High rate of clinically unrecognized SARS-CoV-2 infections in pediatric palliative care patients.

Little is known about the frequency and clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in pediatric patients with severe comorbidities. In this prospective cross-sectional trial, the seroprevalence of SARS-CoV-2-IgG in patients with life-limiting conditions being treated by a large specialized pediatric palliative home-care team was determined. In order to gain insight into the infection chain, close contacts of seropositive patients were also included in the study. We analyzed the sera of 39 patients and found a 25.6% seroprevalence for SARS-CoV-2. No SARS-CoV-2 infections were known prior to the study. No significant difference was found in the symptom load between seropositive and seronegative patients during the risk period for SARS-CoV-2 infections. Of the 20 close contacts tested, only one was seropositive for SARS-CoV-2.Conclusions: Our results indicate a substantially high prevalence of silent SARS-CoV-2 infections in pediatric palliative care patients. Surprisingly, no severe outcomes were seen in this fragile patient collective with severe comorbidities. The chain of infection and thus the reason for the high frequency of SARS-CoV-2 infections in pediatric palliative care patients remain unclear. What is Known: •Even though severe disease courses of COVID-19 have been reported in children, there are yet no established risk factors for SARS-CoV-2 in pediatric patients. What is New: •In this cross-sectional seroprevalence study of palliative pediatric patients with severe life-limiting conditions, a high rate of seropositive patients (25.6%) was found. •Surprisingly, all seropositive patients were previously unrecognized, despite the severe comorbidities of our collective.

[Antibacterial Prophylaxis in Children and Adolescents Undergoing Therapy for Cancer - Statement of the Society of Pediatric Oncology and Hematology (GPOH) and of the German Society for Pediatric Infectious Diseases (DGPI) on Two Current International Guidelines]. / Antibakterielle Prophylaxe in der Pädiatrischen Hämatologie und Onkologie.

Immunocompromised children and adolescents receiving treatment for cancer have an increased risk for potentially life-threatening infectious complications such as blood stream infections with Gram-positive and Gram-negative pathogens. Therefore, several centers for Pediatric Hematology and Oncology administer antibacterial prophylaxis to these patients to lower morbidity and mortality. Two pediatric specific guidelines on antibacterial prophylaxis were recently published. One of these guidelines was drawn up by an international group of pediatric experts of Europe, North and South America and Australia. The other guideline was prepared by an European group convened at the Eighth European Conference on Infections in Leukaemia (ECIL-8). In this review article, the working groups "Infections" of the Society of Pediatric Oncology and Hematology (GPOH) and "Fever in the neutropenic host" of the German Society for Pediatric Infectious Diseases" (DGPI) summarize the available data from randomized studies, systematic reviews and meta-analyses on antibacterial prophylaxis as well of current data on the emergence of resistance and discuss methodological aspects and the recommendations of the two guidelines.

Case Report: Convalescent Plasma Achieves SARS-CoV-2 Viral Clearance in a Patient With Persistently High Viral Replication Over 8 Weeks Due to Severe Combined Immunodeficiency (SCID) and Graft Failure.

We describe the unique disease course and cure of SARS-CoV-2 infection in a patient with SCID and graft failure. In absence of a humoral immune response, viral clearance was only achieved after transfusion of convalescent plasma. This observation underscores the necessity of the humoral immune response for SARS-CoV-2 clearance.

Reducing Hematologic Toxicity With Short Course Postexposure Prophylaxis With Zidovudine for HIV-1 Exposed Infants With Low Transmission Risk.

Using retrospectively collected data from 383 infants born to HIV-1-infected mothers receiving antiretroviral therapy, we compared transmission rates and hematologic toxicity between infants receiving 2-week (short course) versus longer duration zidovudine postexposure prophylaxis. Short course resulted in lower hematologic toxicity without evidence of increased vertical transmission risk.

HIV-1 Subtype Diversity and Prevalence of Primary Drug Resistance in a Single-Center Pediatric Cohort in Germany.

OBJECTIVES: Data on drug-resistant mutations (DRMs) in HIV-1-infected therapy-naïve children are scarce. The aim of this study was to determine the HIV-1 subtype distribution and the prevalence of DRMs in therapy-naïve HIV-1-infected children who received routine care at the University Hospital Düsseldorf, Düsseldorf, Germany. METHODS: Records of all HIV-1-infected children who received routine care between January 2005 and December 2015 were analyzed retrospectively. The collected data included demographics, clinical characteristics, CD4 cell count, viral load, HIV-1 subtype, and resistance genotype at baseline. RESULTS: 83 HIV-1-infected children received routine care during the observation period. HIV-1 subtypes were available in 61/83 patients (73.5%) and baseline HIV-1 resistance in 24 (29%). The prevalence of major DRMs was 29% (21% nucleoside reverse-transcriptase inhibitors [NRTIs], 12.5% non-NRTIs, and 4% protease inhibitors). Minor mutations in the protease gene were common (58%). Non-B subtypes were predominant (77%). CONCLUSIONS: We report a predominance of non-subtype-B infections and a higher prevalence of DRMs compared to other pediatric cohorts from resource-rich settings. The difference in HIV-1 subtype distribution is due to the fact that a relevant proportion of pediatric patients in Germany are immigrants from high-prevalence settings in sub-Saharan Africa where non-B subtypes predominate.

HIV-1 seroreversion in HIV-1-infected children: do genetic determinants play a role?

BACKGROUND: HIV-1 seroreversion in infants with vertically transmitted HIV-1 infection who started ART in the first months of life has been reported in only a subset of patients. However, the reason why most infants remain seropositive despite similar treatment response is not understood. Here, we assessed whether HIV-1 seroreversion in maternally infected infants is associated with genetic determinants. METHODS: HIV-1-infected infants with a history of documented HIV-1 seroreversion were identified throughout Germany using a standardized questionnaire. At study entry immune reconstitution and anti-HIV-1 antibody expression were monitored as clinical parameters. To search for genetic determinants high-resolution HLA genotyping was performed. In addition, the coding sequence of the chemokine receptor CCR5 was analyzed by Sanger sequencing regarding potential mutations. RESULTS: Patients showed normal numbers and frequencies of lymphocyte subpopulations. Five out of eight patients still had seronegative HIV-1 antibody status at study entry. HLA genotyping revealed the enrichment of HLA-DQB1*03 and DQB1*06 alleles within the patient cohort. Only one patient was found to carry a 32 bp-deletion within the CCR5 gene. CONCLUSION: Our results indicate that the phenotype of HIV-1 seroreversion in infants might correlate with the presence of HLA class II alleles DQB1*03 and DQB1*06. This finding supports the idea of genetic predisposition determining HIV-1 seroreversion in vertically infected infants effectively treated with ART.

Risk adapted transmission prophylaxis to prevent vertical HIV-1 transmission: effectiveness and safety of an abbreviated regimen of postnatal oral zidovudine.

BACKGROUND: Antiretroviral drugs including zidovudine (ZDV) are effective in reducing HIV mother to child transmission (MTCT), however safety concern remains. The optimal duration of postnatal ZDV has not been established in clinical studies and there is a lack of consensus regarding optimal management. The objective of this study was to investigate the effectiveness and safety of a risk adapted two week course of oral postnatal ZDV as part of a combined intervention to reduce MTCT. METHODS: 118 mother infant pairs were treated according to the German-Austrian recommendations for HIV therapy in pregnancy and in HIV exposed newborns between 2000-2010. In the absence of factors associated with an increased HIV-1 transmission risk, children were assigned to the low risk group and treated with an abbreviated postnatal regimen with oral ZDV for 2 weeks. In the presence of risk factors, postnatal ZDV was escalated accordingly. RESULTS: Of 118 mother-infant pairs 79 were stratified to the low risk group, 27 to the high risk group and 11 to the very high risk group for HIV-1 MTCT. 4 children were lost to follow up. Overall Transmission risk in the group regardless of risk factors and completion of prophylaxis was 1.8% (95% confidence interval (CI) 0.09-6.6). If transmission prophylaxis was complete, transmission risk was 0.9% (95% CI 0.01-5.7). In the low risk group receiving two week oral ZDV transmission risk was 1.4% (95% CI 0.01-8.4) CONCLUSION: These data demonstrate the effectiveness of a short neonatal ZDV regimen in infants of women on stable ART and effective HIV-1 suppression. Further evaluation is needed in larger studies.

Association of nephrotic syndrome with immune reconstitution inflammatory syndrome.

BACKGROUND: Up to 50% of patients with severe immune deficiency experience an excessive inflammatory response called immune reconstitution inflammatory syndrome (IRIS) after the initiation of antiretroviral therapy (ART). IRIS has been observed after various opportunistic infections with pathogens such as mycobacteria, including Bacille Calmette-Guérin, cryptococci, human herpesvirus-8, non-Hodgkin's lymphoma, and progressive multifocal leukoencephalopathy. Non-acquired immune deficiency-defining illnesses can also deteriorate after commencement of ART. Renal IRIS has been reported in a few patients with mycobacterial infections, but to the best of our knowledge no cases of nephrotic syndrome and IRIS have been described. CASE-DIAGNOSIS/TREATMENT: We report the case of an infant with human immunodeficiency virus-1 (HIV-1) infection, Pneumocystis pneumonia, and encephalopathy. During immune reconstitution the patient developed nephrotic syndrome. Treatment of nephrotic syndrome was initiated with prednisone, an angiotensin-converting enzyme inhibitor (lisinopril), and low-molecular-weight heparin. ART was continued, but only a low level of lopinavir/ritonavir could be achieved. There was no relapse of nephrotic syndrome during 10 months of follow-up. CONCLUSIONS: Nephrotic syndrome may occur in infants during immune reconstitution and should not be overlooked.

polyethylene glycol-conjugated adenosine deaminase (ADA) therapy provides temporary immune reconstitution to a child with delayed-onset ADA deficiency.

We describe the effects of polyethylene glycol-conjugated adenosine deaminase (ADA) replacement therapy on lymphocyte counts, activation, apoptosis, proliferation, and cytokine secretion in a 14-month-old girl with "delayed-onset" ADA deficiency and marked immunodysregulation. Pretreatment lymphopenia affected T cells (CD4, 150/microl; CD8, 459/microl), B cells (16/microl), and NK cells (55/microl). T cells were uniformly activated and largely apoptotic (CD4, 59%; CD8, 82%); and T-cell-dependent cytokine levels in plasma were elevated, including the levels of interleukin 2 (IL-2; 26 pg/ml), IL-4 (81 pg/ml), IL-5 (46 pg/ml), gamma interferon (1,430 pg/ml), tumor necrosis factor alpha (210 pg/ml), and IL-10 (168 pg/ml). Mitogen-stimulated peripheral blood mononuclear cells show reduced IL-2 secretion and proliferation. During the first 5 months of therapy there was clinical improvement and partial immune reconstitution, with nearly normal lymphocyte subset numbers, reduced T-cell activation and CD4-cell apoptosis, and decreased plasma cytokine levels. In parallel, IL-2 secretion and the lymphocyte mitogenic response improved. Between 4 and 7 months, immunoglobulin G antibodies to bovine ADA developed and resulted in the complete reversal of immune recovery.

A novel mutation in the interleukin-2 receptor gamma gene as the cause of lymphopenia in a neonate vertically exposed to human immunodeficiency virus.

Perinatal transmission prophylaxis has led to a significant reduction of vertical human immunodeficiency virus (HIV) infection. Antiretroviral drugs are being widely used before and during pregnancy, although these drugs can have possible adverse effects on the fetus and newborn. In this context, we report a unique case of X-linked severe combined immunodeficiency in a neonate vertically exposed to HIV.

Nuclear factor kappaB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia.

BACKGROUND: Amorphic mutations in the X-linked nuclear factor kappaB essential modulator ( NEMO ) gene cause Incontinentia pigmenti, which is lethal in hemizygous male patients. Hypomorphic NEMO mutations in male patients lead to anhidrotic ectodermal dysplasia (EDA) with immunodeficiency. OBJECTIVE: To report the clinical features of a child bearing a NEMO mutation who displayed an immunodeficiency without EDA. METHODS: Documentation of clinical care, chart review, standard immunologic and microbiological laboratory techniques, mutation analysis of the NEMO gene. RESULTS: Since the age of 15 months, the patient had Mycobacterium avium disease, beginning with multiple adenitis, later followed by disseminated osteomyelitis and dermatitis. In addition, Haemophilus influenzae and Streptococcus pneumoniae infections led to bronchiectasis. An immunologic work-up revealed a low production of IFN-gamma by PBMCs associated with a hyper-IgM phenotype. Despite treatment using repeated cycles of a 4-drug antimycobacterial regimen, continuous subcutaneous IFN-gamma, repeated antibiotic treatment, and intravenous immunoglobulin substitution, the boy remained chronically ill. At the age of 12 years, the disease was complicated by severe autoimmune hemolytic anemia and eventually fatal herpes simplex virus 1 encephalitis despite high-dose acyclovir therapy. Although he did not present any sign of EDA, a novel type of disease-causing hypomorphic NEMO mutation (110-111insC in exon 2) was identified. CONCLUSION: This case demonstrates that patients hemizygous for NEMO mutations can present with an immunodeficiency without EDA. An investigation of NEMO should thus be undertaken in selected children with immunodeficiency despite the lack of EDA.

Safety and efficacy of a NRTI-sparing HAART regimen of efavirenz and lopinavir/ritonavir in HIV-1-infected children.

We studied a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the treatment of children infected with NRTI-resistant HIV-1. The combination of lopinavir/ritonavir and efavirenz suppressed HIV-1 levels for a prolonged period and resulted in a significant increase in CD4+ T cell numbers despite an extensive prior treatment with NRTI (>4 years). Observed side effects were transient with the exception of dyslipidaemia.