The First Case of a Child Infected with SARS-CoV-2 Omicron Variant in Japan, December 2021.

We report the first pediatric patient infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Japan. The patient was a one-year-old boy who resided in Japan. He went abroad with his parents from November 12, 2021 to November 28, 2021 and had no known contact with coronavirus disease (COVID-19) patients there. Upon arrival at the Narita International Airport on November 28, 2021, his father tested positive for SARS-CoV-2 via a quantitative antigen test. Because the boy and his mother tested negative for SARS-CoV-2, they quarantined together at a hotel separately from his father. On December 4, 2021, the boy tested positive by reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2, without symptoms, and was hospitalized with his mother; he and his father were both found to be infected with the SARS-CoV-2 Omicron variant. The boy was not vaccinated against COVID-19. RT-PCR results were negative starting on December 20, 2021. The incubation period and required period for negative conversion of SARS-CoV-2 RNA of the Omicron variant case were similar to those of the cases of conventional strains. We should carefully consider the potential of the SARS-CoV-2 Omicron variant to spread widely among unvaccinated children.

Adapting pediatric health care responses to the COVID-19 pandemic in Japan: A clinical perspective.

The COVID-19 pandemic required our pediatric health care staff to adjust to many irregularities and solve serious issues in our routine clinical practice. In outpatient clinics, many children exhibited common cold symptoms that mimic COVID-19, thus we initially screened patients via an interview form, then later via SARS-CoV-2 antigen test. Cluster infections were entirely avoided by following systematic, everyday precautions. Patientsquality of life has been difficult to maintain during the pandemic, due to social and staffing restrictions. Other unexpected repercussions - such as an unexpected lack of seasonal virus infections, then a respiratory syncytial (RS) virus outbreak - required agile management of hospital resources. While we must continue to adapt our treatment programs in response to the evolving COVID-19 crisis, it remains essential to support the well-being of children through regular health check-ups, mental health support, educational opportunities, proper socialization, and close communication with parents and families.

Case Report: Ciclosporin A for Refractory Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a new syndrome involving the development of severe dysfunction in multiple organs after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Because the pathophysiology of MIS-C remains unclear, a treatment strategy has not yet been established. We experienced a 12-year-old boy who developed MIS-C at 56 days after SARS-CoV-2 infection and for whom ciclosporin A (CsA) was effective as a third-line treatment. He had a high fever on day 1, and developed a rash on the trunk, swelling in the cervical region, and palmar erythema on day 2. On days 3, he developed conjunctivitis and lip redness, and fulfilled the criteria for classical Kawasaki disease (KD). Although intravenous immunoglobulin infusion (IVIG) was started on day 4, fever persisted and respiratory distress and severe abdominal pain developed. On day 5, because he fulfilled the criteria for MIS-C, methylprednisolone pulse was started for 3 days as a second-line treatment. However, he did not exhibit defervescence and the symptoms continued. Therefore, we selected CsA as a third-line treatment. CsA was so effective that he became defervescent and his symptoms disappeared. In order to clarify the relationship with treatment and the change of clinical conditions, we examined the kinetics of 71 serum cytokines to determine their relationships with his clinical course during the three successive treatments. We found that CsA suppressed macrophage-activating cytokines such as, IL-12(p40), and IL-18 with improvement of his clinical symptoms. CsA may be a useful option for additional treatment of patients with MIS-C refractory to IVIG + methylprednisolone pulse.

The first eleven cases of SARS-CoV-2 Omicron variant infection in Japan: A focus on viral dynamics.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has spread rapidly worldwide. We report the clinical characteristics and threshold cycle (Ct) values of the first 11 patients infected with the SARS-CoV-2 Omicron variant in Japan. All patients were younger returnees from abroad; 10 patients had received two doses of vaccine. Estimated Ct values for the 11 patients were 6.0 (95% confidence interval [CI] 4.2-7.3) days for > 30, 10.6 (95% CI 9.5-11.9) days for > 35, 15.1 (95% CI 13.6-17.6) days for > 40, and 19.7 (95% CI 17.3- 23.7) days for > 45. Our results provide important insights for indicators of infection control.

[Hematological neoplasia associated with primary mediastinal germ-cell tumor treated with hematopoietic stem cell transplantation].

The occurrence of a primary mediastinal germ cell tumor and hematological neoplasia provides a poor prognosis that is known to be fatal at a median of 6 months after onset. We report the case of a 15-year-old male who was treated with chemotherapy and hematopoietic cell transplantation based on a report of a surviving case. At diagnosis, the patient had an unresectable mediastinal tumor with elevated alpha-fetoprotein and human chorionic gonadotropin levels and acute megakaryoblastic leukemia. We prioritized treatment with chemotherapy for the tumor owing to the oncological emergency. We then performed leukemia induction therapy and achieved complete remission. Although we used CDDP in combination with intensive therapy, the mediastinal tumor grew too large for it to be safely resected. We transplanted bone marrow from the patient's human leukocyte antigen-haploidentical sibling upon conditioning with busulfan-melphalan. After 44 days, the leukemia recurred in the patient's central nervous system. This was followed by various post-transplant complications, and the patient died of organ failure that was associated with infectious diseases. At necropsy, a poorly engrafted bone marrow was observed. The mediastinal tumor was primarily necrotic, although some immature teratoma components were observed. No leukemic precursor cells were detected. Residual mediastinal tumors may be associated with the recurrence of leukemias. We seek a treatment strategy that enables early tumor resection and high-dose chemotherapy. Further case studies are warranted along with the development of effective treatment methods.

Case Report: Changes in Cytokine Kinetics During the Course of Disease in a Japanese Patient With Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe disease that is reportedly linked to coronavirus disease 2019. Affected patients present with gastrointestinal symptoms and cardiovascular dysfunction, in addition to Kawasaki disease-like features, suggesting the potential for overlapping disease mechanisms. Kawasaki disease has been reported among individuals of East Asian ethnicities, whereas there is minimal clinical literature regarding the occurrence of MIS-C among individuals of Asian ethnicities. A few reports thus far have described changes in cytokine kinetics during the course of disease in patients with MIS-C. We followed the temporal cytokine kinetics in a 9-year-old Japanese girl who exhibited a classical trajectory of MIS-C. The patient exhibited right cervical swelling and pain, abdominal pain, vomiting, and lip reddening, which developed 31 days after she was diagnosed with severe acute respiratory syndrome coronavirus-2 infection. The patient was diagnosed with Kawasaki disease on her fifth day of illness; because she fulfilled the criteria for MIS-C, she was also diagnosed with this disease on her fifth day of illness. Her fever rapidly resolved upon administration of intravenous immunoglobulin, aspirin, and prednisolone. On the patient's sixth day of illness, she developed acute myocarditis, which was treated with two diuretics and one vasodilator; the myocarditis ameliorated within a few days. Analyses of temporal kinetics for 71 serum cytokines revealed several patterns of cytokine changes that were consistent with the patient's clinical course of disease. Importantly, there was a clear distinction between cytokines that did and did not decrease rapidly following post-treatment fever resolution. These findings may be useful for the assessment of disease status and selection of therapy in patients with similar symptoms; they may also provide insights for basic and clinical research regarding MIS-C.

Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers.

Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.