The impact of pre-transplant respiratory virus detection on post-transplant outcomes in children undergoing hematopoietic cell transplantation.

BACKGROUND: Pre-transplant respiratory virus (RV) infections have been associated with negative transplant outcomes in adult hematopoietic cell transplantation (HCT) recipients. In the era of HCT delay due to high-risk RVs, we examined the impact of pre-transplant RV detection on transplant outcomes in a pediatric HCT recipients. METHODS: This retrospective cohort study included myeloablative allogeneic HCT recipients from 2010 to 2019. All patients were screened for RV at least once within 90 days before HCT using RT-PCR, regardless of symptoms. Post-transplant outcomes included days alive and out of hospital (DAOH) and progression to lower respiratory tract infection (LRTI). RESULTS: Among 310 patients, 134 had a RV detected in the 90 days prior to HCT. In univariable analysis, transplant factors including younger age, total body irradiation, umbilical cord blood transplantation, lymphocyte count less than 100/mm3, and HCT comorbidity index score ≥3, and viral factors including symptomatic infection, human rhinovirus (HRV) as a virus type, and symptomatic pre-transplant upper respiratory tract infection (URTI) were associated with fewer DAOH. In multivariable analysis, transplant factors remained significant, but not viral factors. There was a higher incidence of progression to post-transplant LRTI with the same pre-transplant RV if the last positive PCR before HCT was ≤30 days compared to >30 days (p=0.007). CONCLUSION: In the setting of recommending HCT delay for high-risk RVs, symptomatic URTI, including HRV infections, may lead to increased duration of hospitalization and early progression to LRTI when transplantation is performed within 30 days of the last positive PCR test.

Safety and antibody response of the BNT162b2 SARS-CoV-2 vaccine in children aged 5-11 years with underlying diseases: A prospective observational study.

BACKGROUND: Data on the safety and antibody response of the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in children aged 5-11 years with underlying diseases are limited. Thus, our study aimed to address this gap. METHODS: This prospective observational study investigated the antibody titers for SARS-CoV-2 spike protein receptor-binding domain (S-IgG) and nucleocapsid protein (N-IgG) in patients aged 5-11 years with chronic underlying diseases following two doses of BNT162b2. Additionally, a questionnaire was used to assess adverse events (AEs) arising within 7 days after each dose. Data on severe AEs arising within 28 days after each dose were extracted from the patients' electronic medical records. RESULTS: Among 122 patients, 24.6% (30/122) were immunocompromised. Furthermore, 79 patients experienced at least one AE following vaccination, but all recovered without sequelae, including one severe case after the first dose. The seropositivity rate after the second dose was 99.1% (116/117). Excluding 19 N-IgG-positive patients, the geometric mean antibody titer (GMT) was significantly higher in immunocompetent patients than in immunocompromised patients (1496 U/mL [95% confidence interval 1199-1862] vs. 472 U/mL [200-1119], p = 0.035). Additionally, the GMT of S-IgG was higher in N-IgG-positive patients than in N-IgG-negative patients (8203 [5847-11482] U/mL vs. 1127 [855-1486] U/mL, p < 0.001). CONCLUSIONS: BNT162b2 is acceptably safe and immunogenic for children aged 5-11 years with underlying diseases. Although seroconversion was satisfactory in immunocompromised patients, the titers were lower than in immunocompetent patients.

Association between use of antipyretics and antibody titers after two doses of the BNT162b2 SARS-CoV-2 vaccine in adolescents and young adults with underlying diseases.

There are few reports on the association between antipyretic use and antibody titers in adolescents and young adults following SARS-CoV-2 vaccination. Multivariable linear regression analyses were performed to examine the association between antipyretic use and antibody titers. The use of antipyretics was not associated with antibody titers (ß coefficient [95% CI] = -0.107 [-0.438 to 0.224]).

Clinical Practice Patterns and Risk Factors for Severe Conditions in Pediatric Hospitalizations With Respiratory Syncytial Virus in Japan: A Nationwide Analyses (2018-2022).

BACKGROUND: Respiratory syncytial virus (RSV) represents a global health challenge, especially among younger children. While the disease burden in Japan has been preliminarily quantified, there remains a lack of comprehensive understanding regarding treatment patterns and the influence of known risk factors at a national scale. MATERIALS AND METHODS: We conducted a retrospective cohort study consisting of 50,482 children under 5 years hospitalized with RSV infections during 2018-2022 using the Medical Data Vision database. We investigated trends in patient characteristics, health resource use, treatment patterns, and laboratory data. Additionally, multivariable modified Poisson regression models were used to investigate the risk factors associated with severe conditions. RESULTS: We observed an increasing trend in the inpatient healthcare costs and decreasing trends in the use of antibiotics, bronchodilators, systemic corticosteroids and other symptomatic medications from 2018 to 2022. Risk factors associated with severe RSV infections were children less than 1 year (risk ratio, 2.90; 95% CI: 2.53-3.32) and the number of complex chronic diseases (risk ratio for 1 disease, 2.68; 95% CI: 2.34-3.06: risk ratio for 2 or more diseases, 6.91; 95% CI: 5.81-8.21). Annual inpatient healthcare costs for RSV infections were estimated at 11-14 billion Japanese Yen for younger children. CONCLUSIONS: Our study observed the changes in practice patterns and health resource use for children hospitalized with RSV infections and identified risk factors associated with severe conditions. These findings provide insights for policymakers and clinicians aiming to devise strategies for further improving clinical practices, including newly developed vaccines and single-dose long-acting monoclonal antibodies.

Natural course of acute COVID-19 among healthy children in a tertiary hospital.

BACKGROUND: Previous studies have reported the clinical and epidemiological characteristics of children with coronavirus disease 2019 (COVID-19) in a cross-sectional fashion; however, the natural course of each symptom based on a daily basis during the acute phase has not yet been clarified. This retrospective study aimed to describe the natural course of COVID-19 in children according to dominant variants. METHODS: We conducted our study on symptomatic children with COVID-19 who were hospitalized at the National Center for Child Health and Development, in Japan. We excluded patients who were observed for less than 9 days and those with underlying disease, COVID-19 vaccination, coinfection, complications, or therapeutic intervention. We collected the data on each participant's age at admission, sex, medical history, observation period, hospitalization period, SARS-CoV-2 test results, and 10 daily symptoms in the first 9 days from the illness onset. RESULTS: Eventually, 115 children were included in this study. The prevalence of fever during the omicron era declined more rapidly over time than that during the pre-omicron era. The prevalence of cough and rhinorrhea did not decline during the observation period, and these clinical manifestations were more common during the pre-omicron era at any point. The prevalence of dysgeusia and/or dysosmia steadily increased over time in the pre-omicron era. This study demonstrated that the prevalence of some symptoms differed not only at the onset but also over time during the acute phase. CONCLUSION: Details of the natural clinical course of children with COVID-19 help primary care physicians to manage these patients.

Risk factors for severity in seasonal respiratory viral infections and how they guide management in hematopoietic cell transplant recipients.

PURPOSE OF REVIEW: Seasonal respiratory virus infections (RVIs) often progress to severe diseases in hematopoietic cell transplant (HCT) recipients. This review summarizes the current evidence on risk factors for the severity of RVIs in this high-risk population and provides clinical management. RECENT FINDINGS: The likelihood of the respiratory viral disease progression depends on the immune status of the host and the type of virus. Conventional host factors, such as the immunodeficiency scoring index and the severe immunodeficiency criteria, have been utilized to estimate the risk of progression to severe disease, including mortality. Recent reports have suggested nonconventional risk factors, such as hyperglycemia, hypoalbuminemia, prior use of antibiotics with broad anaerobic activity, posttransplant cyclophosphamide, and pulmonary impairment after RVIs. Identifying novel and modifiable risk factors is important with the advances of novel therapeutic and preventive interventions for RVIs. SUMMARY: Validation of recently identified risk factors for severe RVIs in HCT recipients is required. The development of innovative interventions along with appropriate risk stratification is critical to improve outcomes in this vulnerable population.

Septic Arthritis Caused by Haemophilus parainfluenzae : A Pediatric Case Report and Literature Review.

We report a healthy 5-year-old boy without apparent risk factors who developed septic arthritis of the hip from Haemohilus parainfluenzae infection. A literature review revealed only 4 pediatric cases of osteoarticular infection caused by this pathogen. To our knowledge, our case may be the first pediatric case of septic arthritis of the hip caused by H. parainfluenzae .

Acute cerebellar ataxia during acute COVID-19: A case series and review of the literature.

Acute coronavirus disease 2019 (COVID-19)-associated cerebellar ataxia without multisystem inflammatory syndrome in children (MIS-C) or encephalopathy in children has been rarely reported. We reviewed medical records of hospitalized children who had developed cerebellar ataxia during the acute phase of COVID-19 infection, without MIS-C or encephalopathy, in our center. We also conducted a literature review and summarized the clinical characteristics, treatment, and outcomes. We found three cases in our center and additional three cases in the literature. All patients were male and five were preschool children. The cerebellar symptoms started between day 2 and day 10 during the acute phase of the COVID-19 infection. Two cases were complicated by mutism. One patient received therapy for acute cerebellar ataxia with corticosteroids, and others did not receive any specific therapy for acute cerebellar ataxia. The symptoms improved completely in all patients, with the recovery interval ranging from one week to two months. Further studies are warranted to elucidate the pathogenesis of acute cerebellar ataxia during acute COVID-19 in children.

Etiology of Severe Acute Hepatitis in a Pediatric Transplant Center in Japan.

The proportion of pediatric cases with severe acute hepatitis of unknown etiology in the coronavirus disease 2019 era was higher than that in the pre-coronavirus disease 2019 era in Japan's largest pediatric transplant center. Further research and monitoring are essential.

Successful pediatric liver transplantation case with a positive SARS-CoV-2 test at the time of transplant.

AIM: We report a successful liver transplantation (LT) in a child with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CASE PRESENTATION: A 3-year-old female patient with decompensated cirrhosis due to Alagille syndrome underwent a split LT with a left lateral segment graft. She had a history of SARS-CoV-2 infection 4 months before LT. She was exposed to SARS-CoV-2 after the decision for organ acceptance. We repeatedly confirmed the negative SARS-CoV-2 test by polymerase chain reaction (PCR) before LT. Liver transplantation was carried out in the negative pressure operational theater with full airborne, droplet, and contact precautions as the patient was considered to be within the incubation period of SARS-CoV-2. The SARS-CoV-2 PCR test became positive in the nasopharyngeal swab specimen at the operation. Remdesivir, the antiviral treatment, was held off due to potential hepatotoxicity and no exacerbation of COVID-19. She received tacrolimus and low-dose steroids per protocol. She remained SARS-CoV-2 positive on postoperative days (PODs) 1, 2, and 5. The presence of antibodies for SARS-CoV-2 at LT was confirmed later. On POD 53, she was discharged without any symptomatic infection. CONCLUSION: This case demonstrated that a positive SARS-CoV-2 result was not an absolute contraindication for a life-saving LT. Liver transplantation could be safely performed in a pediatric patient with asymptomatic COVID-19 and S-immunoglobulin G antibodies for SARS-CoV-2.

Immunogenicity and safety of SARS-CoV-2 mRNA vaccine in patients with nephrotic syndrome receiving immunosuppressive agents.

BACKGROUND: As there are no large-scale reports of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with nephrotic syndrome using immunosuppressive agents, we conducted the prospective study. METHODS: SARS-CoV-2 mRNA vaccines were administered to patients with nephrotic syndrome receiving immunosuppressive agents. The titers of SARS-CoV-2 spike protein receptor-binding domain antibodies were measured before and after vaccination. We evaluated factors associated with antibody titers after vaccination and analyzed adverse events. RESULTS: We enrolled 40 patients and evaluated vaccine immunogenicity in 35 of them. Seroconversion (> 0.8 U/mL) was achieved in all patients, and the median antibody titer was 598 U/mL (interquartile range, 89-1380 U/mL). Patients using mycophenolate mofetil (MMF) showed lower antibody titers than those who were not (median: 272 U/mL vs. 2660 U/mL, p = 0.0002), and serum immunoglobulin G (IgG) levels showed a weak linear relationship with antibody titers (R2 = 0.16). No breakthrough infections were noted. Three patients (7.5%) suffered from a relapse of nephrotic syndrome (2 and 3 days, respectively, after the first dose and 8 days after the second dose), two of whom had a history of relapse within 6 months before the vaccination. CONCLUSIONS: The SARS-CoV-2 mRNA vaccine was immunogenic in patients with nephrotic syndrome using immunosuppressive agents, although the use of MMF and low levels of serum IgG were associated with lower antibody titers after vaccination. Patients with high disease activity may experience a relapse of nephrotic syndrome after vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.

Safety of and antibody response to the BNT162b2 COVID-19 vaccine in adolescents and young adults with underlying disease.

BACKGROUND: Data are limited regarding the safety of and antibody response to the BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid vaccine in adolescents and young adults with underlying disease. METHODS: This prospective observational study enrolled patients age 12-25 years with chronic underlying disease who received 2 doses of BNT162b2. A 18-item questionnaire was used to assess adverse events within 7 days post-vaccination, and data regarding severe adverse events were collected from electronic medical records. An antibody titer for the receptor-binding domain of the spike protein in SARS-CoV-2 was used to assess antibody response after the second vaccine dose. RESULTS: Study participants were 429 patients (241 [56.2%] age 12-15 years; 188 [43.8%] age 16-25 years). The most common underlying diseases were genetic or chromosomal abnormalities and/or congenital anomalies, followed by endocrine or metabolic diseases; 32% of participants were immunocompromised. Severe adverse events were observed after the second dose in 1 (0.4%) patient age 12-15 years and in 2 (1.1%) patients age 16-25 years; all patients recovered. Seropositivity after the second vaccine dose was 99.0%. The geometric mean antibody titer was higher in patients age 12-15 years versus 16-25 years (1603.3 [1321.8-1944.7] U/mL vs. 949.4 [744.2-1211.0] U/mL). Compared with immunocompetent patients, immunocompromised patients had a lower antibody titer (2106.8 [1917.5-2314.7] U/mL vs. 467.9 [324.4-674.8] U/mL). CONCLUSIONS: Vaccination with BNT162b2 was acceptably safe and immunogenic for adolescents and young adults with underlying disease.

Immunogenicity and safety of SARS-CoV-2 vaccine with immunosuppressive agents.

BACKGROUND: We conducted a prospective study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccination in children and adolescents who were taking immunosuppressive agents. METHODS: Two doses of SARS-CoV-2 mRNA vaccine were administered to patients taking immunosuppressive agents. Titers of SARS-CoV-2 spike protein receptor-binding domain antibodies were measured before and after vaccination. Vaccine failure was defined as a postvaccination antibody titer of <0.8 U/mL. Seroconversion rates, factors associated with antibody titers after vaccination, clinical effectiveness against breakthrough infection, and adverse events were evaluated. RESULTS: A total of 42 patients (median age, 18.1 years) were enrolled. Immunogenicity was measured in 34 patients. The median SARS-CoV-2 spike antibody titer was 329 U/mL (interquartile range [IQR] 50-812 U/mL). Seroconversion (≥0.8 U/mL) was achieved in 29 patients (85%), whereas vaccine failure was diagnosed in five (15%). All patients with vaccine failure were recipients of solid organ transplants (SOTs) and were taking two immunosuppressants. The median antibody titer in SOT recipients (57 U/mL) was significantly lower than that in non-recipients (653 U/mL, P = 0.0002); that of patients taking two immunosuppressive agents (93 U/mL) was lower than that of patients taking one (506 U/mL, P = 0.003). Breakthrough infection occurred in three patients (7%). Adverse events were non-specific, and no flares of primary disease or acute rejection in SOT recipients occurred. CONCLUSIONS: SARS-CoV-2 mRNA vaccine was immunogenic in children and adolescents taking immunosuppressive agents, although SOT recipients and patients taking two immunosuppressive agents tended to show lower postvaccination antibody titers.

Exposure to antibiotics with anaerobic activity before respiratory viral infection is associated with respiratory disease progression after hematopoietic cell transplant.

We examined associations between specific antibiotic exposures and progression to lower respiratory tract disease (LRTD) following individual respiratory viral infections (RVIs) after hematopoietic cell transplantation (HCT). We analyzed allogeneic HCT recipients of all ages with their first RVI during the first 100 days post-HCT. For the 21 days before RVI onset, we recorded any receipt of specific groups of antibiotics, and the cumulative sum of the number of antibiotics received for each day (antibiotic-days). We used Cox proportional hazards models to assess the relationship between antibiotic exposure and progression to LRTD. Among 469 patients with RVI, 124 progressed to LRTD. Compared to no antibiotics, use of antibiotics with broad anaerobic activity in the prior 21 days was associated with progression to LRTD after adjusting for age, virus type, hypoalbuminemia, neutropenia, steroid use, and monocytopenia (HR 2.2, 95% CI 1.1-4.1). Greater use of those antibiotics (≥7 antibiotic days) was also associated with LRTD in adjusted models (HR 2.2, 95% CI 1.1-4.3). Results were similar after adjusting for lymphopenia instead of monocytopenia. Antibiotic use is associated with LRTD after RVI across different viruses in HCT recipients. Prospective studies using anaerobe-sparing antibiotics should be explored to assess impact on LRTD in patients undergoing HCT.

Change in Seizure Incidence in Febrile Children With COVID-19 in the Era of Omicron Variant of Concern.

In this single-center retrospective observational study, we report that the incidence of seizures in febrile children with COVID-19 was significantly higher in the Omicron era than in the pre-Omicron era (14.6% vs 1.7%, P < .001). One-third of the cases in the Omicron era were older than 5 years.

Clinical characteristics of pediatric patients with COVID-19 between Omicron era vs. pre-Omicron era.

INTRODUCTION: Detailed data on clinical characteristics in children with the omicron strain of SARS-COV-2 are limited. METHODS: We conducted a retrospective observational study of children with COVID-19 at the National Center for Child Health and Development to evaluate the clinical manifestations during and before the emergence of the omicron variant. Only symptomatic patients without underlying diseases were included. Participants were divided into two temporal groups: the "omicron era" (1/2022-2/2022) and the "pre-omicron era," where the delta variant predominated (7/2021-11/2021). The patients were subclassified into an older vaccine-eligible group (aged 12-17 years), a younger vaccine-eligible group (aged 5-11 years), and a vaccine-ineligible group (aged 0-4 years). RESULTS: We compared 113 patients in the omicron era with 106 in the pre-omicron era. Most patients in both eras had non-severe disease, and no patients required mechanical ventilation or died. Among patients aged 0-4 years, sore throat and hoarseness were more common during the omicron era than the pre-omicron era (11.1% vs. 0.0% and 11.1% vs. 1.5%, respectively). Croup syndrome was diagnosed in all patients with hoarseness. Among patients aged 5-11 years, vomiting was more frequent during the omicron era (47.2%) than during the pre-omicron era (21.7%). Cough and rhinorrhea were less common during the omicron era in patients aged 0-4 and 5-11 years, respectively, than during the pre-omicron era. CONCLUSIONS: In children with COVID-19, clinical manifestations differed between the omicron and pre-omicron eras. In the Omicron era, croup syndrome was more frequent in vaccine-ineligible children.

Updates on Coronavirus Disease 2019 in Children in Japan.

This review provides updates on coronavirus disease 2019 (COVID-19) in children in Japan by summarizing published data. By the end of March 2022, Japan had experienced 6 waves of COVID-19 outbreaks. Over this time, the clinical features presented among children have changed in the context of the predominant variants. Although the COVID-19 pandemic affected children in terms of medical, physical and psychosocial aspects, the clinical outcomes have been favorable in Japan compared with those in some European countries and the United States, which may be partly due to a lower incidence of multisystem inflammatory syndromes in children and obesity. The COVID-19 vaccine has been available for children; however, the vaccination rate in children 5-11 years of age is lower than that in older children due to the government's lack of an active approach in this specific population. Further action is needed to improve the overall vaccination rates in children.

Correlation of initial upper respiratory tract viral burden with progression to lower tract disease in adult allogeneic hematopoietic cell transplant recipients.

BACKGROUND: Some respiratory viruses have been evaluated for the association between viral burden and respiratory disease progression in hematopoietic cell transplant (HCT) recipients, and no significant association has been reported. OBJECTIVES: To assess whether initial viral burden of respiratory viruses predicts risk of progression to lower respiratory tract infection (LRTI) among adult allogeneic HCT recipients who presented with upper respiratory tract infection (URTI) with 12 viruses in the PCR era. STUDY DESIGN: We reviewed adult allogeneic HCT recipients (4/2008-9/2018) who presented with their first symptomatic respiratory viral infection following transplantation at the Fred Hutchinson Cancer Center. Cox proportional hazards models were used to investigate whether viral burden as measured by initial Ct values at the diagnosis of URTI is associated with progression to LRTI within 90 days for each virus, treating death as a competing risk. RESULTS: Among 2,148 adult HCT recipients during the study periods, 1,102 episodes of URTI met the study inclusion criteria. Higher viral burden (lower Ct value) were associated with an increased risk of progression to LRTI for influenza after adjusting for immunodeficiency scoring index and initiation of antiviral therapy, respectively. The association between viral burden and progression to LRTI was not found for other viruses. CONCLUSIONS: Our findings suggest that routine reporting of viral burden in current molecular diagnostic platforms may be beneficial. Further studies are needed to investigate the impact of viral burden on LRTI in other populations including pediatric HCT recipients.

Respiratory viruses in hematopoietic cell transplant candidates: impact of preexisting lower tract disease on outcomes.

Pretransplant respiratory virus infections (RVIs) have been shown to negatively affect hematopoietic cell transplantation (HCT) outcomes. The impact of and need for delay of HCT for pretransplant infection with human rhinovirus (HRV) or endemic human coronavirus (HCoV; 229E, OC43, NL63, and HKU1) remain controversial. We analyzed the impact of symptomatic RVI within ≤90 days before HCT on overall mortality, posttransplant lower respiratory tract disease (LRD), and days alive and out of hospital (DAOH) by day 100 post-HCT in multivariable models. Among 1,643 adult HCT recipients (58% allogeneic recipients), 704 (43%) were tested for RVI before HCT, and 307 (44%) tested positive. HRV was most commonly detected (56%). Forty-five (15%) of 307 HCT recipients had LRD with the same virus early after HCT. Pretransplant upper respiratory tract infection (URI) with influenza, respiratory syncytial virus, adenovirus, human metapneumovirus, parainfluenza virus, HRV, or endemic HCoV was not associated with increased overall mortality or fewer DAOH. However, in allogeneic recipients who received myeloablative conditioning, LRD due to any respiratory virus, including HRV alone, was associated with increased overall mortality (adjusted hazard ratio, 10.8 [95% confidence interval, 3.29-35.1] for HRV and 3.21 [95% confidence interval, 1.15-9.01] for all other viruses). HRV LRD was also associated with fewer DAOH. Thus, the presence of LRD due to common respiratory viruses, including HRV, before myeloablative allogeneic HCT was associated with increased mortality and hospitalization. Pretransplant URI due to HRV and endemic HCoV was not associated with these outcomes. Improved management strategies for pretransplant LRD are warranted.