Search

Background Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. Objective The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. Methods PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. Results Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. Conclusions PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

BackgroundOur understanding of SARS-CoV-2 evolution and mutation rate is limited. The rate of SARS-CoV-2 evolution is minimized through a proofreading function encoded byNSP-14and may be affected by patient comorbidity. Current understanding of SARS-CoV-2 mutational rate is through population based analysis while intra-host mutation rate remains poorly studied.MethodsViral genome analysis was performed between paired samples and mutations quantified at allele frequencies (AF) ≥0.25, ≥0.5 and ≥0.75. Mutation rate was determined employing F81 and JC69 evolution models and compared between isolates with (ΔNSP-14) and without (wtNSP-14) non-synonymous mutations in NSP-14 and by patient comorbidity.ResultsForty paired samples with median interval of 13 days [IQR 8.5-20] were analyzed. The estimated mutation rate by F81 modeling was 93.6 (95%CI:90.8-96.4], 40.7 (95%CI:38.9-42.6) and 34.7 (95%CI:33.0-36.4) substitutions/genome/year at AF ≥0.25, ≥0.5, ≥0.75 respectively. Mutation rate in ΔNSP-14 were significantly elevated at AF>0.25 vs wtNSP-14. Patients with immune comorbidities had higher mutation rate at all allele frequencies.DiscussionIntra-host SARS-CoV-2 mutation rates are substantially higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated mutation rate at low AF. Immunosuppressed patients have elevated mutation rate at all AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling.

OBJECTIVES Kaposi sarcoma (KS) is one of the most common childhood cancers in eastern and central Africa. It has become a treatable disease with increasing availability of antiretroviral therapy (ART) and chemotherapy. We aimed to fill the data gap in establishing whether long-term survival is achievable for children in low-income countries. METHODS We retrospectively analysed data for children and adolescents aged ≤ 18.9 years diagnosed with HIV-related or endemic KS from 2006 to 2015 who received standardized institutional treatment regimens utilizing chemotherapy plus ART (if HIV-positive) at a tertiary care public hospital in Lilongwe, Malawi. Long-term survival was analysed and mortality was associated with KS for those with refractory/progressive disease at the time of death. RESULTS There were 207 children/adolescents with KS (90.8% HIV-related); 36.7% were alive, 54.6% had died, and 8.7% had been lost to follow-up. The median follow-up time for survivors was 6.9 years (range 4.2-13.9 years). Death occurred at a median of 5.3 months after KS diagnosis (range 0.1-123 months). KS progression was associated with mortality for most (61%) early deaths (survival time of < 6 months); conversely, KS was associated with a minority (31%) of late-onset deaths (after 24 months). The 7-year overall survival was 37% [95% confidence interval (CI) 30-44%] and was higher for those diagnosed between 2011 and 2015 compared to 2006-2010: 42% (95% CI 33-51%) versus 29% (95% CI 20-39%), respectively (P = 0.01). Among the 66 HIV-positive survivors, 58% were still on first-line ART. CONCLUSIONS Long-term survival is possible for pediatric KS in low-resource settings. Despite better survival in more recent years, there remains room for improvement.

Background Our understanding of SARS-CoV-2 evolution is limited. Most estimates arise from analysis of global databases populated with unrelated sequences and is currently estimated at ∼27.7 substitutions/genome/year. SARS-CoV-2 polymerase contains a proofreading function encoded by NSP-14 limiting change. Additionally, virus evolution may be influenced by patient comorbidity. Intra-host mutational rate (MR) during infection remain poorly studied. Methods To minimize effect of vaccination and/or natural immunity on MR analysis, paired samples from adults originating from the initial pandemic wave (3/17/2020 through 5/27/2020) were retrieved and analyzed at Cleveland Clinic. Viral genome analysis was performed using next generation sequencing, and mutations between paired samples were quantified at allele frequencies (AF) ≥ 0.1, ≥ 0.5 and ≥ 0.75 and compared. MR was calculated employing F81 and JC69 evolution­­­­ models and compared between isolates with (Δ NSP-14) and without (wildtype, wt) non-synonymous mutations in NSP-14 and by comorbidity. Results A total of 40 patients (80 sample pairs) were identified. Median interval between paired tests was 15 days [range 5-32]. The estimated MR by F81 modeling was 317.2 (95%CI 312.0-322.3), 54.6 (95%CI 52.5-56.7) and 45.1 (95%CI 43.1-47.0) substitutions/genome/year at AF of ≥0.1, ≥0.5, ≥0.75 respectively. Rates in ΔNSP-14 (n=13) vs wt (n=27) groups were 557.7 (95%CI 537.0-578.2) vs 193.1 (95%CI 187.1-199.1) p-value 0.001, 50.8 (95%CI 44.3-57.3) vs 56.3 (95%CI 53.1-59.4) p-value 0.144, and 31.0 (95%CI 25.9-36.1) vs 51.3 (95%CI 48.3-54.3) p- value < 0.001 at AF ≥0.1, ≥0.5, ≥0.75 respectively. Patients with immune comorbidities (n=6) had significantly higher MR of 137.6 (95%CI 114.6-160.5) vs 40.5 (95%CI 38.4-42.7) p-value < 0.001, and 113.7 (95%CI 92.8-134.5) vs 33.4 (95%CI 31.5-35.4) p-value < 0.001 at AF ≥0.5 and ≥0.75 respectively. Similar results were obtained when using the JC69 model. Conclusion Intra-host SARS-CoV-2 mutation rates are higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated MR at low AF. Immunosuppressed patients have elevated MR at higher AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling. Disclosures Frank Esper, M.D, Johnson and Johnson: Advisor/Consultant Daniel D. Rhoads, M.D. PhD, Luminex: Advisor/Consultant|Talis Biomedical: Advisor/Consultant|Thermo Fisher: Advisor/Consultant.

The HIV/AIDS epidemic has driven the rise in cases of Kaposi sarcoma (KS) among children and adolescents living with HIV in countries with high Human gammaherpesvirus 8 (HHV-8) seroprevalence, such as Tanzania, where specialized oncology programs are sparse. Consequently, descriptions of successful treatment of KS in children and adolescents by general pediatricians are important. A retrospective analysis was performed of children and adolescents diagnosed with KS and treated with chemotherapy and combination antiretroviral therapy (cART) at the Baylor College of Medicine Children's Foundation Tanzania Center of Excellence - Mbeya between 2011 and 2017. Sixty-one patients were diagnosed with KS with a median age of 12.6 years (interquartile range (IQR) 9.4 - 15.5). Diagnosis was confirmed by histopathology in 36% (22/61). Among HIV positive patients (59/61), 78% (46/59) were on cART at KS diagnosis. Severe immunosuppression was present in 63% (35/56) of those with CD4 data and 44% (27/61) had SAM. Advanced-stage T1 disease was present in 64% (39/61), including 28% (17/61) with visceral/disseminated KS. Two-year estimated overall survival (OS) was 72% (95% Confidence Interval (CI): 58%-82%) and median follow up for survivors was 25.7 months (IQR 14.2-53.8). No patients were lost to follow up. Two-year OS was 63% (95% CI: 44%-77%) in patients with severe immune suppression and 60% (95% CI: 37%-76%) in patients with SAM. Among patients with visceral/disseminated KS, 53% (9/17) survived. This retrospective analysis demonstrated favorable outcomes in a complex cohort of children and adolescents with KS treated with chemotherapy by general pediatricians in Tanzania.

High-dose methotrexate (HD-MTX) with rigorous supportive care is essential to the treatment of pediatric non-Hodgkin lymphomas (NHL). We describe the safety and tolerability of HD-MTX in patients with NHL treated at our center. In our cohort of 46 patients, the majority had at least one course of delayed clearance and/or creatinine elevation. Additionally, more than one-third of patients experienced an episode of grade ≥3 mucositis. Creatinine elevations and delayed clearance were independently associated with subsequent grade ≥3 mucositis. We advocate for greater availability of methotrexate monitoring to allow dose escalation of this essential modality around the world.

This is a study to examine whether those individuals with more internet gaming disorder symptoms are likely to choose video games to cope with negative emotions than those who have no symptoms.

Background Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants remains limited. Method Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes. Results In total 2779 patients identified with either Alpha (n = 1153), Gamma (n = 122), Delta (n = 808), or Omicron variants (n = 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (χ2 = 12.8, P < .001; χ2 = 21.6, P < .002; χ2 = 9.6, P = .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 [26.9%] and 513/696 [73.7%], respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2. Conclusions Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.

Long-term cure of childhood Burkitt lymphoma (BL) in sub-Saharan Africa after treatment with single-agent cyclophosphamide has been documented for more than half of a century. Contemporary cure rates for the highest-risk patients with BL in high-income countries exceed 90% using intensive multiagent chemotherapy. By contrast, the majority of African children with BL still die. Data spanning 5 decades in Africa have repeatedly shown that the children most likely to achieve cure with limited cyclophosphamide regimens are those with lower-stage disease isolated to the jaw. Attempts to intensify the cyclophosphamide monotherapy backbone with the addition of vincristine, low-dose methotrexate, prednisone, doxorubicin, and/or low-dose cytarabine have not yielded significant improvement. High-dose methotrexate is a critical component in the treatment of childhood BL worldwide. Although initial efforts in Africa to incorporate high-dose methotrexate resulted in high treatment-related mortality, more recent collaborative experiences from North and West Africa, as well as Central America, demonstrate that it can be administered safely and effectively, despite limitations in supportive care resources. Recognizing the unacceptable disparity in curative outcomes for BL between the United States/Europe and equatorial Africa, there is a critical need to safely adapt contemporary treatment regimens to optimize curative outcomes amid the resource limitations in regions where BL is endemic. Here, we critically review reports of BL treatment outcomes from low- and middle-income countries, in addition to data from high-income countries that predated modern intensified regimens, to identify potential strategies to improve the therapeutic approach for children suffering from BL in sub-Saharan Africa.

Vivid descriptions of Kaposi sarcoma (KS) occurring in children and adolescents from central and eastern Africa originated over fifty years ago. Unique clinical characteristics of pediatric KS in Africa were well described within these geographic regions that were eventually understood to be endemic for human herpesvirus-8/Kaposi sarcoma herpesvirus (HHV-8/KSHV) infection, the causative agent of KS. Having catapulted in incidence with the HIV epidemic, KS is currently among the top five most common childhood cancers in numerous countries throughout the region. The main feature that differentiates the childhood form of KS from adult disease is clinical presentation with primarily bulging lymphadenopathy. This group of patients represents the most common clinical subtype of pediatric KS in KSHV-endemic regions. Lymphadenopathic KS in children is associated with other distinct features, such as sparse occurrence of prototypical hyperpigmented cutaneous lesions, frequent presentation with severe cytopenias and a normal CD4 count, and a fulminant clinical course if untreated with chemotherapy. Increased awareness and improved recognition of lymphadenopathic KS is critically important, particularly because this subset of patients typically experiences a favorable response to chemotherapy characterized by durable complete remission. Clinical phenotypes typically observed in adult KS also occur in children—mild/moderate disease limited to cutaneous and oral involvement, woody edema, and visceral disease. This review summarizes the heterogeneous patterns of disease presentation and treatment response observed among the divergent clinical phenotypes of pediatric KS, highlights additional KSHV-related malignancies, and explores some of the potential biological drivers of such clinical phenomena.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non-familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X-linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non-neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders and lymphomas can cause neoplasia-associated HLH. The present review will discern between EBV-associated familial and non-familial HLH and highlight diagnostic and therapeutic considerations. Non-familial EBV-associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non-neoplastic EBV-HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV-positive T-cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV-related complications is desperately needed to improve survival for patients with neoplasia-associated HLH.

Treating Kaposi sarcoma (KS) in children, adolescents, and young adults (AYA) remains a challenge in low- and middle-income countries (LMIC) where chemotherapy options and availability are limited. We describe a retrospective cohort review of pediatric patients with KS treated with paclitaxel in Mbeya, Tanzania, between 1 March 2011 and 31 December 2019. Paclitaxel was given to patients who had KS relapse, a contraindication to bleomycin, vincristine, and doxorubicin (ABV), special circumstances in which a clinician determined that paclitaxel was preferable to ABV, or experienced treatment failure, defined as persistent KS symptoms at the completion of treatment. All patients also received multidisciplinary palliative care. Seventeen patients aged 5.1–21.3 years received paclitaxel, of whom 47.1% (8/17) had treatment failure, 29.4% (5/17) received paclitaxel as initial treatment, and 23.5% (4/17) had relapsed. All HIV positive patients (16/17) were given anti-retroviral therapy (ART) and 87.5% (14/16) achieved viral load &lt, 1000 cp/mL. At censure, 82.3% (14/17) of patients were alive—71.4% (10/14) achieved complete clinical remission and 28.6% (4/14) achieved a partial response. The median follow up was 37.3 months (range 8.0–83.5, IQR 19.7–41.6), and no patients were lost to follow up. In this cohort, high rates of long-term survival and favorable outcomes were possible with paclitaxel treatment.

Simple Summary Most children infected with HIV live in Sub-Sahara Africa (SSA). These children are at risk of cancers related to HIV infection, but the degree of this risk and how it is influenced by antiretroviral therapy (ART) is unknown. In this study, we determined the subtypes, incidence, and risk factors of cancers in children with HIV in SSA and receiving ART with the goal of learning how we may prevent these cancers. We found that Kaposi sarcoma and lymphoma are the most common, comprising about 77% and 19% of cancers in these children, respectively. For every 100,000 person-years, 47.6 children developed cancer. Waiting to start ART until after 2 years old and having had severe immunosuppression were the two biggest risk factors for cancer that we identified. The findings justify the recommendations to start children on ART as soon as they are diagnosed with HIV regardless of their CD4 immune status. Abstract 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.

Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed&ndash, Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3&ndash, 18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-&alpha, IFN-&gamma, IL-8) and slow early response (CCL13, IFN-&lambda, 1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.

Acute hemorrhagic edema of infancy is a benign rare presentation of leukocytoclastic vasculitis that affects children between 4 and 24 months of age. It usually involves the distal extremities, face, and ears. We report an atypical presentation of AHEI in a 1 year 5 months old boy starting initially over the trunk and back, then spreading to the face and extremities. Mycoplasma pneumonia IgM was found to be positive. The rash resolved spontaneously within two weeks. Herein we present a case of Mycoplasma induced AHEI with an atypical clinical presentation followed by a review of the literature.

Background Clinical manifestations of extraneural infection with the pork tapeworm Taenia solium typically affect the muscles, eyes, alimentary canal, and/or subcutaneous tissues. Children living with HIV are at increased risk for more widespread and severe manifestations of food-borne opportunistic infections, including T. solium, due to fluctuating levels of immunosuppression. We present a case of disseminated T. solium in a HIV-positive child with Kaposi sarcoma living in Tanzania with cysticercosis presenting as widespread subcutaneous nodules. Case presentation A 4-year-old HIV-positive boy in Southern Tanzania presented for evaluation of > 30 violaceous skin lesions, few subcutaneous nodules, and a circumferential violaceous penile lesion which rapidly grew after initiation of ART. The patient was clinically diagnosed with Kaposi sarcoma and started on chemotherapy with bleomycin, vincristine, and doxorubicin. He completed 10 cycles of chemotherapy, with full resolution of the violaceous skin and penile lesions but persistence of his subcutaneous nodules, thus paclitaxel was added. After 12 additional cycles of paclitaxel, his subcutaneous nodules enlarged, and biopsy of a scapular subcutaneous nodule was performed. Histopathology revealed a cystic structure with a central larval scolex and serrated spiral canal consistent with T. solium, which confirmed a diagnosis of disseminated cysticercosis. He completed a 10-day course of praziquantel and albendazole with resolution of the subcutaneous nodules. Conclusions Disseminated cysticercosis is an unusual opportunistic infection which can present as subcutaneous nodules without other typical cysticercosis symptoms. Immunosuppression – from HIV and/or chemotherapy – may unmask cysticercosis in children in endemic regions and result in more severe manifestations of this disease. Cysticercosis should remain on a clinician’s differential for subcutaneous nodules, especially in children living with HIV. Cysticercosis can mimic Kaposi sarcoma, and histopathology is essential to accurately diagnose and manage patients with concerning skin lesions.