Treatment of hepatitis C in children with direct-acting antiviral drugs.

The primary purpose of treating chronic hepatitis C (HCV) is to prevent the development of liver fibrosis, cirrhosis, and cancer. In the last decade, direct-acting antiviral medicine (DAA) has been approved to treat children with HCV. This treatment has a higher efficacy, shorter duration, and milder side effects than the previously approved treatment. In this review, it is recommended to track down children who might be infected with HCV to enhance early treatment to prevent transmission of the virus and the possible complications.

STK4 Deficiency Impairs Innate Immunity and Interferon Production Through Negative Regulation of TBK1-IRF3 Signaling.

BACKGROUND: STK4 deficiency due to homozygous mutations in the STK4 gene encoding the STK4/MST1 kinase was first described in 2012. STK4/MST1 kinase regulates cell proliferation, survival, differentiation, and immune responses through canonical and non-canonical Hippo signaling pathways. OBJECTIVE: We describe an 11-year-old girl with a clinical presentation consisting of severe recurrent herpes zoster, chronic warts, and recurrent pneumonias, as well as a somatic phenotype with hypothyroidism and low stature. Whole exome sequencing revealed STK4 deficiency due to homozygosity for a novel frameshift variant in STK4, c.523dupA, p.(L174fsTer45), resulting in a premature stop codon within the kinase domain. METHODS: We performed a thorough investigation of the genetics and innate and adaptive immunological abnormalities in STK4 deficiency. RESULTS: We show significantly impaired type I, II, and III interferon (IFN) responses and partly reduced proinflammatory cytokine responses to ligands of Toll-like receptor (TLR)3, TLR9, and the cytosolic RNA and DNA sensors as well as to microorganisms. Impaired IFN responses could be attributed to reduced phosphorylation of TBK1 and IRF3. Moreover, virus infection induced enhanced cell death by apoptosis. Importantly, autophagy pathways were slightly disturbed, with enhanced LC3B-Ito LCB3-II conversion at the single cell level but normal overall formation of LCB3 punctae. Finally, the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions, although with largely normal T cell proliferation and normal IFNg production. CONCLUSION: Here, we demonstrate disturbances in various immune cell populations and pathways involved in innate immune responses, cell death, autophagy, and adaptive immunity in a patient homozygous for a novel STK4 frameshift mutation.

[Multisystem inflammatory syndrome in children after SARS-CoV-2 infection].

In the era of the coronavirus disease pandemic, a new disease entity named multisystem inflammatory syndrome in children has emerged. This is a case report of a seven-year-old boy with hyperinflammation and cardiac involvement, compatible with this disease entity. Antibody tests and symptoms indicated previous severe acute respiratory syndrome coronavirus 2 infection. The patient was treated according to international guidelines with full symptom resolution. Awareness of this inflammatory syndrome should prompt immediate treatment and could possibly avoid fatal outcomes.

Paediatric hepatitis B and hepatitis C virus infections: An observational study of a Danish cohort.

AIM: The aim of this study was to describe the epidemiological and clinical characteristics in children with either chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in Denmark. METHODS: In this observational study, children and adolescents with either chronic HBV or HCV infection followed at the largest paediatric departments in Denmark between 2001 and 2013 were included. Data collection included as well epidemiological data as clinical data like virus genotype, viral load, serological markers, liver biochemistry, liver elastography and histology if available. RESULTS: The study included 131 children. None of the patients had decreased liver function or end-stage liver disease during follow-up. Ten of the 18 children who underwent liver biopsy had signs of fibrosis. Thirteen (11%) children with HBV and one (7%) child with HCV received treatment. Different indications and different treatment regimens were used. CONCLUSION: This study confirms that chronic HBV and HCV infections are often mild diseases during childhood. Nevertheless, children are at higher risk of serious liver disease early in life because of the early time of infection and probably also because of the high viral loads.

Association between neutropenia and IgG antineutrophil antibodies in a case of CD40LG deficiency due to two novel mutations.

This case suggests a mechanistic rationale for the clinical efficacy of intravenous immunoglobulins (IVIG) in treating CD40 ligand (CD40L) deficiency associated neutropenia as it is the first reported instance of free and cell-bound antineutrophil antibodies in a case of CD40L deficiency, accompanied by a prolonged and clinically severe neutropenia.

Meropenem to Children With Febrile Neutropenia Induces Monoresistant Pseudomonas aeruginosa.

Antimicrobial resistance in Pseudomonas aeruginosa is a threat to children with cancer. We explored the association between P. aeruginosa resistance and previous antibiotic exposure. All children with cancer and P. aeruginosa bacteremia in 2007 to 2016 in Denmark, a country with an overall resistance rate of ∼3%, were included. Twenty percent (10/49) of isolates from children previously exposed to meropenem were meropenem nonsusceptible. The only significant risk factor of meropenem nonsusceptibility was previous meropenem therapy (P=0.03). On the basis of these results, we suggest that meropenem should be reserved as a last resort for children with febrile neutropenia in countries with low antimicrobial resistance.

[Rat bite fever in a three-year-old child].

Rat bite fever (RBF) is rare in Denmark. It can be very difficult to diagnose, as the causative agent is an extremely fastidious organism which needs microaerophilic conditions to grow. We report a case of arthritis in the right ankle due to Streptobacillus moniliformis in a three-year-old girl who fully recovered after 14-day treatment of intravenous administrated penicillin followed by four weeks of orally administrated amoxicillin. Social history revealed the presence of two domestic rats living in the child's home. As rodents are becoming more popular as pets, RBF must be considered in patients with a history of relevant exposure.

Oral Clefts and Academic Performance in Adolescence: The Impact of Anesthesia-Related Neurotoxicity, Timing of Surgery, and Type of Oral Clefts.

OBJECTIVE: Early life exposure to anesthesia and surgery is suspected to associate with cognitive impairment later in life. We compared academic achievement among adolescents with cleft lip only (CL), cleft palate only (CP), and cleft lip and cleft palate (CLP) with a noncleft control group to investigate whether outcome depends on timing and number of operations during childhood and/or type of oral cleft. DESIGN: Nationwide register-based follow-up study. SETTING: Danish birth cohort 1986 to 1990. PARTICIPANTS: Five hundred fifty-eight children with isolated CL (n = 171), CLP (n = 222), or CP (n = 195), of which 509 children had been exposed to anesthesia and one or more cleft operation(s), and a 5% sample of the birth cohort (n = 14,677). MAIN OUTCOME MEASURE(S): Test score in the Danish standardized ninth-grade exam and proportion of nonattainment, defined as "results for ninth-grade exam unavailable." Data adjusted for sex, birth weight, parental age, and parental level of education. RESULTS: Compared to controls, children with CL achieved higher scores (mean difference 0.12, 95% CI -0.05; 0.29) and children with CLP presented with lower scores (mean difference -0.06, 95% CI -0.21; 0.09), albeit both statistically insignificant. Children with CP achieved significantly lower scores, mean difference -0.20 (95% CI -0.38; -0.03). Odds ratios for nonattainment at final exam were: CL 0.79 (95% CI 0.46; 1.35), CLP 1.07 (95% CI 0.71; 1.61), CP 2.59 (95% CI 1.78; 3.76). CONCLUSIONS: Oral cleft type rather than number and timing of anesthesia and operations associate to poorer academic performance. Although a potential neurotoxic effect due to anesthetic agents is not reflected in the data, it cannot be completely excluded.

Risk of oral clefts in twins.

BACKGROUND: Small studies have indicated that twinning increases the risk of oral cleft. METHODS: We used data from a Danish national population-based cohort study to investigate whether twinning was associated with isolated oral cleft, and to estimate the twin probandwise concordance rate and heritability. Twins (207 affected/130,710) and singletons (7766 affected/4,798,526) born from 1936 through 2004 in Denmark were ascertained by linkage among the Danish Facial Cleft Database, the Danish Twin Registry, and the Civil Registration System. We computed oral cleft prevalence and prevalence proportion ratio for twins versus singletons, stratified for 3 subphenotypes. Probandwise concordance rates and heritability for twins were estimated for 2 phenotypes--cleft lip with or without cleft palate (CL/P) and cleft palate (CP). RESULTS: The prevalence of oral cleft was 15.8 per 10,000 twins and 16.6 per 10,000 singletons (prevalence proportion ratio = 0.95; 95% confidence interval = 0.83-1.1). This prevalence was similar for monozygotic and dizygotic twins. The probandwise concordance rate was higher for CL/P for monozygotic twins than for dizygotic twins (50% vs. 8%, respectively). A similar contrast was present for CP. Recurrence risk for both types of clefts was greater in dizygotic twins than in non-twin siblings. Heritability estimates were above 90% for both CL/P and CP. CONCLUSIONS: No excess risk of oral cleft could be demonstrated for twins compared with singletons. The concordance rates and heritability estimates for both types of clefts show a strong genetic component.

Recurrence risk for offspring of twins discordant for oral cleft: a population-based cohort study of the Danish 1936-2004 cleft twin cohort.

Our objective in this Danish population-based cohort study was to estimate the recurrence risk of isolated oral cleft (OC) for offspring of the unaffected co-twins of OC discordant twin pairs and to compare this risk to the recurrence risk in the offspring of the affected co-twin as well as to the risk in the background population. During 1936-2004, 207 twin pairs were ascertained, among whom at least one twin had an OC. The index persons were twins discordant for OC who had children (N=117), and their offspring (N=239). The participants were ascertained by linkage between The Danish Facial Cleft Database, The Danish Twin Registry and The Danish Civil Registration System. In the study OC recurrence risk for offspring of the affected and unaffected twin and relative risk were compared to the background prevalence. We found that among 110 children of the 54 OC affected twins, two (1.8%) children had OC corresponding to a significantly increased relative risk (RR=10; 95% CI 1.2-35) when compared to the frequency in the background population. Among the 129 children of the 63 unaffected twins, three (2.3%) children were affected, corresponding to a significantly increased relative risk (RR=13; 95% CI 2.6-36) when compared the background prevalence. We concluded that in OC discordant twin pairs similar increased recurrence risks were found among offspring of both OC affected and OC unaffected twins. This provides further evidence for a genetic component in cleft etiology and is useful information for genetic counseling of twin pairs discordant for clefting.

A cohort study of recurrence patterns among more than 54,000 relatives of oral cleft cases in Denmark: support for the multifactorial threshold model of inheritance.

OBJECTIVES: To determine if the anatomical severity of oral clefting affects familial recurrence in a large population based sample. To provide reliable recurrence risk estimates for oral cleft for first, second, and third degree relatives. DESIGN: Population based cohort study. SETTING: Denmark. PARTICIPANTS: 6776 individuals affected with an oral cleft born from 1952 to 2005 and 54 229 relatives. MAIN OUTCOME MEASURES: Recurrence risk estimates for oral cleft for first, second, and third degree relatives and stratification by severity, specificity, parent of origin effect, and family size for first degree relatives. RESULTS: For cleft lip and palate probands we observed recurrence risks for first, second, and third degree relatives of respectively 3.5% (95% CI 3.1% to 4.0%), 0.8% (95% CI 0.6% to 1.0%), and 0.6% (95% CI 0.4% to 0.8%). Individuals affected by the most severe oral cleft had a significantly higher recurrence risk among both offspring and siblings, eg, the recurrence risk for siblings of a proband with isolated bilateral cleft lip with cleft palate was 4.6% (95% CI 3.2 to 6.1) versus 2.5% (95% CI 1.8 to 3.2) for a proband born with a unilateral defect. CONCLUSIONS: Anatomical severity does have an effect on recurrence in first degree relatives and the type of cleft is predictive of the recurrence type. Highly reliable estimates of recurrence have been provided for first cousins in addition to more accurate estimates for first and second degree relatives. These results and the majority of prior data continue to support a multifactorial threshold model of inheritance.