Sequential Treatment by Antiviral Drugs Followed by Immunosuppressive Agents for COVID-19 Patients with Hematological Malignancy

Masafumi Seki,1,2 Kosuke Hashimoto,2 Nami Kondo,2 Yoshitaka Ohya,2 Futoshi Kotajima,2 Kotaro Mitsutake1,2 1Division of Infectious Diseases and Infection Control, International Medical Center, Saitama Medical University, Hidaka City, Saitama, Japan; 2COVID-19 Management Team, International Medical Center, Saitama Medical University, Hidaka City, Saitama, JapanCorrespondence: Masafumi Seki, Division of Infectious Diseases and Infection Control, International Medical Center, Saitama Medical University, Yamane 1397-1, Hidaka City, Saitama, 350-1298, Japan, Tel +81-42-984-4392, Fax +81-42-984-0280, Email [email protected]: The detailed treatment regimen of COVID-19 patients with hematological malignancies has been unclear, and some fatalities have occurred, although combination therapy with antiviral agents and corticosteroids has been established for moderate to severe COVID-19 patients.Case Series: Case 1 was a 57-year-old woman who had malignant lymphoma and received CHOP therapy with obinutuzumab, and case 2 was a 70-year-old-man who had myeloma and received molecular targeted therapy with weekly corticosteroid. In both cases, SARS-CoV-2 genes and antigens were detected from their nasal swabs, and treatment was started for moderate to severe COVID-19. Case 1 received antiviral agents with high doses of corticosteroids for a long term simultaneously, but the high titer of viral antigens in her nasal swabs persisted. Ground-glass opacities and interstitial shadows also worsened in both lungs, and she finally died on day 60. In contrast, in case 2, antiviral agents were started first, and restarted the immunosuppressive agents, such as gamma globulin and corticosteroids after no titer of SARS-CoV-2 antigens was confirmed. The patient survived, and his abnormal chest shadows showed gradual improvement. Both of the patients received two vaccinations, but showed the low antibody titers for SARS-CoV-2.Conclusion: Administration of both antiviral agents and corticosteroids has been recommended for moderate to severe COVID-19 patients, but in patients with hematological malignancies, it might be better to use antiviral agents first to reduce the viral titers, and then add steroid and related immunosuppressive agents later appropriately to inhibit the excessive inflammatory state. The dose, timing, and order of the antivirals and immunosuppressive agents for COVID-19 should be considered carefully in the patients with hematological malignancies who showed low vaccine effectiveness.Keywords: SARS-CoV-2, B cell depleting agents, corticosteroid, obinutuzumab, rituxima

Brain hyperserotonemia causes autism-relevant social deficits in mice

Abstract Background Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. Methods We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Results Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. Conclusions These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits