosteroids (ICS), through their anti-inflammatory effects have been the mainstay of treatment of asthma for many years. Systemic and ICS are also used in the treatment of acute asthma exacerbations. Several international asthma management guidelines recommend the use of systemic corticosteroids in the management of moderate to severe acute asthma early upon presentation to the ED. On the other hand, ICS use in the management acute asthma has been studied in different contexts with encouraging results in some and negative in others. This review sheds some light on the role of systemic and ICS in the management of acute asthma and discusses the current evidence behind their different ways of application particularly in relation to new developments in the field.

Budesonide nebulization added to systemic prednisolone in the treatment of acute asthma in children: a double-blind, randomized, controlled trial.

BACKGROUND: Inhaled corticosteroids, known to be effective as a maintenance medication in chronic asthma, have also been suggested as a therapy for acute asthma when given at high doses. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in children aged 2 to 12 years with moderate or severe acute asthma, as determined based on a clinical score of 5 to 15 points, where 15 is the most severe. We compared the addition of budesonide 1,500 µg vs placebo to standard acute asthma treatment, which included salbutamol, ipratropium bromide, and a single dose of prednisolone 2 mg/kg given at the beginning of therapy. The primary outcome was hospital admission rate within 4 h. RESULTS: A total of 906 ED visits by children with moderate or severe acute asthma were evaluated. Seventy-five cases out of 458 (16.4%) in the budesonide group vs 82 of 448 (18.3%) in the placebo group were admitted (OR, 0.84; 95% CI, 0.58-1.23; P=.38). However, among cases with high baseline clinical score (≥13), significantly fewer children were admitted in the budesonide group (27 of 76 [35.5%]) than in the placebo group (39 of 73 [53.4%]; OR, 0.42; 95% CI, 0.19-0.94; P=.03). CONCLUSIONS: The addition of budesonide nebulization did not decrease the admission rate of children with acute asthma overall. However, it may decrease the admission rate of children with severe acute asthma. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01524198; URL: www.clinicaltrials.gov

Menetrier`s disease in a Saudi child.

Menetrier`s disease is a rare form of acquired gastropathy that presents mostly during adulthood, but is extremely rare in children. It is a clinicopathological diagnosis that typically presents with abdominal pain, vomiting, and edema secondary to hypoalbuminemia. Endoscopy usually shows giant gastric mucosal folds, and gastric biopsy shows foveolar hyperplasia and decreased oxyntic glands. Here, we describe a 5-year-old boy from Saudi Arabia with typical presentation of Menetrier`s disease and serological evidence of acute cytomegalovirus infection.

A novel homozygous mutation in G6PC3 presenting as cyclic neutropenia and severe congenital neutropenia in the same family.

PURPOSE: Patients with autosomal recessive cyclic neutropenia have no known causative genetic defect yet. METHODS: Autozygosity mapping on two branches of an extended multiplex consanguineous family presenting with cyclic neutropenia or severe congenital neutropenia to look for candidate gene, followed by candidate gene selection and sequencing. RESULTS: A single autozygous interval on Chr17:33,901,938-45,675,414 that is exclusively shared by the affected members was identified. This interval spans 11.8 Mb and contains 30 genes. Review of these genes highlighted G6PC3 as the most likely candidate given its known role in neutrophil biology. Direct sequencing revealed a novel homozygous mutation (NM_138387.3, c.974T > G, p.Leu325Arg). Two of our patients had associated congenital defects that are known to occur in patients with G6PC3 mutations, including congenital heart disease and intermittent thrombocytopenia. CONCLUSION: Biallelic G6PC3 defects should be considered in patients with autosomal recessive cyclic neutropenia, especially those with typical associated congenital defects.