Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome-like Clinical Presentation in Human Immunodeficiency Virus-infected Children in Malawi.

We describe 7 human immunodeficiency virus-infected Malawian children with Kaposi sarcoma who met criteria for Kaposi sarcoma herpesvirus (KSHV) inflammatory cytokine syndrome. Each presented with persistent fevers, bulky lymphadenopathy, massive hepatosplenomegaly, and severe cytopenias. Plasma analyses were performed in 2 patients, both demonstrating extreme elevations of KSHV viral load and interleukin 6.

KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions.

Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.

The Standardized Pediatric Expedited Encounters for ART Drugs Initiative (SPEEDI): description and evaluation of an innovative pediatric, adolescent, and young adult antiretroviral service delivery model in Tanzania.

BACKGROUND: As countries scale up antiretroviral therapy (ART) for children, innovative strategies to deliver quality services to children are needed. Differentiated ART delivery models have been successful in adults, but no such program has been described in children. We describe the Standardized Pediatric Expedited Encounters for ART Drugs Initiative (SPEEDI). METHODS: Descriptive analysis of patients eligible for SPEEDI was done via retrospective review of children, adolescents, and young adults on ART at the Baylor Centre of Excellence (COE) in Mbeya, Tanzania between January 2013 and December 2015. Eligibility for SPEEDI visits included the following: stable children, adolescents, and young adults on ART for approximately 3 months or longer, no medical or social complications, good adherence to ART, and presence of reliable caregiver. During a SPEEDI visit, patients were fast tracked in triage to collect medications directly without physically seeing a clinician. SPEEDI patients came to clinic every two months, and alternated SPEEDI visits with standard visits. Baseline characteristics, mortality, and lost-to-follow up rates of SPEEDI patients were analyzed. RESULTS: One thousand one hundred sixty-four patients utilized SPEEDI, totaling 3493 SPEEDI visits. SPEEDI reached 51.3% (1164/2269) of pediatric ART patients, accounting for 7.7% (3493/44489) of total patient encounters. SPEEDI patients were 52% (605/1164) female, median age of 11.7 years (range 1.2-25.5 yr), median time on ART of 21 months (range 4-130 months) and 83.5% (964/1155) categorized as no or mild HIV-associated immunodeficiency. SPEEDI patients had good outcomes (98.8%), low LTFU (0.1%) and low mortality rates (0.61 deaths per 100 patient-years). CONCLUSION: SPEEDI was an effective model for delivering ART to children, adolescents, and young adults in our setting, leading to good clinical outcomes, low mortality, and low LTFU. The SPEEDI program safely and effectively expedited and spaced out ART visits for children, adolescents, and young adults, and can serve as an adaptable ART delivery model for other resource limited settings.

Authorship in paediatric research conducted in low- and middle-income countries: parity or parasitism?

OBJECTIVES: Interest in global health has increased greatly in the past two decades. Concomitantly, the number and complexity of research partnerships between high-income (HIC) and low- and middle-income countries (LMICs) has grown. We aimed to determine whether there is authorship parity (equitable representation and author order) or parasitism (no authors from study countries) in paediatric research conducted in LMICs. METHODS: We reviewed all articles published from 2006 to 2015 in the four paediatric journals with the highest Eigenfactor scores. We limited our review to articles from LMICs and abstracted information on author affiliation and order, funding source and study design. We calculated Student's t-tests and chi-square using Fisher's exact test with Monte Carlo estimates. RESULTS: There were 24 169 articles published during the study period, and 1243 met inclusion criteria. Of those, 95.9% (n = 1,192) included at least one author affiliated with a LMIC. Among multicountry studies (n = 165), 40.4% did not include authors from every LMIC involved. Of the 9876 authors, most were affiliated with institutions from upper-middle-income countries (41.7%) and HICs (32.7%), with far fewer affiliated with lower middle-income (15.5%) and low-income countries (5.4%) (P < 0.001). In articles from low-income countries, first and last authors from HICs were more common than authors with low-income country affiliations (P < 0.001). CONCLUSIONS: Authorship parasitism was rare overall but common in multicountry studies. In studies conducted in low-income countries, HIC authors more commonly occupied first and last author positions than authors from the study countries. Where LMIC authors make substantial contributions, researchers should strive for authorship parity.

A Novel Approach to Combining Pediatric Emergency Medicine and Global Health Fellowships.

OBJECTIVES: To describe the creation of the first known combined Pediatric Emergency Medicine-Global Health (PEM-GH) fellowship for graduates of pediatric or emergency medicine residency programs. METHODS: We detail the necessary infrastructure for a successfully combined PEM-GH fellowship including goals, objectives, curriculum, timeline, and funding. The fellowship is jointly supported by the department of pediatrics, section of pediatric emergency medicine (PEM), and the hospital. Fellows complete all requirements for the PEM fellowship and Global Health, the latter requiring an additional 12 months of training. Components of the Global Health fellowship include international fieldwork, scholarly activity abroad, advanced degree coursework, disaster training, and didactic curricula. RESULTS: Since 2005, 9 fellows (8 pediatric-trained and 1 emergency medicine-trained) have completed or are enrolled in the PEM-GH fellowship; 3 have graduated. All fellows have completed or are working toward advanced degrees and have or will participate in the disaster management course. Fellows have had 7 presentations at national or international meetings and have published 6 articles in peer-reviewed journals. Of the three graduates, all are working in academic PEM-GH programs and work internationally in Africa and/or Latin America. CONCLUSIONS: Our response to a global trend toward improvement in PEM care was the development of the first combined PEM-GH fellowship program. Recognizing the value of this program within our own institution, we now offer it as a model for building such programs in the future. This fellowship program promises to be a paradigm that can be used nationally and internationally, and it establishes a foundation for a full-fledged accredited and certified subspecialty.

Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana.

BACKGROUND: Kaposi sarcoma (KS) is the most common HIV-associated malignancy in sub-Saharan Africa. The presentation and outcomes of pediatric KS are not well understood. PROCEDURE: We performed a retrospective cohort analysis of 81 HIV-infected children with KS at the Baylor Children's Clinical Centres of Excellence in Malawi and Botswana from March 2003 to October 2009. RESULTS: Eighty-one children with KS were identified whose median age was 8.0 (inter-quartile range 5.1-11.3) years. KS lesions were presented primarily on the skin (83%), lymph nodes (52%), and oral mucosa (41%). Occasionally disease was limited to the lymph nodes only (10%). Severe immunosuppression (70%), anemia (29%), and thrombocytopenia (17%) were common laboratory findings. Highly active antiretroviral therapy (HAART) was administered to 94% of children, including 77% who received HAART plus chemotherapy. KS immune reconstitution inflammatory syndrome (IRIS) occurred in 22%. Disease status 12 months after KS diagnosis was determined for 69 children: 43% were alive and 57% had died. Severe immunosuppression was independently associated with mortality in multivariate analysis (OR = 4.3; 95% CI 1.3-14.6; P = 0.02). CONCLUSION: KS occurs in a significant number of HIV infected children in sub-Saharan Africa. Pediatric KS is distinct from KS in adults. Lymph node involvement was a common manifestation of KS in children, and severe immunosuppression was associated with the highest mortality risk. Though overall mortality was high in children with KS, patients did achieve clinical remission in settings with limited diagnostic and therapeutic resources.

Pneumonia and malnutrition are highly predictive of mortality among African children hospitalized with human immunodeficiency virus infection or exposure in the era of antiretroviral therapy.

OBJECTIVE: To identify clinical characteristics predicting death among inpatients who are infected with or exposed to human immunodeficiency virus (HIV) during a period of pediatric antiretroviral therapy scale-up in sub-Saharan Africa. STUDY DESIGN: Retrospective review of medical records from every child with HIV infection (n = 834) or exposure (n = 351) identified by routine inpatient testing in Kamuzu Central Hospital, Lilongwe, Malawi, September 2007 through December 2008. RESULTS: The inpatient mortality rate was high among children with HIV infection (16.6%) and exposure (13.4%). Clinically diagnosed Pneumocystis pneumonia or very severe pneumonia independently predicted death in inpatients with HIV infection (OR 14; 95% CI 8.2 to 23) or exposure (OR 21; CI 8.4 to 50). Severe acute malnutrition independently predicted death in children who are HIV infected (OR 2.2; CI 1.7 to 3.9) or exposed (OR 5.1; CI 2.3 to 11). Other independent predictors of death were septicemia, Kaposi sarcoma, meningitis, and esophageal candidiasis for children infected with HIV, and meningitis and severe anemia for inpatients exposed to HIV. CONCLUSIONS: Severe respiratory tract infections and malnutrition are both highly prevalent and strongly associated with death among hospitalized children who are HIV infected or exposed. Novel programmatic and therapeutic strategies are urgently needed to reduce the high mortality rate among inpatients with HIV infection and HIV exposure in African pediatric hospitals.

Association between Antiretroviral Therapy and Cancers among Children Living with HIV in Sub-Saharan Africa.

Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0-18 years from 2004-2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART.

Leprosy and international adoption: a case report and review of diagnostic and treatment dilemmas.

Hansen disease, commonly known as leprosy, is uncommon in the United States and poses difficult diagnostic and treatment challenges. A 10-year-old girl was adopted from Ethiopia with a history of "multibacillary leprosy" and "multidrug treatment" for 12 months. Three months after her arrival in the United States and 4 months after treatment was completed, she presented with new papules and plaques on her left nose and ear. Herein, we present her case and review current treatment options in leprosy in children and the management of immunologic reactions.

Global Disparities Between Pediatric Publications and Disease Burden From 2006 to 2015.

There is a disproportionate burden of pediatric disease in low- and middle-income countries (LMICs); however, the proportion and relation of published articles to childhood disease burden in LMICs have not been assessed previously. This study aimed to determine whether published articles and disease topics from research conducted in LMICs in the most widely cited pediatric journals reflected the global burden of childhood disease. We reviewed all articles published from 2006 to 2015 in the 3 pediatric journals with the highest Eigenfactor scores to identify studies conducted in the World Bank-designated LMICs. We abstracted study topic, design, purpose, country, and funding sources. We derived descriptive statistics, Fisher's exact χ2 test, Monte Carlo estimates, and Spearman's rank order coefficients. Of the 19 676 articles reviewed, 10 494 were original research articles. Of those, 965 (9.2%) were conducted in LMICs. Over the study period, the proportion of published articles originating from LMICs increased (r 2 = 0.77). Disease topics did not reflect the underlying burden of disease as measured in disability-adjusted life years (Spearman's rank order coefficient = 0.25). Despite bearing the majority of the world's burden of disease, articles from LMICs made up a small proportion of all published articles in the 3 pediatric journals with the highest Eigenfactor scores. The number of published articles from LMICs increased over the study period; nevertheless, the topics did not coincide with the burden of disease in LMICs. These discrepancies highlight the need for development of a research agenda to address the diseases that are the greatest threat to the majority of children worldwide.

Reciprocity? International Preceptors' Perceptions of Global Health Elective Learners at African Sites.

BACKGROUND: Short-term global health electives (STGHEs) have become increasingly common, with evidence showing educational and clinical benefits for short-term learners (STLs). Despite increased recognition that STGHEs should be mutually beneficial for host sites and STLs, evidence demonstrating the impact on international host preceptors is lacking. OBJECTIVES: To understand international host preceptors' perceptions regarding benefits and burdens of hosting STLs. METHODS: Focus group discussions with a convenience sample of 10 of 18 eligible preceptors were conducted at pediatric STGHE sites in Malawi and Lesotho. Qualitative content analysis was performed to identify themes using a deductive-inductive approach. FINDINGS: Common themes regarding benefits to preceptors included increased knowledge and resources for learning from STLs, broadened differential diagnoses, and the satisfaction of teaching. Regarding burdens, preceptors perceived that supervising STLs decreases efficiency. Preceptors identified the burden of having to intervene in instances that could lead to patient harm. Some preceptors perceived that STLs under-valued preceptors' clinical decision-making in resource-limited contexts. CONCLUSIONS: Our findings emphasize the need for institutions to identify mutuality of benefits between STLs and host sites when developing STGHEs. Host preceptors identified robust pre-departure training for STLs, lengthened duration of STGHEs, and formal preceptor orientation as ways to enhance mutuality of benefits.

Host clinical preceptors' perceptions of professionalism among learners completing global health electives.

OBJECTIVES: This study aims to gain an understanding of the perceptions of host clinical preceptors in Malawi and Lesotho of the professionalism exhibited by short-term learners from the United States and Canada during short-term global health electives. METHODS: Focus group discussions were conducted with 11 host clinical preceptors at two outpatient pediatric HIV clinics in sub-Saharan Africa (Malawi and Lesotho). These clinics host approximately 50 short-term global health learners from the United States and Canada each year. Focus group moderators used open-ended discussion guides to explore host clinical preceptors' perceptions of the professionalism of short-term global health learners. Thematic analysis with an inductive approach was used to identify salient themes from these focus group discussions. RESULTS: Eleven of the 18 possible respondents participated in two focus group discussions. Adaptability, eagerness to learn, active listening, gratitude, initiative, and punctuality was cited as professional behaviors among short-term global health learners. Cited unprofessional behaviors included disregard of local clinicians' expertise and unresponsiveness to feedback. Host clinical preceptors described difficulty providing feedback to short-term global health learners and discrepancies between what may be considered professional in their home setting versus in the study settings. Respondents requested pre-departure orientation for learners and their own orientation before hosting learners. CONCLUSIONS: Both host clinical preceptors and short-term global health learners should be aware that behaviors that may be considered best practice in one clinical setting may be perceived as unprofessional in another. Future studies to develop a common definition of professionalism during short-term global health electives are merited.

Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children.

OBJECTIVES: To describe the clinical characteristics and course of children with laboratory-diagnosed Rocky Mountain spotted fever (RMSF) and to identify clinical findings independently associated with adverse outcomes of death or discharge with neurologic deficits. STUDY DESIGN: Retrospective chart review of 92 patients at six institutions in the southeastern and southcentral United States from 1990 to 2002. Statistical analyses used descriptive statistics and multiple logistic regression. RESULTS: Children with RMSF presented to study institutions after a median of 6 days of symptoms, which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%); no other symptom or sign was present in >50% of children. Only 49% reported antecedent tick bites. Platelet counts were <150,000/mm3 in 59% of children, and serum sodium concentrations were <135 mEq/dL in 52%. Although 86% sought medical care before admission, only 4 patients received anti-rickettsial therapy during this time. Three patients died, and 13 survivors had neurologic deficits at discharge. Coma and need for inotropic support and intravenous fluid boluses were independently associated with adverse outcomes. CONCLUSIONS: Children with RMSF generally present with fever and rash. Delays in diagnosis and initiation of appropriate therapy are unacceptably common. Prognosis is guarded in those with hemodynamic instability or neurologic compromise at initiation of therapy.

Human monocytic ehrlichiosis in children.

BACKGROUND: Human monocytic ehrlichiosis (HME) is a tick-borne illness caused by Ehrlichia chaffeensis. Data about disease in children have been largely derived from case reports or small case series. METHODS: A retrospective review of all medical and laboratory records from 6 sites located in the "tick belt" of the Southeastern United States was carried out. Demographic, history and laboratory data were abstracted from the identified medical records of patients. Bivariate statistical comparisons were performed using Fisher exact test or Wilcoxon rank sum tests. RESULTS: Common clinical signs and symptoms of patients with HME (n = 32) included fever (100%), headache (69%), myalgia (69%), rash (66%), nausea/vomiting (56%), altered mental status (50%) and lymphadenopathy (47%). Only 48% had a complaint of fever, headache and rash. Common laboratory abnormalities included thrombocytopenia (94%), elevated aspartate aminotransferase (90%), elevated alanine aminotransferase (74%), hypoalbuminemia (65%), lymphopenia (57%), leukopenia (56%) and hyponatremia (55%). The median number of days of illness before the initiation of antirickettsial therapy was 6. Patients who received sulfonamides before starting doxycycline therapy developed a rash, were admitted to the hospital, and started doxycycline at a later date. Twenty-two percent of patients were admitted to the intensive care unit with 12.5% of patients requiring ventilatory and blood pressure support. CONCLUSIONS: Although HME has been recognized among children for almost 20 years, there is only a limited knowledge about its clinical course. Even among physicians practicing in endemic regions, few cases are diagnosed each year. More work is needed to understand the true burden of disease and the natural history among asymptomatically and symptomatically infected children.

Recurrent systemic pneumococcal disease in children.

BACKGROUND: Recurrent systemic pneumococcal infection usually occurs in immunocompromised patients and patients with underlying conditions. METHODS: Between 1993 and 2006, investigators at 8 pediatric hospitals prospectively identified cases of invasive pneumococcal disease (IPD) and retrospectively documented demographics and clinical information. Antibiotic susceptibility was determined for penicillin and ceftriaxone by microbroth dilution. Isolates were serotyped and molecular relatedness determined using pulse field gel electrophoresis (PFGE). RESULTS: Four thousand sixty-seven children were diagnosed with IPD over 12.3 years. One hundred and 8 episodes of recurrent disease were seen in 90 children (2.6%); 75 experienced 2 infections, 12 experienced 3 infections and 3 experienced 4 infections. Fourteen of the 15 children with >2 episodes of infection had underlying conditions. The mean duration between 1st and 2nd infection was 22.9 weeks for children with no known underlying condition and 43.0 weeks for children with an underlying condition (P = 0.001). Seventy episodes of IPD among the 90 patients were caused by a different serotype or a different genotype as demonstrated by the PFGE. Sixteen children had intervals <30 days between infections; 7 were caused by different strains. CONCLUSIONS: Approximately 80% of the children with recurrent invasive pneumococcal disease had underlying conditions. Seven of 16 children with recurrent infection <30 days apart were caused by acquisition of a new strain. Relapse of infection requires documentation that the pneumococcal isolates are not only the same serotype but also have the same PFGE patterns.

Creating a medical education enterprise: leveling the playing fields of medical education vs. medical science research within core missions.

BACKGROUND: Unlike publications of medical science research that are more readily rewarded, clinician-educators' scholarly achievements are more nebulous and under-recognized. OBJECTIVE: Create an education enterprise that empowers clinician-educators to engage in a broad range of scholarly activities and produce educational scholarship using strategic approaches to level the playing fields within an organization. DESIGN: The authors analyzed the advantages and disadvantages experienced by medical science researchers vs. clinician educators using Bolman and Deal's (B&D) four frames of organization (structural, human resource, political, symbolic). The authors then identified organizational approaches and activities that align with each B&D frame and proposed practical strategies to empower clinician-educators in their scholarly endeavors. RESULTS: Our medical education enterprise enhanced the structural frame by creating a decentralized medical education unit, incorporated the human resource component with an endowed chair to support faculty development, leveraged the political model by providing grant supports and expanding venues for scholarship, and enhanced the symbolic frame by endorsing the value of education and public recognition from leaderships. In five years, we saw an increased number of faculty interested in becoming clinician-educators, had an increased number of faculty winning Educational Awards for Excellence and delivering conference presentations, and received 12 of the 15 college-wide awards for educational scholarship. These satisfactory trends reflect early success of our educational enterprise. CONCLUSIONS: B&D's organizational frames can be used to identify strategies for addressing the pressing need to promote and recognize clinician-educators' scholarship. We realize that our situation is unique in several respects, but this approach is flexible within an institution and transferable to any other institution and its medical education program. ABBREVIATIONS: B&D: Bolman and Deal; CRIS: Center for Research, Innovation, and Scholarship; OOR: Office of Research.