A case of mother and child with CANDLE syndrome: Diagnosis and subsequent treatment with baricitinib.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) or proteasome-associated autoinflammatory syndrome is a rare autoinflammatory disorder that typically presents in infancy with characteristic symptoms, including recurrent fever, panniculitis, and progressive lipodystrophy, among other findings. We present a case of mother and child with CANDLE syndrome. The child was eventually started on baricitinib with normalization of rash and systemic findings.

Multiplexed Functional Assessment of Genetic Variants in CARD11.

Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.

A Simple Allergist-Led Intervention Improves Resident Training in Anaphylaxis.

Physicians underrecognize and undertreat anaphylaxis. Effective interventions are needed to improve physician knowledge and competency regarding evidence-based anaphylaxis diagnosis and management (ADAM). We designed and evaluated an educational program to improve ADAM in pediatrics, internal medicine, and emergency medicine residents from two academic medical centers. Anonymous questionnaires queried participants' demographics, prior ADAM clinical experience, competency, and comfort. A pretest assessing baseline knowledge preceded a 45-minute allergist-led evidence-based presentation, including practice with epinephrine autoinjectors, immediately followed by a posttest. A follow-up test assessed long-term knowledge retention twelve weeks later. 159 residents participated in the pretest, 152 participated in the posttest, and 86 participated in the follow-up test. There were no significant differences by specialty or site. With a possible score of 10, the mean pretest score (7.31 ± 1.50) was lower than the posttest score (8.79 ± 1.29) and follow-up score (8.17 ± 1.72) (P < 0.001 for both). Although participants' perceived confidence in diagnosing or managing anaphylaxis improved from baseline to follow-up (P < 0.001 for both), participants' self-reported clinical experience with ADAM or autoinjector use was unchanged. Allergist-led face-to-face educational intervention improves residents' short-term knowledge and perceived confidence in ADAM. Limited clinical experience or reinforcement contributes to the observed decreased knowledge.

Conservative long-term treatment of children with eosinophilic esophagitis.

BACKGROUND: Current treatments of eosinophilic esophagitis (EoE), including restrictive diets or glucocorticoids, provide only transient improvement. Proton pump inhibitor (PPI) use in EoE does not lead to histologic improvement; however, the long-term use of PPI on symptoms and prevention of complications has not been evaluated. OBJECTIVE: To evaluate the use of PPI as maintenance therapy in children with EoE. METHODS: Eosinophilic esophagitis was diagnosed based on initial endoscopic biopsies and persistent eosinophilic inflammation despite PPI therapy. Inclusion criteria included diagnosis of EoE and PPI use as primary maintenance treatment. Patients were excluded if they were treated with dietary or glucocorticoid therapy. Histologic evidence of inflammation as well as degree of subepithelial fibrosis at presentation was compared with most recent biopsies while receiving PPI therapy. RESULTS: Thirty-eight patients (30 males and 8 females; average age 6.7 ± 5.4 years) fulfilled inclusion criteria. Duration of follow-up was 3.0 ± 2.4 years. At presentation, vomiting was significantly more frequent in the younger patients, whereas dysphagia occurred more frequently in the older patients. At follow-up, 26 patients were asymptomatic, and the remaining 12 patients' symptoms were significantly improved. No complications of stricture or food impaction were seen. Significant eosinophilic inflammation persisted in 28 patients. No difference in degree of subepithelial fibrosis at diagnosis compared with most recent biopsies. The z-scores of the treated EoE patients significantly improved. CONCLUSION: Patients with EoE treated with PPIs show an improvement in symptoms and z-scores despite persistent eosinophilic inflammation. PPI treatment may be useful maintenance therapy in children with EoE.

Pharmacotherapy of pediatric and adolescent HIV infection.

Significant advances have been made in the treatment of human immunodeficiency virus (HIV) infection over the past two decades. Improved therapy has prolonged survival and improved clinical outcome for HIV-infected children and adults. Sixteen antiretroviral (ART) medications have been approved for use in pediatric HIV infection. The Department of Health and Human Services (DHHS) has issued "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection", which provide detailed information on currently recommended antiretroviral therapies (ART). However, consultation with an HIV specialist is recommended as the current therapy of pediatric HIV therapy is complex and rapidly evolving.

Interleukin 7 receptor alpha-chain-mutation severe combined immunodeficiency without lymphopenia: correction with haploidentical T-cell-depleted bone marrow transplantation.

BACKGROUND: Severe combined immunodeficiency (SCID) is a rare primary immunodeficiency characterized by abnormal lymphocyte development and lymphopenia. It often presents during the first year of life with recurrent, opportunistic infections, failure to thrive, and malabsorption. OBJECTIVE: To advocate newborn screening for SCID. METHODS: We reviewed the case histories of dizygotic twins with Pneumocystis carinii pneumonia (PCP) at the age of 6 months. RESULTS: Full-term fraternal twin girls were born to nonconsanguineous parents. Twin A developed recurrent oral candidiasis at 2 months, followed by pneumococcal bacteremia and PCP. At 5 months she had failure to thrive, but her absolute lymphocyte count was normal (5,887 cells/mm3). Subsequently, twin B presented with acute respiratory distress and was also diagnosed as having PCP; her absolute lymphocyte count was 5,852 cells/mm3. Flow cytometric analysis of peripheral blood lymphocytes from both girls demonstrated a T-B+NK+ phenotype consistent with interleukin 7 receptor alpha-chain-mutation SCID. Both girls received a haploidentical T-cell-depleted bone marrow transplant from their mother. In the interim, a homozygous point mutation in the interleukin 7 receptor alpha-chain gene was identified in twin B. Both parents were found to be carriers. Twin A died of chronic lung disease 8 months after transplantation; twin B is currently thriving. CONCLUSIONS: Early diagnosis and treatment of SCID are associated with an increased rate of survival and improved long-term outcome. Some patients with SCID can present without lymphopenia. Thus, we advocate that more sensitive screening tests be considered for inclusion in the newborn screening program currently used in most states.

GB virus C infection in children with perinatal human immunodeficiency virus infection.

BACKGROUND: GB virus C (GBV-C) infection occurs in 20-40% of human immunodeficiency virus (HIV)-infected adults, and coinfection is associated with improved HIV disease outcome. METHODS: To determine the prevalence of GBV-C infection in children who were perinatally infected with HIV, we conducted a cross-sectional prevalence survey in a cohort of perinatally infected HIV-positive children selected from a large, multicenter observational protocol. A blood specimen was obtained and tested for GBV-C viremia with the use of a qualitative GBV-C RNA assay and screened for past GBV-C infection with enzyme-linked immunosorbent assay to detect antibodies to the GBV-C envelope protein E2 (E2 Ab). RESULTS: The 354 children who participated in the substudy were relatively healthy, with a median CD4 of 784 cells/mm and median HIV-1 viral load of 1055 copies/mL. The prevalence of GBV-C viremia was 20 of 353 or 5.7% (95% confidence interval, 3.5-8.6%), and the prevalence of E2 Ab was 12 of 354 or 3.4% (95% confidence interval, 1.8-5.8%). GBV-C viremic patients were older than patients without past GBV-C infection (median age, 12.8 years versus 10.7 years). Median CD4 lymphocyte counts were highest in subjects without GBV-C infection and lowest in those with E2 Ab. CONCLUSIONS: GBV-C prevalence rates are lower in children with perinatal HIV infection than those reported for HIV-infected adults. With the exception of evidence that GBV-C viremic children had lower rates of Centers for Disease Control and Prevention HIV disease category C disease before GBV-C testing, we did not find evidence of improved HIV disease outcome in coinfected patients, but the number of HIV/GBV-C-coinfected children was small.

Hepatitis C prevalence in children with perinatal human immunodeficiency virus infection enrolled in a long-term follow-up protocol.

OBJECTIVE: To evaluate the prevalence of hepatitis C virus (HCV) infection in children with perinatal human immunodeficiency virus (HIV) infection. DESIGN: Cross-sectional substudy. SETTING: Multicenter study from 41 sites in the United States. PATIENTS: Children with perinatal HIV infection were randomly selected from a large, long-term, follow-up protocol. MAIN OUTCOME MEASURE: Hepatitis C infection was defined as having positive test results on both HCV antibody and HCV RNA assays. RESULTS: Five hundred thirty children enrolled in the substudy; definitive HCV test results were available for 525 children. Eighty-three percent were of a minority race or ethnicity. They were equally distributed by sex, had a median age of 10.7 years, and were relatively healthy, with 75% having CD4+ lymphocyte counts greater than 500 cells/mm3. Eight of 525 children (1.5%; 95% confidence interval [CI], 0.7%-3.0%) infected with HIV were coinfected with HCV. In contrast, the rate of HCV infection in a serosurvey of more than 2700 children aged 6 to 11 years from the National Health and Nutrition Examination Survey was 0.2% (95% CI, 0.04%-0.6%). In our study, there were no differences between children coinfected with HIV and HCV and those without HCV infection in terms of demographic characteristics, CD4+ or CD8+ T-lymphocyte counts, HIV 1 RNA levels, preterm or mode of delivery, or liver disease; however, the number of children coinfected with HIV and HCV was small. CONCLUSION: While HCV prevalence infection rates are low in children with perinatal HIV infection, they are 8 to 10 times higher than reported in HCV serosurveys of children in the United States.

Virologic testing in the management of perinatal HIV exposure.

Over the last several years, virologic assays for the detection and measurement of HIV-1 RNA have become important in the diagnosis and management of perinatal HIV infection. Since AIDS Clinical Trials Group 076, a number of prospective and retrospective analyses have investigated the role of viral load in perinatal transmission. Although no universal virologic threshold for perinatal HIV transmission has been established, much has been learned about the timing of perinatal transmission and the relationship between maternal viral load and disease progression in HIV-infected neonates. Virologic assays have become accepted as standards of care in monitoring viral load during pregnancy, diagnosing neonatal infection, and establishing prognosis and response to therapy in infected infants.