Expert consensus on vaccination in patients with inflammatory bowel disease in Japan.

Immunosuppressive therapies can affect the immune response to or safety of vaccination in patients with inflammatory bowel disease (IBD). The appropriateness of vaccination should be assessed prior to the initiation of IBD treatment because patients with IBD frequently undergo continuous treatment with immunosuppressive drugs. This consensus was developed to support the decision-making process regarding appropriate vaccination for pediatric and adult patients with IBD and physicians by providing critical information according to the published literature and expert consensus about vaccine-preventable diseases (VPDs) [excluding cervical cancer and coronavirus disease 2019 (COVID-19)] in Japan. This consensus includes 19 important clinical questions (CQs) on the following 4 topics: VPDs (6 CQs), live attenuated vaccines (2 CQs), inactivated vaccines (6 CQs), and vaccination for pregnancy, childbirth, and breastfeeding (5 CQs). These topics and CQs were selected under unified consensus by the members of a committee on intractable diseases with support by a Health and Labour Sciences Research Grant. Physicians should provide necessary information on VPDs to their patients with IBD and carefully manage these patients' IBD if various risk factors for the development or worsening of VPDs are present. This consensus will facilitate informed and shared decision-making in daily IBD clinical practice.

Child Neurology: Pathologically Confirmed Thrombotic Microangiopathy Caused by Onasemnogene Abeparvovec Treatment for SMA.

Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy for spinal muscular atrophy (SMA). Although several cases of drug-induced thrombotic microangiopathy due to onasemnogene abeparvovec have been reported, none has been confirmed pathologically. Here, we present renal histopathologic findings of TMA due to onasemnogene abeparvovec. On day 5 after receiving onasemnogene abeparvovec, a 23-month-old girl with SMA type 1 developed thrombocytopenia, microangiopathic hemolytic anemia, liver dysfunction, acute kidney injury, and hypertension. She was diagnosed with TMA and received an increased dose of prednisolone, antihypertensives, diuretics, packed red blood cell and platelet transfusion, a single dose of eculizumab, 4 cycles of plasmapheresis, and intermittent and continuous hemodialysis. Her TMA resolved by day 30. On day 49, renal biopsy was performed. Light microscopy revealed proliferation of glomerular mesangial cells and matrix, with mesangiolysis, endothelial cell swelling, and partial double contours of the glomerular basement membrane. Electron microscopy showed endothelial injury, with edematous changes of the subendothelial spaces and neoformation of the basement membrane, without electron-dense depositions. These findings are compatible with the recovery phase of TMA. One year after drug administration, her motor function is improved. She can hold her posture against gravity and has neither dysphagia nor respiratory disturbance, but mild hypertension persists. Physicians should be vigilant regarding TMA as a severe side effect of onasemnogene abeparvovec treatment, especially when thrombocytopenia, hemolytic anemia, increased lactate dehydrogenase, or acute kidney injury is present.

Cord Blood-Based Approach to Assess Candidate Vaccine Adjuvants Designed for Neonates and Infants.

Neonates and infants are particularly susceptible to infections, for which outcomes tend to be severe. Vaccination is a key strategy for preventing infectious diseases, but the protective immunity achieved through vaccination typically is weaker in infants than in healthy adults. One possible explanation for the poor acquisition of vaccine-induced immunity in infants is that their innate immune response, represented by toll-like receptors, is immature. The current system for developing pediatric vaccines relies on the confirmation of their safety and effectiveness in studies involving the use of mature animals or adult humans. However, creating vaccines for neonates and infants requires an understanding of their uniquely immature innate immunity. Here we review current knowledge regarding the innate immune system of neonates and infants and challenges in developing vaccine adjuvants for those children through analyses of cord blood.

Cell surface antigens of neonatal monocytes are selectively impaired in basal expression, but hyperresponsive to lipopolysaccharide and zymosan.

Toll-like receptors (TLRs) are important components of the innate immune system, but how neonatal TLR-mediated immune responses differ from those of adults is unknown. We aimed to clarify the TLR-mediated expression profiles of cell surface antigens related to antigen presentation in neonates. CD14-positive monocytes were isolated from human cord blood and adult peripheral blood and then stimulated with lipopolysaccharide (LPS; TLR4 agonist) or zymosan (TLR2/6 agonist) or left unstimulated. Expression levels of the surface antigens major histocompatibility (MHC)-class II, CD80, CD86, CD11b, CD11c, CD14, and CD16 were then evaluated by flow cytometry. Cord blood CD14+CD16high monocytes (CBM) showed significantly lower basal levels of MHC-class II, CD80, and CD11b than adult blood CD14+CD16intermediate monocytes (ABM) (P < 0.01, P < 0.001, P < 0.001, respectively). LPS stimulation enhanced expression of MHC class II, CD80, and CD11b significantly more in CBM than in ABM (P < 0.001, P < 0.01, P < 0.01, respectively), resulting in levels that did not differ between CBM and ABM. Zymosan stimulation also enhanced expression of MHC class II, CD86, CD11b, and CD11c significantly more in CBM than in ABM (P < 0.001, P < 0.01, P < 0.001, P < 0.01, respectively), resulting in levels of CD86 and CD11c that did not differ in CBM and ABM. However, MHC class II, CD80, and CD11b remained significantly higher in ABM than in CBM (P < 0.05, P < 0.01, P < 0.05, respectively). These data indicate that CBM and ABM have distinct phenotypes and responses to stimulation.

Relationship between Severity of Aseptic Meningitis and Cerebrospinal Fluid Cytokine Levels.

BACKGROUND: Pediatricians sometimes see patients with severe aseptic meningitis and prolonged fever or severe headache, or both. This condition generally has a good prognosis and is usually treated with supportive therapy. However, there is neither guideline nor consensus for the treatment of patients with severe aseptic meningitis. Here, we investigated the relationship between disease severity and biomarkers. METHODS: The subjects were 32 children aged 0 to 14 years, 23 of whom had aseptic meningitis and 9 of whom were meningitis-free controls. Aseptic meningitis was retrospectively categorized into two subgroups, namely mumps meningitis (MM) and viral meningitis excluding that caused by mumps (EM). We defined a novel aseptic meningitis severity score (AMSS) from the signs and symptoms of aseptic meningitis and thus evaluated disease severity. We analyzed the profiles of cytokines in the patients' cerebrospinal fluid (CSF). RESULTS: The AMSS in MM was significantly higher than that in EM. IL-4, IL-6, IL-8, IL-10, and G-CSF levels in MM and EM CSF were higher than those in control CSF. IFN-γ levels were higher in MM than in controls (p<0.01). IL-10 and IFN-γ levels in MM were higher than those in EM. CONCLUSIONS: MM was more severe than EM. One likely reason is the higher CSF cytokine levels in MM. IFN-γ may be a potentially strong biomarker of MM severity. Our findings would help further understanding

Twelve-year-old girl with intracranial epidural abscess and sphenoiditis.

We report the case of a 12-year-old girl with an intracranial epidural abscess and sphenoiditis. Although she had no history of sinusitis, she developed acute severe headache, fever, and vomiting. Emergent CT and MRI showed a spherical space-occupying lesion of diameter 3 cm in the right cranial fossa with rim enhancement. The lesion was thought to be an epidural abscess adjacent to the right sphenoiditis. On the basis of the MRI findings, we performed emergent surgery to drain the abscess and sinusitis because of severe and rapidly worsening headaches. The patient showed great improvement the day after the operation. Intravenous antibiotics were administered for 8 days. She has completely recovered, with neither sequelae nor recurrence at 7 months after the operation. We believe that this report will be a useful reference for cases of acute onset headache and may be helpful in diagnosis and treatment decisions for severe sinusitis-related intracranial abscess in childhood.

A case of TUBA1A mutation presenting with lissencephaly and Hirschsprung disease.

Gene mutation of tubulin alpha-1A (TUBA1A), a critical component of microtubules of the cytoskeleton, impairs neural migration and causes lissencephaly (LIS). The approximately 45 cases of disease-associated TUBA1A mutations reported to date demonstrate a wide spectrum of phenotypes. Here we describe an 8-year-old girl with lissencephaly, microcephaly, and early-onset epileptic seizures associated with a novel mutation in the TUBA1A gene. The patient developed Hirschsprung disease and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which had not previously been described in TUBA1A mutation-associated disease. Our case provides new insight into the wide spectrum of disease phenotypes associated with TUBA1A mutation.