Severe congenital neutropenia due to jagunal homolog 1 (JAGN1) mutation: a case report and literature review.

Severe congenital neutropenia caused by jagunal homolog 1 (JAGN1) mutation is a rare condition resulting from maturation arrest secondary to endoplasmic reticulum stress response from impaired neutrophil protein glycosylation. Here, we report a case of a 4-year-old boy who presented with a history of recurrent infections and manifestations, including recurrent intracranial hemorrhage. A review of similar cases reported in the literature indicates that a bleeding diathesis has not been previously described in these patients. We hypothesize that this newly described association of bleeding complications in this patient with JAGN1 mutation is secondary to defective glycosylation in the normal functioning of platelets or clotting factors. Recurrent infections with intracranial hemorrhage, new focal neurologic defects, or altered mental status in a child should warrant a suspicion for this immunodeficiency for the prompt initiation of treatment and prophylaxis for life-threatening infections or trauma.

Buprenorphine treatment receipt characteristics and retention among people who inject drugs at Integrated Care Centers in India.

BACKGROUND: India is facing overlapping opioid injection and HIV epidemics among people who inject drugs (PWID) in several cities. Integrated Care Centers (ICCs) provide single-venue HIV and substance use services to PWID. We evaluated PWID engagement in daily observed buprenorphine treatment at 7 ICCs to inform interventions. METHODS: We analyzed 1-year follow-up data for PWID initiating buprenorphine between 1 January - 31 December 2018, evaluating receipt frequency, treatment interruptions (no buprenorphine receipt for 60 consecutive days with subsequent re-engagement), and drop-out (no buprenorphine receipt for 60 consecutive days without re-engagement). Using descriptive statistics, we explored differences between ICCs in the opioid-endemic Northeast region and ICCs in the emerging opioid epidemic North/Central region. We used a multivariable logistic regression model to determine predictors of treatment drop-out by 6 months. RESULTS: 1312 PWID initiated buprenorphine (76% North/Central ICCs vs. 24% Northeast ICCs). 31% of PWID in North/Central, and 25% in Northeast ICCs experienced ≥ 1 treatment interruption in 1 year. Over 6 months, 48% of PWID in North/Central vs. 60% in Northeast ICCs received buprenorphine ≤ 2 times/week (p < 0.0001). A third of PWID in North/Central vs. half in Northeast ICCs experienced treatment drop-out by 6 months (p < 0.001). In the multivariable model, living in Northeast cities was associated with increased odds of drop-out while counseling receipt was associated with decreased odds. CONCLUSIONS: Retention among PWID initiating buprenorphine at ICCs was comparable to global reports. However, regional heterogeneity in retention, and low daily buprenorphine receipt suggest patient-centered interventions adapted to regional contexts are urgently needed.

Monoclonal Antibody Use for Coronavirus Disease 2019 in Pediatric Patients: A Multicenter Retrospective Study.

Monoclonal antibodies for COVID-19 are authorized in high-risk patients aged ≥12 years, but evidence in pediatric patients is limited. In our cohort of 142 patients treated at seven pediatric hospitals between 12/1/20 and 7/31/21, 9% developed adverse events, 6% were admitted for COVID-19 within 30 days, and none received ventilatory support or died.

Lessons from SARS-CoV-2 in India: A data-driven framework for pandemic resilience.

India experienced a massive surge in SARS-CoV-2 infections and deaths during April to June 2021 despite having controlled the epidemic relatively well during 2020. Using counterfactual predictions from epidemiological disease transmission models, we produce evidence in support of how strengthening public health interventions early would have helped control transmission in the country and significantly reduced mortality during the second wave, even without harsh lockdowns. We argue that enhanced surveillance at district, state, and national levels and constant assessment of risk associated with increased transmission are critical for future pandemic responsiveness. Building on our retrospective analysis, we provide a tiered data-driven framework for timely escalation of future interventions as a tool for policy-makers.

Impact of decreasing vancomycin exposure on acute kidney injury in stem cell transplant recipients.

OBJECTIVE: To evaluate the change in vancomycin days of therapy (DOT) and vancomycin-associated acute kidney injury (AKI) after an antimicrobial stewardship program (ASP) intervention to decrease vancomycin use in stable patients after hematopoietic stem cell transplantation (HSCT). DESIGN: Retrospective cohort study and quasi-experimental interrupted time series analysis. Change in unit-level vancomycin DOT per 1,000 inpatient days after the intervention was assessed using segmented Poisson regression. Subject-specific risk of vancomycin-associated AKI was evaluated using a random intercept logistic regression model with mediation analysis. SETTING: HSCT unit at a single quaternary-care pediatric hospital. PARTICIPANTS: Inpatients aged 3 months and older who underwent HSCT between January 1, 2015, and March 31, 2019 (27 months before and after the intervention) who received any dose of vancomycin. INTERVENTION: An ASP intervention in April 2017 creating a new practice guideline to decrease prolonged (>72 hours) vancomycin courses for stable HSCT patients with febrile neutropenia. RESULTS: Overall, 439 vancomycin exposures (234 before the intervention and 205 after the intervention) occurring across 300 transplants and 259 subjects were included. The mean vancomycin DOT was 307 per 1,000 inpatient days (95% confidence interval [CI], 272-342) and decreased after the intervention to 207 per 1,000 inpatient days (95% CI, 173-240). In multivariable analyses, the odds of AKI in the postintervention period were 37% lower than in the preintervention period (adjusted OR, 0.63; 95% CI, 0.42-0.95; P = .0268); 56% of the excess risk was mediated by vancomycin DOT. CONCLUSIONS: An ASP intervention successfully decreased vancomycin use after HSCT and resulted in a decrease in AKI. Reducing empiric antibiotic exposure for stable patients after HSCT can improve clinical outcomes.

Young and invisible: a qualitative study of service engagement by people who inject drugs in India.

OBJECTIVES: The HIV epidemic in India is concentrated in key populations such as people who inject drugs (PWID). New HIV infections are high among young PWID (≤30 years of age), who are hard to engage in services. We assessed perspectives of young PWID to guide development of youth-specific services. SETTING: We conducted focus group discussions (FGDs) with PWID and staff at venues offering services to PWID in three Indian cities representing historical and emerging drug use epidemics. PARTICIPANTS: PWID were eligible to participate if they were between 18 and 35 years, had initiated injection as adolescents or young adults and knew adolescent PWID in their networks. 43 PWID (81% male, 19% female) and 10 staff members participated in FGDs. A semistructured interview guide was used to elicit participants' narratives on injection initiation experiences, barriers to seeking harm reduction services, service delivery gaps and recommendations to promote engagement. Thematic analysis was used to develop an explanatory model for service engagement in each temporal stage across the injection continuum. RESULTS: Injection initiation followed non-injection opioid dependence. Lack of services for non-injection opioid dependence was a key gap in the preinjection initiation phase. Lack of knowledge and reliance on informal sources for injecting equipment were key reasons for non-engagement in the peri-injection phase. Additionally, low-risk perception resulted in low motivation to seek services. Psychosocial and structural factors shaped engagement after established injection. Housing and food insecurity, and stigma disproportionately affected female PWID while lack of confidential adolescent friendly services impeded engagement by adolescent PWID. CONCLUSIONS: Development of youth-specific services for young PWID in India will need to address unique vulnerabilities and service gaps along each stage of the injection continuum. Scaling-up of tailored services is needed for young female PWID and adolescents, including interventions that prevent injection initiation and provision of confidential harm reduction services.

Trends in Pediatric Candidemia: Epidemiology, Anti-Fungal Susceptibility, and Patient Characteristics in a Children's Hospital.

Candida bloodstream infections (CBSIs) have decreased among pediatric populations in the United States, but remain an important cause of morbidity and mortality. Species distributions and susceptibility patterns of CBSI isolates diverge widely between children and adults. The awareness of these patterns can inform clinical decision-making for empiric or pre-emptive therapy of children at risk for candidemia. CBSIs occurring from 2006-2016 among patients in a large children's hospital were analyzed for age specific trends in incidence rate, risk factors for breakthrough-CBSI, and death, as well as underlying conditions. Candida species distributions and susceptibility patterns were evaluated in addition to the anti-fungal agent use. The overall incidence rate of CBSI among this complex patient population was 1.97/1000 patient-days. About half of CBSI episodes occurred in immunocompetent children and 14% in neonatal intensive care unit (NICU) patients. Anti-fungal resistance was minimal: 96.7% of isolates were fluconazole, 99% were micafungin, and all were amphotericin susceptible. Liposomal amphotericin was the most commonly prescribed anti-fungal agent included for NICU patients. Overall, CBSI-associated mortality was 13.7%; there were no deaths associated with CBSI among NICU patients after 2011. Pediatric CBSI characteristics differ substantially from those in adults. The improved management of underlying diseases and antimicrobial stewardship may further decrease morbidity and mortality from CBSI, while continuing to maintain low resistance rates among Candida isolates.

Impact of standardized protocols for cytomegalovirus disease prevention in pediatric solid organ transplant recipients.

End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre- and post-implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention. The pre- and post-intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (P < .01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P < .001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.

Young people who inject drugs in India have high HIV incidence and behavioural risk: a cross-sectional study.

INTRODUCTION: There are limited data on young people who inject drugs (PWID) from low- and middle-income countries where injection drug use remains a key driver of new HIV infections. India has a diverse injection drug use epidemic and estimates suggest that at least half of PWID are ≤30 years of age. We compared injection and sexual risk behaviours and HIV incidence between younger and older PWID and characterized uptake of HIV testing and harm reduction services to inform targeted HIV prevention efforts. METHODS: We analysed cross-sectional data from 14,381 PWID recruited from cities in the Northeast and North/Central regions of India in 2013 using respondent driven sampling (RDS). We compared "emerging-adult" (18 to 24 years, 26% of sample) and "young-adult" PWID (25 to 30 years, 30% of sample) to older PWID (>30 years, 44% of sample) using logistic regression to evaluate factors associated with three recent risk behaviours: needle-sharing, multiple sexual partners and unprotected sex. We estimated age-stratified cross-sectional HIV incidence using a validated multi-assay algorithm. RESULTS: Compared to older adults, emerging-adults in the Northeastern states were significantly more likely to share needles (males adjusted odds ratio [aOR] 1.82; females aOR 2.29, p < 0.01), have multiple sexual partners (males aOR 1.56; females aOR 3.75, p < 0.01), and engage in unprotected sex (males aOR 2.29, p < 0.01). In the North/Central states, young-adult males were significantly more likely to needle-share (aOR 1.23, p < 0.05) while emerging-adult males were significantly more likely to have multiple sexual partners (aOR 1.74, p < 0.05). In both regions, emerging-adults had the lowest HIV testing. Participation in harm reduction services was low across all age groups. Annual HIV incidence was higher in emerging- and young-adult PWID in the North/Central region: emerging-adults: 4.3% (95% confidence interval [CI] 3.0, 5.6); young-adults: 4.9% (95% CI 3.7, 6.2); older adults: 2.1% (95% CI 1.4, 2.8). CONCLUSIONS: Higher HIV incidence and engagement in risky behaviours among younger PWID compared to older PWID, coupled with low utilization of harm reduction services highlight the importance of targeting this population in HIV programming. Age-specific interventions focused on addressing the needs of young PWID are urgently needed to curb the HIV epidemic in this vulnerable population.

Trainee Needs in Pediatric Transplant Infectious Diseases Education.

BACKGROUND: Pediatric transplant infectious diseases (PTID) is emerging as an area of expertise within pediatric infectious diseases. Although guidelines for training in PTID have been published, no prior national survey has been conducted to identify trainee-described needs for instruction in PTID. METHODS: A survey was designed through collaboration between the American Society of Transplantation and the Pediatric Infectious Diseases Society, to assess trainee exposure, self-knowledge, and self-competency in PTID. RESULTS: Sixty of 169 trainees replied (response rate 35%) with 93% of respondents from centers that performed transplants. Eighty-two percent of trainees were unaware of the recommended curriculum for PTID. Although a majority of trainees (78%) indicated they had received structured teaching in PTID, most (>50%) ranked their knowledge in donor selection, donor-derived infections, and candidate risk assessment as poor or fair. A majority (>50%) also reported their competency in areas regarding pre- and posttransplant guidance as poor or fair. Trainees identified the following strategies to augment their PTID training: additional rotations, teaching by experts, case-based learning, and a reference guide. CONCLUSIONS: This survey highlights significant trainee-identified gaps in PTID knowledge and competency. Limitations include low survey response rate but appears weighted towards centers with transplantation. Suggested strategies can inform the development of learner-specific initiatives and curriculum in PTID.

Use of cidofovir in pediatric patients with adenovirus infection.

Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity.   Methods: We conducted a retrospective 5-year review at Boston Children's Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction.   Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions:  CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.

In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant.

Most infections occur in early life, prompting development of novel adjuvanted vaccines to protect newborns and infants. Several Toll-like receptor (TLR) agonists (TLRAs) are components of licensed vaccine formulations or are in development as candidate adjuvants. However, the type and magnitude of immune responses to TLRAs may vary with the TLR activated as well as age and geographic location. Most notably, in newborns, as compared to adults, the immune response to TLRAs is polarized with lower Th1 cytokine production and robust Th2 and anti-inflammatory cytokine production. The ontogeny of TLR-mediated cytokine responses in international cohorts has been reported, but no study has compared cytokine responses to TLRAs between U.S. neonates and infants at the age of 6months. Both are critical age groups for the currently pediatric vaccine schedule. In this study, we report quantitative differences in the production of a panel of 14 cytokines and chemokines after in vitro stimulation of newborn cord blood and infant and adult peripheral blood with agonists of TLR4, including monophosphoryl lipid A (MPLA) and glucopyranosyl lipid Adjuvant aqueous formulation (GLA-AF), as well as agonists of TLR7/8 (R848) and TLR9 (CpG). Both TLR4 agonists, MPLA and GLA-AF, induced greater concentrations of Th1 cytokines CXCL10, TNF and Interleukin (IL)-12p70 in infant and adult blood compared to newborn blood. All the tested TLRAs induced greater infant IFN-α2 production compared to newborn and adult blood. In contrast, CpG induced greater IFN-γ, IL-1ß, IL-4, IL-12p40, IL-10 and CXCL8 in newborn than in infant and adult blood. Overall, to the extent that these in vitro studies mirror responses in vivo, our study demonstrates distinct age-specific effects of TLRAs that may inform their development as candidate adjuvants for early life vaccines.

Perspectives of host faculty and trainees on international visiting faculty to paediatric academic departments in East Africa.

BACKGROUND: Investments in faculty exchanges to build physician workforce capacity are increasing. Little attention has been paid to the expectations of host institution faculty and trainees. This prospective qualitative research study explored faculty and resident perspectives about guest faculty in paediatric departments in East Africa, asking (1) What are the benefits and challenges of hosting guest faculty, (2) What factors influence the effectiveness of faculty visits and (3) How do host institutions prepare for faculty visits? METHODS: We recruited 36 faculty members and residents from among four paediatric departments in East Africa to participate in semistructured interviews which were audio recorded and transcribed. Data were qualitatively analysed using principles of open coding and thematic analysis. We achieved saturation of themes. RESULTS: Benefits of faculty visits varied based on the size and needs of host institutions. Emergent themes included the importance of guest faculty time commitment, and mutual preparation to ensure that visit goals and scheduling met host needs. We documented conflicts that developed around guest emotional responses and ethical approaches to clinical resource limitations, which some hosts tried to prepare for and mitigate. Imbalance in resources led to power differentials; some hosts sought partnerships to re-establish control over the process of having guests. CONCLUSIONS: We identified that guest faculty can assist paediatric institutions in building capacity; however, effective visits require: (1) mutually agreed on goals with appropriate scheduling, visit length and commitment to ensure that the visits meet the host's needs, (2) careful selection and preparation of guest faculty to meet the host's goals, (3) emotional preparation by prospective guests along with host orientation to clinical work in the host's setting and (4) attention to funding sources for the visit and mitigation of resulting power differentials.

The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes.

BACKGROUND: Newborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848). METHODS: TLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2. RESULTS: Hybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1ß. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848. CONCLUSIONS: Hybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.

Overcoming challenges to develop pediatric postgraduate training programs in low- and middle-income countries.

BACKGROUND: Interest is growing in strengthening postgraduate medical education in low-income countries. The purpose of this study was to understand how postgraduate pediatric training programs are developed in countries with no or few pediatric training opportunities. The authors sought to describe and compare a purposive sample of such new programs, and identify challenges and solutions for successful program establishment and sustainability. METHODS: The authors queried national pediatric email lists and the Accreditation Council for Graduate Medical Education (ACGME) accredited pediatric residency programs in the United States to identify four pediatric training programs that met study criteria. All four programs responded to a questionnaire with quantitative and qualitative components. Qualitative responses were analyzed for themes. RESULTS: Four centers - in Kenya, Laos, Eritrea and Cambodia - met study criteria. Reported challenges to program development and sustainability centered on faculty development and retention, training in pediatric subspecialties, creating pipelines for applicants and graduates, and funding. These themes were used to develop a logic model, which provides a framework for planning, implementing and evaluating new postgraduate general pediatric training program in low-income countries. DISCUSSION: This study compares four postgraduate general pediatric training programs that were recently established and now continue to graduate pediatric residents in low-income countries. Lessons derived from these programs may help guide practice and research for other centers seeking to establish similar programs.

Factors associated with encephalopathy in patients with Salmonella enterica serotype Typhi bacteremia presenting to a diarrheal hospital in Dhaka, Bangladesh.

To characterize clinical correlates of typhoid fever-associated encephalopathy, we performed a retrospective chart review of patients with Salmonella enterica serotype Typhi bacteremia who were hospitalized at the International Centre for Diarrhoeal Disease Research, Bangladesh, from February of 2009 to June of 2011. Of 207 patients bacteremic with Salmonella Typhi who were ≥ 5 years of age, we identified 43 (21%) patients with encephalopathy. Univariate analysis revealed that patients with encephalopathy more often presented at ages of 10-24 years and had severe dehydration, low oxygen saturation, high respiratory rate, low leukocyte count, low platelet count, and Widal flagellar H agglutinin (TH) titer ≥ 1:640 compared with typhoid patients without encephalopathy. Multivariate analysis using logistic regression showed that age, dehydration, leukocyte count, and Widal TH titer were independently associated with encephalopathy. Our findings suggest that age, severity of disease, and immune responses are associated with encephalopathy during Salmonella Typhi bacteremia, perhaps reflecting the impact of prominent inflammatory responses.