Disseminated Enterovirus Infection Complicated by Rhabdomyolysis in a Child with Acute Lymphoblastic Leukemia.

Enterovirus is not a common cause of myositis and rhabdomyolysis in children. We report a case of a two-year-old boy with acute lymphoblastic leukemia with disseminated enterovirus infection complicated by hepatitis, myositis, and rhabdomyolysis. The case was managed successfully with supportive care and high-dose intravenous immunoglobulins.

Evaluation of cardiac fibrosis and subclinical cardiac changes in children with sickle cell disease using magnetic resonance imaging, echocardiography, and serum galectin-3.

BACKGROUND: Myocardial fibrosis has recently been proposed as one of the contributing factors to the diverse pathogenicity of cardiomyopathy in sickle cell disease. OBJECTIVE: In this study, cardiac fibrosis and subclinical cardiac changes in children with sickle cell disease were evaluated using cardiac magnetic resonance imaging (MRI), tissue Doppler echocardiography and serum galectin-3. MATERIALS AND METHODS: The study included 34 children with sickle cell disease who were compared with a similar number of healthy controls. Cardiac MRI was used to evaluate late gadolinium enhancement, native T1 mapping, extracellular volume, and T2* for estimation of iron load. Cardiac function and myocardial performance index (MPI, evaluated by tissue Doppler echocardiography) and serum galectin-3 were compared to controls. RESULTS: The mean age of the included patients was 13.3 ± 3.2 years. Myocardial iron load by T2* was normal. The mean level of extracellular volume (35.41 ± 5.02%) was significantly associated with the frequency of vaso-occlusive crises (P = 0.017) and negatively correlated with hemoglobin levels (P = 0.005). Galectin-3 levels were significantly higher among cases than controls (P = 0.00), at a cutoff value on the receiver operating characteristic curve of 6.5 ng/ml, sensitivity of 82.5% and specificity of 72.8%. The extracellular volume was significantly higher in cases, with a MPI > 0.4. CONCLUSION: Diffuse interstitial myocardial fibrosis can be detected early in children with sickle cell disease using T1 mapping and is associated with a high frequency of vaso-occlusive crisis. MPI of the left ventricle and serum galectin-3 are recommended screening tools for subclinical cardiac abnormalities.

Chronic Disseminated Candidiasis in Children and the Role of Corticosteroids Therapy.

BACKGROUND: Little is known about chronic disseminated candidiasis (CDC) in children. This study was done to describe the epidemiology, risk factors and outcome of CDC in children managed at Sultan Qaboos University Hospital (SQUH), Oman, and to describe the role of corticosteroids in the management of immune reconstitution inflammatory syndrome (IRIS) complicating CDC. METHODS: We retrospectively reported demographic, clinical and laboratory data of all children managed in our center for CDC between January 2013 and December 2021. In addition, we discuss the available literature on the role of corticosteroids for management of CDC-related IRIS in children since 2005. RESULTS: Between January 2013 and December 2021, 36 immunocompromised children were diagnosed with invasive fungal infection at our center, of whom 6 had CDC (all with acute leukemia). Their median age was 5.75 years. Prolonged fever despite broad-spectrum antibiotics (6/6) followed by skin rash (4/6) were the most common clinical features of CDC. Four children grew Candida tropicalis from blood or skin. CDC-related IRIS was documented in 5 children (83%) and 2 received corticosteroids. Our literature review revealed that 28 children were managed with corticosteroids for CDC-related IRIS since 2005. The majority of these children had defervescence of fever within 48 hours. Prednisolone of 1-2 mg/kg/day for 2-6 weeks was the most common regimen used. No major side effects reported in these patients. CONCLUSION: CDC is more common in children with acute leukemia and CDC-related IRIS is not uncommon. Corticosteroid therapy looks effective and safe as adjunctive therapy for CDC-related IRIS.

Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency-causing KNG1 variants, and estimated prevalence.

BACKGROUND: Severe high-molecular-weight kininogen (HK) deficiency is a poorly studied autosomal recessive contact system defect caused by pathogenic, biallelic KNG1 variants. AIM: We performed the first comprehensive analysis of diagnostic, clinical, genetic, and epidemiological aspects of HK deficiency. METHODS: We collected clinical information and blood samples from a newly detected HK-deficient individual and from published cases identified by a systematic literature review. Activity and antigen levels of coagulation factors were determined. Genetic analyses of KNG1 and KLKB1 were performed by Sanger sequencing. The frequency of HK deficiency was estimated considering truncating KNG1 variants from GnomAD. RESULTS: We identified 48 cases of severe HK deficiency (41 families), of these 47 have been previously published (n = 19 from gray literature). We genotyped 3 cases and critically appraised 10 studies with genetic data. Ten HK deficiency-causing variants (one new) were identified. All of them were truncating mutations, whereas the only known HK amino acid substitution with a relevant phenotype instead causes hereditary angioedema. Conservative estimates suggest an overall prevalence of severe HK deficiency of approximately one case per 8 million population, slightly higher in Africans. Individuals with HK deficiency appeared asymptomatic and had decreased levels of prekallikrein and factor XI, which could lead to misdiagnosis. CONCLUSION: HK deficiency is a rare condition with only few known pathogenic variants. It has an apparently good prognosis but is prone to misdiagnosis. Our understanding of its clinical implications is still limited, and an international prekallikrein and HK deficiency registry is being established to fill this knowledge gap.

Hermansky-Pudlak Syndrome: Spectrum in Oman.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, characterized by oculocutaneous albinism, a hemorrhagic diathesis secondary to storage pool-deficient platelets, and in some patients' pulmonary fibrosis, granulomatous colitis, and immunodeficiency. To date, 11 different types of Hermansky-Pudlak syndrome were identified. HPS type 2 is distinctively characterized by severe neutropenia and recurrent sinopulmonary infections. HPS is more common in Puerto Rico, and this is the first report deciphering the genotypic spectrum of HPS in Oman. Between 2001 and 2021, 8 Omani cases with HPS (3 HPS type 2, 1 HPS type 3, and 4 HPS type 6) had been suspected clinically and confirmed through genetic mutation analysis. Patients had mild hemorrhagic phenotype, and variable platelet aggregation defects with different platelet agonists. All patients had characteristic eye manifestations. In addition, patients with HPS type 2 had severe neutropenia. Novel mutations in AP3B1(c.205-1G>C, c.12_13delTA (p.Asn4Lysfs*6) and HPS6 (c.19_20delCT (p. Leu7Alafs*168) were not reported in population variant databases. Diagnosis of HPS had markedly improved in Oman; however, increased clinician awareness is needed. A high index of suspicion and early referral for diagnosis and initiation of proper treatment might help improve outcomes.

Disseminated Adenoviral Infection Complicated by Fatal Hemorrhagic Enterocolitis in a Child with Acute Myeloid Leukemia.

Adenovirus infections are common and self-limiting in young children except those with compromised cellular immunity. However, serious adenovirus infections are rare in children with acute leukemia. We report a rare case of a toddler with acute myeloid leukemia who developed a disseminated adenoviral infection complicated by hemorrhagic enterocolitis and septic shock that led to a fatal outcome.

Cardio-protective effect of regular transfusion in children with non-transfusion dependent thalassemia (NTDT): A cohort study.

BACKGROUND AND AIM OF THE WORK: Cardiac complications occur in patients with non-transfusion dependent thalassemia (NTDT). The study aimed to evaluate transfusion effect on systolic and diastolic cardiac function in young NTDT patients.  Methods:  Study design: Cohort study. Seventeen regularly-transfused patients with NTDT (12.5±5.3 years; group 1) and 15 none/minimally transfused patients (13.2±4.8 years; group 2) were followed up for 5 years and compared as regards their clinical parameters, echocardiographic and Tissue-Doppler-Imaging. RESULTS: Group 2 patients had significantly higher peak late-diastolic velocity of the left-ventricular-inflow Doppler (Am). Mitral-valve A-wave duration/pulmonary-veins, A-wave duration-ratio and pulmonary-vein S/D velocities-ratio were larger in group 2 as well (p = < 0.01). The diameters of right and left outflow-tract were larger with a higher cardiac-index in patients of group 2. Systolic-function was similar in the 2 studied groups. CONCLUSION: Diastolic function assessment revealed indicators of an abnormal relaxation of left-ventricle in non-transfused patients, which suggests a diastolic dysfunction. An increase in the diameter of the outflow-tract is likely attributed to high cardiac-output status in non-transfused NTDT patients as they have a higher cardiac index. Early start of regular transfusion for NTDT patients might prevent serious long-term cardiac complications.

Incorporation of Evidence-based Guidelines on Bleeding Risk Assessment Prior to Surgery into Practice: Real-time Experience.

Objectives: Despite guidelines recommending no need for coagulation testing before surgeries when a history of bleeding is negative, surgeons still overuse it in this part of the world. We aim to measure unbiased estimates of hemostatic outcomes in ear, nose, and throat (ENT) surgeries and assess the surgeons' behavior of preoperative coagulation testing. Methods: We enrolled all patients who underwent ENT surgeries from July 2017 to January 2018. The primary outcome was postoperative bleeding. Surgeons were asked about their decision on history alone or doing coagulation testing and their reason. Results: We recruited 730 patients; 372 were interviewed for a challenging bleeding history alone (group 1), and 358 had preoperative coagulation testing (group 2). Coagulation testing was repeated twice or more in 55.0% of patients, and more than half had coagulation factor and Von Willebrand factor assays. Most surgeons performed coagulation testing because of habitual practice. Conclusions: Almost half of the local surgeons consider coagulation testing as standard to evaluate bleeding risk before surgical procedures. This resulted in unnecessary delays in surgeries, parent/patient anxiety, and additional total cost. We recommend awareness campaigns for surgeons and the involvement of surgical societies to adhere to guidelines of detailed hemostatic history.

Outcome of Viral-associated Hemophagocytic Lymphohistiocytosis at a Tertiary Hospital.

BACKGROUND: Little is known about viral-associated hemophagocytic lymphohistiocytosis (HLH) in Oman. This study was done to assess the epidemiology, clinical features and outcome of viral-associated HLH in our setting. METHODS: We retrospectively reviewed children (0-18 years) managed for viral-associated HLH at the Sultan Qaboos University Hospital, Oman, over a 15-year period (2006-2020). Patients' medical records were used to describe their demographic, clinical and laboratory features, management and outcome. RESULTS: Fifty-six children were managed for HLH at Sultan Qaboos University Hospital over the last 15 years (2006-2020) of whom a third (19; 34%) had a viral trigger. The median age at the time of diagnosis of viral-associated HLH was 83 (13-96) months. Fever, cytopenia, hyperferritinemia and evidence of hemophagocytosis in bone marrow were the most consistent findings. Most of these children had either genetic predisposition to HLH (8/19; 42%) or underlying immunodeficiency secondary to malignant conditions or chemotherapy/hematopoietic stem cell transplantation (6/19; 32%). Epstein-Barr virus (9; 47%) followed by cytomegalovirus (6; 31%) was the most common viral trigger in our setting. Treatment included antivirals (8; 42%), HLH 2004 protocol (4; 21%), rituximab (4; 21%) and hematopoietic stem cell transplantation (3; 16%). Fourteen children (74%) had full recovery. CONCLUSIONS: In our small cohort, viral-associated HLH was more frequently encountered in children with genetic predisposition to HLH or children with underlying immunodeficiency. In addition, we found that the outcome is overall good for children who have no genetic predisposition to HLH and children with genetic predisposition who underwent hematopoietic stem cell transplantation.

Hematopoietic Stem Cell Transplantation for Patients with Autosomal Recessive Complete INF-λ Receptor 2 Deficiency: Experience in Oman.

Autosomal recessive complete INF-γ receptor-2 (IFN-γR2) deficiency is a rare, potentially fatal primary immune deficiency that predisposes to disseminated mycobacterial disease. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment. Few patients have been reported so far. Here we report the outcomes of HSCT in 7 patients with IFNγ-R2 deficiency from 3 Omani families who underwent HSCT at Sultan Qaboos University Hospital in Oman. All patients were homozygous for the same mutation (c.-175_+102del) of INFGR2. Four patients underwent HLA-matched related donor (MRD) HSCT (3 siblings and 1 parent), and the other 3 underwent T cell-depleted (TCD) haploidentical HSCT from a family donor. The stem cell source was peripheral blood stem cells in 5 patients and bone marrow in 2 patients. Five patients received myeloablative conditioning, and 2 had reduced-intensity conditioning. The overall survival rate was 85.7%, and the event-free survival was 71.4%. One of the 7 patients died on day +31 with gram-negative sepsis, and the other 6 patients were cured from their original disease (median follow-up of 78.5 months). One patient had primary graft failure following a TCD-haploidentical transplantation and underwent successful retransplantation from another haploidentical relative. Three patients received a donor lymphocyte infusion for mixed chimerism. Our findings indicate that HSCT is curative for complete IFN-γR2 deficiency. In this cohort from Oman, 85.7% of the patients were cured with either an MRD or a TCD haploidentical transplantation. Genetic analysis at birth in children of high-risk couples permits early diagnosis, prevents the morbidity of BCG vaccination, and can enable safer and more successful transplantation outcomes.

c.451dupT in KLKB1 is common in Nigerians, confirming a higher prevalence of severe prekallikrein deficiency in Africans compared to Europeans.

Essentials Prekallikrein (PK) deficiency is a recessive trait with isolated aPTT prolongation. KLKB1 c.451dupT is common in Nigerians (7/600 alleles) and absent in a European group (0/600). To date, all genotyped PK-deficient patients of African ancestry were homozygous for 451dupT. Diagnostics of isolated aPTT prolongation in African descendants should include PK testing. ABSTRACT: Background Severe prekallikrein deficiency (PK deficiency) is an autosomal-recessive condition thought to be very rare. Recently we reported that the previously unnoticed variant c.451dupT, p.Ser151Phefs*34 in KLKB1, which is listed in databases aggregating genome data, causes PK deficiency and is common in Africans according to gnomAD (allele frequency 1.43%). Patients/Methods The most common African (c.451dupT) and European (c.1643G>A, p.Cys548Tyr) PK deficiency causing KLKB1 variants were analyzed in two population-based collectives of 300 Nigerian and 300 German subjects. Genome databases were evaluated for variant frequencies and ethnicity of the subjects. The geographic origin of PK-deficient cases due to 451dupT was assessed. Results Two of five patients with PK deficiency caused by homozygous 451dupT were African, one African American, one from Oman, and one of unknown origin. The frequency of 451dupT was 1.17% in the Nigerian collective (7/600 alleles); none had Cys548Tyr. Subjects with 451dupT were found among different Nigerian ethnicities. Both variants were absent in the European collective. Database research was compatible with these findings, even though mainly data of African Americans (451dupT: 1.12%-1.78%) was accessible. A relevant number of non-American Africans are included only in the 1000Genomes collective: 451dupT frequency was 1.29% in native Africans and 1.56% in African Caribbeans. Conclusions This study underlines the higher prevalence of PK deficiency among people with African descent compared to Europeans. In order to avoid delay of necessary surgical procedures in patients of African origin, diagnostic algorithms for isolated, unexplained, activated partial thromboplastin time prolongation in these subjects should include PK deficiency screening.

Outcome of Early Hemostatic Intervention in Children With Sepsis and Nonovert Disseminated Intravascular Coagulation Admitted to PICU: A Randomized Controlled Trial.

OBJECTIVES: Evaluation of the outcome of early hemostatic management of disseminated intravascular coagulopathy in patients with severe sepsis/septic shock admitted to PICU, before the development of clinically overt disseminated intravascular coagulopathy. DESIGN: Prospective interventional, open label randomized controlled clinical trial. SETTING: PICU at Alexandria University Children's Hospital. PATIENTS: The study included 80 patients with proven severe sepsis/septic shock in nonovert disseminated intravascular coagulopathy stage. They were randomly assigned into two groups (group 1 and group 2). INTERVENTIONS: Specific intervention was applied for group 1 (plasma transfusion, low-dose unfractionated heparin, and tranexamic acid). MEASUREMENTS: All patients had assessment of Pediatric Index of Mortality 2 score, Pediatric Logistic Organ Dysfunction score, inotropic score, routine laboratory, and hemostatic tests including fibrin degradation products and d-dimers. Disseminated intravascular coagulopathy risk assessment scores were calculated on daily basis. RESULTS: Mortality rate was significantly higher in group 2. Progression to overt disseminated intravascular coagulopathy was significantly more common among group 2 patients than group 1 (45% and 10%, respectively) (p < 0.0001). Disseminated intravascular coagulopathyRisk Assessment Scores were significantly higher on the second and fifth days among group 2 patients. The initial specific hemostatic intervention was the only significant predictor of survival and prevention of progression to overt disseminated intravascular coagulopathy. CONCLUSIONS: Our results suggest that early use of a combination of fresh frozen plasma transfusion, low-dose heparin, and tranexamic acid in children with severe sepsis/septic shock in the "window of opportunity" before the development of overt disseminated intravascular coagulopathy stage was associated with better outcome for survival and prevention of progression to overt disseminated intravascular coagulopathy, with no increase in bleeding risk. Larger multicenter studies are needed to further prove this practice.

Preoperative transfusion versus no transfusion policy in sickle cell disease patients: a randomized trial.

BACKGROUND: Many children with sickle cell disease (SCD) indicated for adenotonsillectomy receive pre-operative transfusion therapy, either simple or exchange transfusion, in order to reduce surgical and sickle cell disease-related complications. SUBJECTS AND METHODS: This is a prospective randomized controlled clinical trial aiming to compare between preoperative simple transfusion and no transfusion in pediatric patients with sickle SCD admitted in Sultan Qaboos University Hospital, Muscat, Oman for adenotonsillectomy during the period from January 2014 through June 2018. They were randomly assigned into two arms (simple transfusion and no transfusion). RESULTS: Postoperative SCD-related complications have been encountered in 6 out of 138 patients (4.3%). There was no statistically significant difference between the two studied groups as regards the development of surgical or SCD-related complications (p = 0.6 and 0.8 respectively). The length of postoperative hospital stay was comparable in the two groups. (p = 0.607). SCD-related complications occurred exclusively in cases with homozygous sickle anemia (4 out of 81 = 4.9%). CONCLUSION: Sickle cell disease patients with a hemoglobin level above 7.5 g/dL do not need PRBCs transfusion prior to adenotonsillectomy. This approach did not increase the risk of postoperative surgical or SCD-related complications.

Sepsis-related anemia in a pediatric intensive care unit: transfusion-associated outcomes.

BACKGROUND: Pediatric patients with sepsis in intensive care units are at high risk of developing anemia, which might have adverse effects on their prognosis. This study aimed to evaluate the impact of red blood cell (RBC) transfusion on the outcomes of patients admitted to a pediatric intensive care unit (PICU) with sepsis. METHODS: We conducted a prospective randomized clinical trial, enrolling 67 children, aged 2 to 144 months who were admitted to a PICU with a new episode of sepsis from November 2017 to April 2018. Patients were allocated randomly to two groups: Group 1, liberal transfusion strategy group, including 33 patients who had initial hemoglobin (Hb) between 7 or greater and less than 10 g/dL and received an RBC top-up transfusion to 12 g/dL; and Group 2, restrictive strategy group, including 34 patients who had the same Hb range and did not receive RBCs. Patients with Hb less than 7 or greater than 10 g/dL were excluded. RESULTS: Of 33 patients who received liberal transfusions, 31 (93.94%) required ventilation, and 29 (87.88%) had multiorgan dysfunction. They had a significantly lengthier hospital stay and a higher incidence of acute respiratory distress syndrome and acute lung injury. Moreover, mortality was significantly higher in the liberal transfusion group (42.4% vs. 17.6%). CONCLUSIONS: Compared to the restrictive transfusion strategy, liberal transfusion might be associated with a worse outcome. However, the possible role of other known and unknown confounding factors and minor protocol violations should be taken into consideration. We recommend minimizing factors worsening anemia in PICU patients to reduce the need for transfusion.

T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation for Patients with Familial Hemophagocytic Lymphohistiocytosis Who Do Not Have Matched Family Donors: Experience in Oman.

Familial hemophagocytic lymphohistiocytosis (FHLH) is a potentially fatal disorder of immune regulation. Management includes chemotherapy followed by hematopoietic stem cell transplantation (HSCT). T cell depleted (TCD)-haploidentical HSCT could be an option for those patients who do not have HLA matching family donor. The objective of this study was to report on the outcome of TCD-haploidentical HSCT in patients with FHLH who underwent transplantation at Sultan Qaboos University Hospital (SQUH). This is a retrospective report on 12 patients with FHLH who received TCD- haploidentical HSCT at SQUH between August 2010 and December 2018. Epidemiologic characteristics and details on the transplantation procedures and complications were collected from patients' electronic records. Twelve patients with FHLH received TCD-haploidentical HSCT after a myeloablative conditioning regimen composed of treosulfan/thiotepa/fludarabine/anti-thymocyte globulin and rituximab. The mean age at transplantation was 11.67 ± 8 months. All patients had Perforin gene mutations, except 1 patient who had an UNC-13D mutation. Most patients received TCRαß+/CD19+ depleted grafts for faster immune reconstitution. Seven patients (58.3%) have been cured with a mean follow-up duration of 3.44 years. Four patients died of multiorgan failure secondary to gram-negative sepsis. One patient had primary graft failure, and 2 patients had mild graft-versus-host disease. Two patients had Pneumocystis carinii pneumonia, 2 had adenoviremia, and 9 patients had cytomegalovirus (CMV) viremia. Among patients with CMV viremia, 2 had evidence of disease (retinitis, enteritis). All patients with CMV viremia were treated successfully with foscarnet pre-engraftment and ganciclovir postengraftment, respectively. TCD-haploidentical HSCT could be a viable option for patients with FHLH who do not have HLA matching family donors. Infectious complications are the leading cause of death in that setting. CMV viremia was the most frequently encountered infectious complication.

E. coli Monomicrobial Necrotizing Fasciitis in an Iron-Overloaded Adolescent.

Escherichia coli is an extremely unusual cause of monomicrobial necrotizing fasciitis of the extremities in children. We report a transfusion-dependent adolescent boy with iron-overload secondary to congenital dyserythropoietic anemia who developed severe E. coli monomicrobial necrotizing fasciitis of the leg following a minor trauma. Combined surgical, antimicrobial and supportive care resulted in a good outcome.

Neutropenia and Life-threatening Agranulocytosis Among Children With ß-Thalassemia Treated With Oral Iron Chelators in a Community With Background of Ethnic Neutropenia.

INTRODUCTION: Neutropenia and agranulocytosis are rare side effects of deferiprone (DFP) in patients treated for iron overload. Unfortunately, no study directly addressed special risks in countries with a background of ethnic neutropenia, such as Oman. AIM: The aim of this study was to report the incidence of neutropenia in Omani children with ß-thalassemia treated with different iron chelators. METHODS/DESIGN: This was a retrospective study that included 179 Omani pediatric patients. For patients who developed neutropenia, demographic data, iron-chelating agent, clinical presentation, management, and outcome were recorded. Detailed clinical, laboratory±radiologic information was added for patients with agranulocytosis. RESULTS: Neutropenia was encountered in 43.6% of patients: severe neutropenia in 10 patients, moderate in 29, and mild in 69 patients. Severe and moderate neutropenia had similar incidence among DFP-exposed and DFP-naive patients (P=0.515 and 0.421, respectively), while mild neutropenia was common among DFP-naive patients (P=0.0001). A higher incidence of DFP-related agranulocytosis (4.1%) was noted compared with previous reports, but none had a fatal outcome. CONCLUSIONS: In a community with ethnic neutropenia, mild to moderate neutropenia is common. Higher incidence of severe neutropenia and agranulocytosis mandates careful monitoring and rational modification of iron-chelating agents to avoid life-threatening complications.

Premature ventricular contractions as a side effect of filgrastim in a child with B-thalassaemia.

Premature ventricular contractions are a rare side effect of filgrastim, reported mainly in elderly men. Here we report the case of a 9-year-old child with thalassaemia who developed frequent premature ventricular contractions after three doses of filgrastim were given for deferiprone-induced agranulocytosis. The arrhythmia resolved 3 weeks after discontinuation of filgrastim. Children treated with filgrastim should be carefully monitored for potentially serious arrhythmia.