The New Normal: Delayed Peak SARS-CoV-2 Viral Loads Relative to Symptom Onset and Implications for COVID-19 Testing Programs.

BACKGROUND: Early in the coronavirus disease 2019 (COVID-19) pandemic, peak viral loads coincided with symptom onset. We hypothesized that in a highly immune population, symptom onset might occur earlier in infection, coinciding with lower viral loads. METHODS: We assessed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A viral loads relative to symptom duration in symptomatic adults (≥16 years) presenting for testing in Georgia (4/2022-4/2023; Omicron variant predominant). Participants provided symptom duration and recent testing history. Nasal swabs were tested by Xpert Xpress SARS-CoV-2/Flu/RSV assay and cycle threshold (Ct) values recorded. Nucleoprotein concentrations in SARS-CoV-2 polymerase chain reaction (PCR)-positive samples were measured by single molecule array. To estimate hypothetical antigen rapid diagnostic test (Ag RDT) sensitivity on each day after symptom onset, percentages of individuals with Ct value ≤30 or ≤25 were calculated. RESULTS: Of 348 newly-diagnosed SARS-CoV-2 PCR-positive individuals (65.5% women, median 39.2 years), 317/348 (91.1%) had a history of vaccination, natural infection, or both. By both Ct value and antigen concentration measurements, median viral loads rose from the day of symptom onset and peaked on the fourth/fifth day. Ag RDT sensitivity estimates were 30.0%-60.0% on the first day, 59.2%-74.8% on the third day, and 80.0%-93.3% on the fourth day of symptoms.In 74 influenza A PCR-positive individuals (55.4% women; median 35.0 years), median influenza viral loads peaked on the second day of symptoms. CONCLUSIONS: In a highly immune adult population, median SARS-CoV-2 viral loads peaked around the fourth day of symptoms. Influenza A viral loads peaked soon after symptom onset. These findings have implications for ongoing use of Ag RDTs for COVID-19 and influenza.

Age, GVHD prophylaxis, and timing matter in thrombotic microangiopathy after haematopoietic cell transplantation-A secondary CIBMTR analysis.

Most reports of risk factors (RF) for developing transplant-associated thrombotic microangiopathy (TA-TMA) and death are derived from paediatric and young adult cohorts, with minimal data on differences in RF and outcomes by age. In this secondary CIBMTR analysis, we used a previously prepared dataset that included all first allogenic haematopoietic cell transplantation (HCT) recipients with malignant or non-malignant diseases between 2008 and 2016. The incidence of TA-TMA 6 months post HCT was similar in children and adults 2.1% and 2.0% respectively. Grade 2-4 acute graft-versus-host disease (aGVHD) was a significant adjusted RF for developing TA-TMA in both children and adults. In adults, additional adjusted RFs for TA-TMA included female sex and black race, and in children an unrelated donor. Compared to a calcineurin inhibitor and sirolimus, other forms of GVHD prophylaxis had an adjusted decreased risk of developing TA-TMA in adults. Adjusted RF for death in those with TA-TMA (n = 652) included age ≥18 years old, early onset of TA-TMA diagnosis (<100 days post HCT), grade 3-4 aGVHD and a performance score of <90 prior to HCT. In this cohort, the incidence of TA-TMA was similar in children and adults, and TA-TMA timing was a newly identified RF for death.

Derivation and Internal Validation of a Novel Risk Assessment Tool to Identify Infants and Young Children at Risk for Post-Discharge Mortality in Dar es Salaam, Tanzania and Monrovia, Liberia.

OBJECTIVE: To derive and validate internally a novel risk assessment tool to identify young children at risk for all-cause mortality ≤60 days of discharge from hospitals in sub-Saharan Africa. STUDY DESIGN: We performed a prospective observational cohort study of children aged 1-59 months discharged from Muhimbili National Hospital in Dar es Salaam, Tanzania and John F. Kennedy Medical Center in Monrovia, Liberia (2019 to 2022). Caregivers received telephone calls up to 60 days after discharge to ascertain participant vital status. We collected socioeconomic, demographic, clinical, and anthropometric data during hospitalization. Candidate variables with P<0.20 in bivariate analyses were included in a multivariable logistic regression model with best subset selection to identify risk factors for the outcome. We internally validated our tool using bootstrapping with 500 repetitions. RESULTS: There were 1,933 young children enrolled in the study. The median (interquartile range) age was 11 (4, 23) months and 58.7% were male. In total, 67 (3.5%) died during follow-up. Ten variables contributed to our tool (total possible score 82). Cancer (adjusted odds ratio [aOR] 10.6, 95% CI 2.58, 34.6), pedal edema (aOR 6.94, 95% CI 1.69, 22.6), and leaving against medical advice (aOR 6.46, 95% CI 2.46, 15.3) were most predictive of post-discharge mortality. Our risk assessment tool demonstrated good discriminatory value (optimism corrected area under the receiver operating characteristic curve 0.77), high precision, and sufficient calibration. CONCLUSIONS: After validation, this tool may be used to identify young children at risk for post-discharge mortality to direct resources for follow-up of high-risk children.

D-dimer and sinusoidal obstructive syndrome-novel poor prognostic features of thrombotic microangiopathy in children after hematopoietic cellular therapy in a single institution prospective cohort study.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common, severe complication of allogeneic hematopoietic cellular therapy (HCT). Even when treated in many studies, morbidity and mortality rates are high. This prospective single-institution cohort study serially enrolled all allogeneic HCT recipients from August 2019-August 2022. Patients were universally screened for TA-TMA and intermediate and high-risk patients were immediately treated with eculizumab. Sub-distribution cox-proportional hazards models were used to identify sub-distribution hazard ratios (sHR)  for multi-organ dysfunction (MOD) and non-relapse-related mortality (NRM). Of 136 patients, 36 (26%) were diagnosed with TA-TMA and 21/36 (58%) developed MOD, significantly more than those without TA-TMA, (p < .0001). Of those with TA-TMA, 18 (50%) had high-risk TA-TMA (HR-TA-TMA), 11 (31%) had intermediate-risk TA-TMA (IR-TA-TMA), and 8 (22%) had standard risk (SR-TA-TMA). Twenty-six were treated with eculizumab (1/8 SR, 7/11 IR, and 18/18 HR). Elevated D-dimer predicted the development of MOD (sHR 7.6, 95% confidence interval [CI] 1.8-32.3). Children with concurrent sinusoidal obstructive syndrome (SOS) and TA-TMA had an excess risk of MOD of 34% and data supported a biologic interaction. The adjusted NRM risk was significantly higher in the TA-TMA patients (sHR 10.54, 95% CI 3.8-29.2, p < .0001), despite prompt treatment with eculizumab. Significant RF for NRM in TA-TMA patients included SOS (HR 2.89, 95% 1.07-7.80) and elevated D-dimer (HR 3.82, 95% CI 1.14-12.84). An unrelated donor source and random urine protein to creatine ratio ≥2 mg/mg were significantly associated with no response to eculizumab (odds ratio 15, 95% CI 2.0-113.6 and OR 6.5, 95% CI 1.1-38.6 respectively). TA-TMA was independently associated with NRM despite early diagnosis and treatment with eculizumab in this large pediatric transplant cohort. Prognostic implications of D-dimer in TA-TMA merit further investigation as this is a readily accessible biomarker. Concurrent SOS is an exclusion criterion of many ongoing clinical trials, but these data highlight these patients could benefit from novel therapeutic approaches. Multi-institutional clinical trials are needed to understand the impact of TA-TMA-targeted therapies.

Body image dissatisfaction during the first year of pediatric inflammatory bowel disease diagnosis.

OBJECTIVES: Dissatisfaction with one's body can be distressing; youth with inflammatory bowel disease (IBD) may be at increased risk for body image dissatisfaction given disease symptoms and treatment side effects. Yet, no studies have examined body image dissatisfaction over time in youth with IBD and whether depressive symptoms are associated with change in dissatisfaction. METHODS: Fifty-seven pediatric participants (8-17 years old) newly diagnosed with IBD were enrolled. Youth completed questionnaires assessing body image dissatisfaction and depressive symptoms shortly after diagnosis (Time 1) and 12 months later (Time 2). Multilevel longitudinal modeling was used to test the extent to which body image dissatisfaction changed across the first year of diagnosis and to test change in body image dissatisfaction as a function of depressive symptoms. RESULTS: Findings indicated significant between- and within-person variance in body image dissatisfaction over the 12 months, yet the sample as a whole did not report significant changes in dissatisfaction from Time 1 to Time 2. Children reporting depressive symptoms greater than their individual average over time reported greater body image dissatisfaction. Between-person variation in depressive symptoms demonstrated a significant interaction with time. As an individual's depressive symptoms exceeded the group average, their body image dissatisfaction increased, although less drastically as time since diagnosis progressed. CONCLUSIONS: Findings suggest that body image dissatisfaction is a complex and dynamic construct across youth and that interventions for pediatric IBD patients need to be tailored to the needs of individuals. Methods for assessing body image dissatisfaction efficiently and repeatedly across multiple visits are provided.

Sensitivity of rapid antigen tests against SARS-CoV-2 Omicron and Delta variants.

Rapid antigen tests (RATs) have become an invaluable tool for combating the COVID-19 pandemic. However, concerns have been raised regarding the ability of existing RATs to effectively detect emerging SARS-CoV-2 variants. We compared the performance of 10 commercially available, emergency use authorized RATs against the Delta and Omicron SARS-CoV-2 variants using both individual patient and serially diluted pooled clinical samples. The RATs exhibited lower sensitivity for Omicron samples when using PCR cycle threshold (CT) value (a rough proxy for RNA concentration) as the comparator. Interestingly, however, they exhibited similar sensitivity for Omicron and Delta samples when using quantitative antigen concentration as the comparator. We further found that the Omicron samples had lower ratios of antigen to RNA, which offers a potential explanation for the apparent lower sensitivity of RATs for that variant when using C T value as a reference. Our findings underscore the complexity in assessing RAT performance against emerging variants and highlight the need for ongoing evaluation in the face of changing population immunity and virus evolution.

Prevalence of SARS-CoV-2 in hemoglobinopathies is modified by age and race.

Prior literature has established a positive association between sickle cell disease and risk of contracting SARS-CoV-2. Data from a cross-sectional study evaluating COVID-19 testing devices (n = 10,567) was used to examine the association between underlying health conditions and SARS-CoV-2 infection in an urban metropolis in the southern United States. Firth's logistic regression was used to fit the model predicting SARS-CoV-2 positivity using vaccine status and different medical conditions commonly associated with COVID-19. Another model using the same method was built using SARS-CoV-2 positivity as the outcome and hemoglobinopathy presence, age (<16 Years vs. ≥16 Years), race/ethnicity and comorbidities, including hemoglobinopathy, as the factors. Our first model showed a significant association between hemoglobinopathy and SARS-CoV-2 infection (OR: 2.28, 95 % CI: (1.17,4.35), P = 0.016). However, in the second model, this association was not maintained (OR: 1.35, 95 % CI: (0.72,2.50), P = 0.344). We conclude that the association between SARS-CoV-2 positivity and presence of hemoglobinopathies like sickle cell disease is confounded by race, age, and comorbidity status. Our results illuminate previous findings by identifying underlying clinical/demographic factors that confound the reported association between hemoglobinopathies and SARS-CoV-2. These findings demonstrate how social determinants of health may influence disease manifestations more than genetics alone.

Vaccine Attitudes and COVID-19 Vaccine Intention Among Parents of Children With Kidney Disease or Primary Hypertension.

RATIONALE & OBJECTIVE: Children with kidney disease and primary hypertension may be more vulnerable to COVID-19. We examined COVID-19 vaccine hesitancy among parents of children with chronic kidney disease or hypertension. STUDY DESIGN: Sequential explanatory mixed-methods design; survey followed by in-depth interviews. SETTING & PARTICIPANTS: Parents of children aged <18 years with kidney disease or primary hypertension within a large pediatric practice. EXPOSURE: Parental attitudes toward general childhood and influenza vaccines assessed by the Vaccine Hesitancy Scale. Kidney disease classification, demographic and socioeconomic factors, experiences with COVID-19, COVID-19 mitigation activities and self-efficacy, and sources of vaccine information. OUTCOME: Willingness to vaccinate child against COVID-19. ANALYTICAL APPROACH: Analysis of variance (ANOVA) test to compare parental attitudes toward general childhood and influenza vaccination with attitudes toward COVID-19 vaccination. Multinomial logistic regression to assess predictors of willingness to vaccinate against COVID-19. Thematic analysis of interview data to characterize influences on parental attitudes. RESULTS: Of the participants, 207 parents completed the survey (39% of approached): 75 (36%) were willing, 80 (39%) unsure, and 52 (25%) unwilling to vaccinate their child against COVID-19. Hesitancy toward general childhood and influenza vaccines was highest among the unwilling group (P < 0.001). More highly educated parents more likely to be willing to vaccinate their children, while Black race was associated with being more likely to be unwilling. Rushed COVID-19 vaccine development as well as fear of serious and unknown long-term side effects were themes that differed across the parental groups that were willing, unsure, or unwilling to vaccinate their children. Although doctors and health care teams are trusted sources of vaccine information, perceptions of benefit versus harm and experiences with doctors differed among these 3 groups. The need for additional information on COVID-19 vaccines was greatest among those unwilling or unsure about vaccinating. LIMITATIONS: Generalizability may be limited. CONCLUSIONS: Two-thirds of parents of children with kidney disease or hypertension were unsure or unwilling to vaccinate their child against COVID-19. Higher hesitancy toward routine childhood and influenza vaccination was associated with hesitancy toward COVID-19 vaccines. Enhanced communication of vaccine information relevant to kidney patients in an accessible manner should be examined as a means to reduce vaccine hesitancy. PLAIN-LANGUAGE SUMMARY: Children with kidney disease or hypertension may do worse with COVID-19. As there are now effective vaccines to protect children from COVID-19, we wanted to find out what parents think about COVID-19 vaccines and what influences their attitudes. We surveyed and then interviewed parents of children who had received a kidney transplant, were receiving maintenance dialysis, had chronic kidney disease, or had hypertension. We found that two-thirds of parents were hesitant to vaccinate their children. Their reasons varied, but the key issues included the need for information pertinent to their child and a consistent message from doctors and other health care providers. These findings may inform an effective vaccine campaign to protect children with kidney disease and hypertension.

Outcomes of children with life-threatening status asthmaticus requiring isoflurane therapy and extracorporeal life support.

BACKGROUND: Severe, refractory asthma is a life-threatening emergency that may be treated with isoflurane and extracorporeal life support. The objective of this study was to describe the clinical response to isoflurane and outcomes after discharge of children who received isoflurane and/or extracorporeal life-support for near-fatal asthma. METHODS: This was a retrospective descriptive study using electronic medical record data from two pediatric intensive care units within a single healthcare system in Atlanta, GA. RESULTS: Forty-five children received isoflurane, and 14 children received extracorporeal life support, 9 without a trial of isoflurane. Hypercarbia and acidosis improved within four hours of starting isoflurane. Four children died during the index admission for asthma. Twenty-seven percent had a change in Functional Status Score of three or more points from baseline to PICU discharge. Patients had median percent predicted FEV1 and FEV1/FVC ratios pre- and post-bronchodilator values below normal pediatric values. CONCLUSION: Children who received isoflurane and/or ECLS had a high frequency of previous PICU admission and intubation. Improvement in ventilation and acidosis occurred within the first four hours of starting isoflurane. Children who required isoflurane or ECLS may develop long-lasting deficits in their functional status. Children with near-fatal asthma are a high-risk group and require improved follow-up in the year following PICU discharge.

Diabetic Ketoacidosis and Long-term Insulin Requirements in Youths with Newly Diagnosed Type 2 Diabetes During the SARS-CoV-2 Pandemic.

OBJECTIVE: SARS-CoV-2 infection increases the risk of diabetes and diabetic ketoacidosis (DKA) in both adults and children. We investigated the clinical course of new-onset type 2 diabetes in youth presenting with DKA during the COVID-19 pandemic. METHODS: This single-center retrospective cohort study included 148 subjects with obesity aged 10 to 21 years, admitted with DKA from January 2018 to January 2022. Groups were defined by the presence of DKA precipitant: any infection (n = 38, 26%), which included the SARS-CoV-2 (n = 10, 7%) and other infection (n = 28, 19%) groups, and no infection (n = 110, 74%). The primary outcome was insulin discontinuation within a 12-month follow-up. RESULTS: The mean age was 14.9 years (IQR, 13.8-16.5), and age-adjusted body mass index (%) was 99.1 (IQR, 98.0-99.5) with 85.8% identifying as Black or Hispanic. There were no differences in DKA severity among groups. The incidence of DKA was higher during the pandemic (March 2020-January 2022, n = 117) than in the prepandemic period (January 2018-February 2020, n = 31). Within the first year after the acute DKA episode, 46 patients discontinued all insulin within 9 months (IQR, 4-14). Sixteen subjects restarted insulin 10 months (IQR, 6.5-11.0) after insulin discontinuation. Infection with SARS-CoV-2 at diagnosis was not associated with the likelihood (P =.57) or timing (P =.27) of discontinuing all insulin within 1 year, nor was having any infection. CONCLUSION: The incidence of DKA at the onset of type 2 diabetes was higher during the SARS-CoV-2 pandemic than in the prepandemic period. SARS-CoV-2 infection was not associated with DKA severity or insulin discontinuation within the first year of diagnosis in youth with new-onset type 2 diabetes and DKA.

Predictive Value of Isolated Symptoms for Diagnosis of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children Tested During Peak Circulation of the Delta Variant.

BACKGROUND: Coronavirus disease 2019 (COVID-19) testing policies for symptomatic children attending US schools or daycare vary, and whether isolated symptoms should prompt testing is unclear. We evaluated children presenting for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to determine if the likelihood of having a positive SARS-CoV-2 test differed between participants with 1 symptom vs ≥2 symptoms, and to examine the predictive capability of isolated symptoms. METHODS: Participants aged <18 years presenting for clinical SARS-CoV-2 molecular testing in 6 sites in urban/suburban/rural Georgia (July-October, 2021; Delta variant predominant) were queried about individual symptoms. Participants were classified into 3 groups: asymptomatic, 1 symptom only, or ≥2 symptoms. SARS-CoV-2 test results and clinical characteristics of the 3 groups were compared. Sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) for isolated symptoms were calculated by fitting a saturated Poisson model. RESULTS: Of 602 participants, 21.8% tested positive and 48.7% had a known or suspected close contact. Children reporting 1 symptom (n = 82; odds ratio [OR], 6.00 [95% confidence interval {CI}, 2.70-13.33]) and children reporting ≥2 symptoms (n = 365; OR, 5.25 [95% CI, 2.66-10.38]) were significantly more likely to have a positive COVID-19 test than asymptomatic children (n = 155), but they were not significantly different from each other (OR, 0.88 [95% CI, .52-1.49]). Sensitivity and PPV were highest for isolated fever (33% and 57%, respectively), cough (25% and 32%), and sore throat (21% and 45%); headache had low sensitivity (8%) but higher PPV (33%). Sensitivity and PPV of isolated congestion/rhinorrhea were 8% and 9%, respectively. CONCLUSIONS: With high Delta variant prevalence, children with isolated symptoms were as likely as those with multiple symptoms to test positive for COVID-19. Isolated fever, cough, sore throat, or headache, but not congestion/rhinorrhea, offered the highest predictive value.

Transmission roles of symptomatic and asymptomatic COVID-19 cases: a modelling study.

Coronavirus disease 2019 (COVID-19) asymptomatic cases are hard to identify, impeding transmissibility estimation. The value of COVID-19 transmissibility is worth further elucidation for key assumptions in further modelling studies. Through a population-based surveillance network, we collected data on 1342 confirmed cases with a 90-days follow-up for all asymptomatic cases. An age-stratified compartmental model containing contact information was built to estimate the transmissibility of symptomatic and asymptomatic COVID-19 cases. The difference in transmissibility of a symptomatic and asymptomatic case depended on age and was most distinct for the middle-age groups. The asymptomatic cases had a 66.7% lower transmissibility rate than symptomatic cases, and 74.1% (95% CI 65.9-80.7) of all asymptomatic cases were missed in detection. The average proportion of asymptomatic cases was 28.2% (95% CI 23.0-34.6). Simulation demonstrated that the burden of asymptomatic transmission increased as the epidemic continued and could potentially dominate total transmission. The transmissibility of asymptomatic COVID-19 cases is high and asymptomatic COVID-19 cases play a significant role in outbreaks.

Parenting Stress over the First Year of Inflammatory Bowel Disease Diagnosis.

OBJECTIVE: A diagnosis of inflammatory bowel disease (IBD) in children can disrupt the family, including altered routines and increased medical responsibilities. This may increase parenting stress; however, little is known about parenting stress changes over the first year following an IBD diagnosis, including what demographic, disease, or psychosocial factors may be associated with parenting stress over time. METHODS: Fifty-three caregivers of children newly diagnosed with IBD (Mage = 14.17 years; Mdays since diagnosis = 26.15) completed parenting stress (Pediatric Inventory for Parents), child anxiety (Screen for Child Anxiety-Related Disorders), and child health-related quality of life (HRQOL; IMPACT) measures within 1 month of diagnosis and 6-month and 1-year follow-ups. Multilevel longitudinal models assessed change and predictors of parenting stress. RESULTS: Parenting stress was significantly associated with greater child anxiety and lower HRQOL at diagnosis (rs = 0.27 to -0.53). Caregivers of color and caregivers of female youth reported higher parenting stress at diagnosis (ts = 2.02-3.01). Significant variability and declines in parenting stress were observed across time (ts = -2.28 and -3.50). In final models, caregiver race/ethnicity and child HRQOL were significantly related to parenting stress over the first year of diagnosis (ts = -2.98 and -5.97). CONCLUSION: Caregivers' parenting stress decreases across 1 year of diagnosis. However, caregivers of color and those rating their child's HRQOL as lower may be at risk for greater parenting stress. More research is needed to understand why caregivers of color reported greater parenting stress compared to White caregivers. Results highlight the importance of providing whole-family care when a child is diagnosed with IBD.

Concordance of SARS-CoV-2 Results in Self-collected Nasal Swabs vs Swabs Collected by Health Care Workers in Children and Adolescents.

Importance: Despite the expansion of SARS-CoV-2 testing, available tests have not received Emergency Use Authorization for performance with self-collected anterior nares (nasal) swabs from children younger than 14 years because the effect of pediatric self-swabbing on SARS-CoV-2 test sensitivity is unknown. Objective: To characterize the ability of school-aged children to self-collect nasal swabs for SARS-CoV-2 testing compared with collection by health care workers. Design, Setting, and Participants: Cross-sectional study of 197 symptomatic children and adolescents aged 4 to 14 years old. Individuals were recruited based on results of testing in the Children's Healthcare of Atlanta system from July to August 2021. Exposures: Children and adolescents were given instructional material consisting of a short instructional video and a handout with written and visual steps for self-swab collection. Participants first provided a self-collected nasal swab. Health care workers then collected a second specimen. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 detection and relative quantitation by cycle threshold (Ct) in self- vs health care worker-collected nasal swabs when tested with a real-time reverse transcriptase-polymerase chain reaction test with Emergency Use Authorization. Results: Among the study participants, 108 of 194 (55.7%) were male and the median age was 9 years (IQR, 6-11). Of the 196 participants, 87 (44.4%) tested positive for SARS-CoV-2 and 105 (53.6%) tested negative by both self- and health care worker-collected swabs. Two children tested positive by self- or health care worker-collected swab alone; 1 child had an invalid health care worker swab. Compared with health care worker-collected swabs, self-collected swabs had 97.8% (95% CI, 94.7%-100.0%) and 98.1% (95% CI, 95.6%-100.0%) positive and negative percent agreement, respectively, and SARS-CoV-2 Ct values did not differ significantly between groups (mean [SD] Ct, self-swab: 26.7 [5.4] vs health care worker swab: 26.3 [6.0]; P = .65). Conclusions and Relevance: After hearing and seeing simple instructional materials, children and adolescents aged 4 to 14 years self-collected nasal swabs that closely agreed on SARS-CoV-2 detection with swabs collected by health care workers.

Dissemination of the Results of Pediatric Clinical Trials Funded by the US National Institutes of Health.

This study examines practices related to trial registration and results submission in ClinicalTrials.gov and publication of pediatric clinical trials funded by the National Institutes of Health.

Real World Application of Recently Proposed ASTCT/CIBMTR/ eBMT/ APBMT Consensus Risk Stratification for Transplant Associated Thrombotic Microangiopathy (TA-TMA) in Children.

BACKGROUND: Consensus diagnostic and risk stratification of transplant associated thrombotic microangiopathy (TA-TMA) was recently achieved from international transplantation groups (Schoettler et al, TCT, 2023). While the diagnostic criteria proposed have been applied to multiple pediatric cohorts, there are scant data applying the novel risk stratification approach in children with TA-TMA. METHODS: In this retrospective cohort study, all children undergoing an allogeneic HCT or autologous HCT for neuroblastoma were prospectively screened for TA-TMA, diagnosed and risk-stratified using Jodele criteria from August 2019- October 2023. Our institutional practice during the study period was treat all Jodele intermediate and high-risk patients (IR, HR) with eculizumab. Harmonization risk stratification criteria were retrospectively applied. All survival analyses were calculated from the day of TA-TMA diagnosis. To identify which specific harmonization high-risk feature(s) were the most important predictors for NRM, full and reduced logistic regression models were tested. The lowest BIC and optimal Mallows' CP statistic were used to identify the best subset. SAS 9.4 (Cary, NC) was used to complete the analysis. RESULTS: Fifty-two children were diagnosed with TA-TMA during the study period a median of 37.5 days post HCT (range 3 to 735). Using Jodele risk stratification, 11 (21%) were SR, 21 (40%) intermediate risk, and 20 (39%) high- risk (HR). Forty (77%) were treated with eculizumab. There were no statistically significant differences in NRM among Jodele risk groups, though overall survival was significantly different. Using the harmonized stratification, 49 (94%) of children were stratified as HR and 3 as SR, there were no statistically significant differences in NRM or OS between groups. Eight (15.4%) children were classified as SR using Jodele risk stratification but re-stratified as HR using the harmonization criteria. One (12.5%) died in the setting of severe GVHD and the remaining 7 patients are alive at last follow up. In a best subset model, LDH >2x ULN (OR 6.52, 95% CI 0.96-44.3, p=0.05), grade 2-4 acute GVHD at the time of TA-TMA diagnosis (OR 15.4, 95% CI 2.14- 110.68, p=0.01), and multi-organ dysfunction at the time of TA-TMA (OR 21.5, 95% CI 2.96-156.37, p=0.002) were significantly associated with NRM; elevated sC5b-9, rUPCR, and viral infections were not significantly associated with NRM. Using these best fit criteria, 14 patients were classified as SR and 38 as HR; NRM was significantly higher and OS significantly lower. DISCUSSION: In this cohort of children with TA-TMA retrospective application of harmonization criteria resulted in more patients stratified as HR than previously described Jodele criteria. The intention of the harmonization criteria was to identify those at highest risk of poor outcomes; while all harmonization SR patients survived, this risk stratification was very sensitive. Previous criticisms of harmonization risk stratification include limited access to sC5b-9 testing- these data suggest that concurrent MOD, acute GVHD, and LDH >2X ULN are the most important predicators of NRM in this cohort, supporting the use of harmonization risk stratification even in the absence of available sC5b-9 testing. Additional studies are needed to validate these findings.

Morbidity and unplanned healthcare encounters after hospital discharge among young children in Dar es Salaam, Tanzania and Monrovia, Liberia.

BACKGROUND: Researchers and healthcare providers have paid little attention to morbidity and unplanned healthcare encounters for children following hospital discharge in low- and middle-income countries. Our objective was to compare symptoms and unplanned healthcare encounters among children aged <5 years who survived with those who died within 60 days of hospital discharge through follow-up phone calls. METHODS: We conducted a secondary analysis of a prospective observational cohort of children aged <5 years discharged from neonatal and paediatric wards of two national referral hospitals in Dar es Salaam, Tanzania and Monrovia, Liberia. Caregivers of enrolled participants received phone calls 7, 14, 30, 45, and 60 days after hospital discharge to record symptoms, unplanned healthcare encounters, and vital status. We used logistic regression to determine the association between reported symptoms and unplanned healthcare encounters with 60-day post-discharge mortality. RESULTS: A total of 4243 participants were enrolled and had 60-day vital status available; 138 (3.3%) died. For every additional symptom ever reported following discharge, there was a 35% greater likelihood of post-discharge mortality (adjusted odds ratio [aOR] 1.35, 95% confidence interval [CI] 1.10 to 1.66; p=0.004). The greatest survival difference was noted for children who had difficulty breathing (2.1% among those who survived vs 36.0% among those who died, p<0.001). Caregivers who took their child home from the hospital against medical advice during the initial hospitalisation had over eight times greater odds of post-discharge mortality (aOR 8.06, 95% CI 3.87 to 16.3; p<0.001) and those who were readmitted to a hospital had 3.42 greater odds (95% CI 1.55 to 8.47; p=0.004) of post-discharge mortality than those who did not seek care when adjusting for site, sociodemographic factors, and clinical variables. CONCLUSION: Surveillance for symptoms and repeated admissions following hospital discharge by healthcare providers is crucial to identify children at risk for post-discharge mortality.

Identifying neonates at risk for post-discharge mortality in Dar es Salaam, Tanzania, and Monrovia, Liberia: Derivation and internal validation of a novel risk assessment tool.

INTRODUCTION: The immediate period after hospital discharge carries a large burden of childhood mortality in sub-Saharan Africa. Our objective was to derive and internally validate a risk assessment tool to identify neonates discharged from the neonatal ward at risk for 60-day post-discharge mortality. METHODS: We conducted a prospective observational cohort study of neonates discharged from Muhimbili National Hospital in Dar es Salaam, Tanzania, and John F Kennedy Medical Centre in Monrovia, Liberia. Research staff called caregivers to ascertain vital status up to 60 days after discharge. We conducted multivariable logistic regression analyses with best subset selection to identify socioeconomic, demographic, clinical, and anthropometric factors associated with post-discharge mortality. We used adjusted log coefficients to assign points to each variable and internally validated our tool with bootstrap validation with 500 repetitions. RESULTS: There were 2344 neonates discharged and 2310 (98.5%) had post-discharge outcomes available. The median (IQR) age at discharge was 8 (4, 15) days; 1238 (53.6%) were male. In total, 71 (3.1%) died during follow-up (26.8% within 7 days of discharge). Leaving against medical advice (adjusted OR [aOR] 5.62, 95% CI 2.40 to 12.10) and diagnosis of meconium aspiration (aOR 6.98, 95% CI 1.69 to 21.70) conferred the greatest risk for post-discharge mortality. The risk assessment tool included nine variables (total possible score=63) and had an optimism corrected area under the receiver operating characteristic curve of 0.77 (95% CI 0.75 to 0.80). A score of ≥6 was most optimal (sensitivity 68.3% [95% CI 64.8% to 71.5%], specificity 72.1% [95% CI 71.5% to 72.7%]). CONCLUSIONS: A small number of factors predicted all-cause, 60-day mortality after discharge from neonatal wards in Tanzania and Liberia. After external validation, this risk assessment tool may facilitate clinical decision making for eligibility for discharge and the direction of resources to follow-up high risk neonates.

Comparison of RT-PCR and antigen test sensitivity across nasopharyngeal, nares, and oropharyngeal swab, and saliva sample types during the SARS-CoV-2 omicron variant.

Limited data highlight the need to understand differences in SARS-CoV-2 omicron (B.1.1.529) variant viral load between the gold standard nasopharyngeal (NP) swab, mid-turbinate (MT)/anterior nasal swabs, oropharyngeal (OP) swabs, and saliva. MT, OP, and saliva samples from symptomatic individuals in Atlanta, GA, in January 2022 and longitudinal samples from a small familial cohort were tested by both RT-PCR and ultrasensitive antigen assays. Higher concentrations in the nares were observed in the familial cohort, but a dominant sample type was not found among 39 cases in the cross-sectional cohort. The composite of positive MT or OP assay for both RT-PCR and antigen assay trended toward higher diagnostic yield but did not achieve significant difference. Our data did not identify a singular preferred sample type for SARS-CoV-2 testing, but higher levels of saliva nucleocapsid, a trend toward higher yield of composite OP/MT result, and association of apparent MT or OP predominance with symptoms warrant further study.