研究者詳細 - 吉藤　歩

論文 - 吉藤　歩

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Canagliflozin protects the cardiovascular system through effects on the gut environment in non-diabetic nephrectomized rats

Matsui A., Yoshifuji A., Irie J., Tajima T., Uchiyama K., Itoh T., Wakino S., Itoh H.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 2023年

ISSN 13421751

Background: The gut produces toxins that contribute to the cardiovascular complications of chronic kidney disease. Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor that is used as an anti-diabetic drug, has a weak inhibitory effect against SGLT1 and may affect the gut glucose concentration and environment. Methods: Here, we determined the effect of canagliflozin on the gut microbiota and the serum gut-derived uremic toxin concentrations in 5/6th nephrectomized (Nx) rats. Results: Canagliflozin increased the colonic glucose concentration and restored the number of Lactobacillus bacteria, which was low in Nx rats. In addition, the expression of tight junction proteins in the ascending colon was low in Nx rats, and this was partially restored by canagliflozin. Furthermore, the serum concentrations of gut-derived uremic toxins were significantly increased by Nx and reduced by canagliflozin. Finally, the wall of the thoracic aorta was thicker and there was more cardiac interstitial fibrosis in Nx rats, and these defects were ameliorated by canagliflozin. Conclusions: The increases in colonic glucose concentration, Lactobacillus numbers and tight junction protein expression, and the decreases in serum uremic toxin concentrations and cardiac interstitial fibrosis may have been caused by the inhibition of SGLT1 by canagliflozin because similar effects were not identified in tofogliflozin-treated rats.

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Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant

Mise-Omata S., Ikeda M., Takeshita M., Uwamino Y., Wakui M., Arai T., Yoshifuji A., Murano K., Siomi H., Nakagawara K., Ohyagi M., Ando M., Hasegawa N., Saya H., Murata M., Fukunaga K., Namkoong H., Lu X., Yamasaki S., Yoshimura A.

Journal of Immunology （Journal of Immunology） 209 （ 11 ） 2104 - 2113 2022年12月

ISSN 00221767

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR62 circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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Investigation for the efficacy of COVID-19 vaccine in Japanese CKD patients treated with hemodialysis

Yoshifuji A., Toda M., Ryuzaki M., Kikuchi K., Kawai T., Sakai K., Oyama E., Koinuma M., Katayama K., Uehara Y., Ohmagari N., Kanno Y., Kon H., Shinoda T., Takano Y., Tanaka J., Hora K., Nakazawa Y., Hasegawa N., Hanafusa N., Hinoshita F., Morikane K., Wakino S., Nakamoto H., Takemoto Y.

Renal Replacement Therapy （Renal Replacement Therapy） 8 （ 1 ） 2022年12月

Background: Dialysis patients are predisposed to severe disease and have a high mortality rate in coronavirus disease 2019 (COVID-19) due to their comorbidities and immunocompromised conditions. Therefore, dialysis patients should be prioritized for vaccination. This study aimed to examine how long the effects of the vaccine are maintained and what factors affect antibody titers. Methods: Hemodialysis patients (HD group) and age- and sex-matched non-dialysis individuals (Control group), receiving two doses of BNT162b2 vaccine, were recruited through the Japanese Society for Dialysis Therapy (JSDT) Web site in July 2021. Anti-SARS-CoV-2 immunoglobulin (IgG) (SARS-CoV-2 IgG titers) was measured before vaccination, 3 weeks after the first vaccination, 2 weeks after the second vaccination, and 3 months after the second vaccination, and was compared between Control group and HD group. Factors affecting SARS-CoV-2 IgG titers were also examined using multivariable regression analysis and stepwise regression analysis (least AIC). In addition, we compared adverse reactions in Control and HD groups and examined the relationship between adverse reactions and SARS-CoV-2 IgG titers. Results: Our study enrolled 123 participants in the Control group (62.6% men, median age 67.0 years) and 206 patients in the HD group (64.1% men, median age 66.4 years). HD group had significantly lower SARS-CoV-2 IgG titers at 3 weeks after the first vaccination (p < 0.0001), 2 weeks after second vaccination (p = 0.0002), and 3 months after the second vaccination (p = 0.045) than Control group. However, the reduction rate of SARS-CoV-2 IgG titers between 2 weeks and 3 months after the second vaccination was significantly smaller in HD group than in Control (p = 0.048). Stepwise regression analysis revealed that dialysis time was identified as the significant independent factors for SARS-CoV-2 IgG titers at 2 weeks after the second vaccination in HD group (p = 0.002) and longer dialysis time resulted in higher maximum antibody titers. The incidences of fever and nausea after the second vaccination were significantly higher in the HD group (p = 0.039 and p = 0.020). Antibody titers in those with fever were significantly higher than those without fever in both groups (HD: p = 0.0383, Control: p = 0.0096). Conclusion: HD patients had significantly lower antibody titers than age- and sex-matched non-dialysis individuals over 3 months after vaccination. Dialysis time was identified as a factor affecting SARS-CoV-2 IgG titers in HD group, with longer dialysis time resulting in higher maximum SARS-CoV-2 IgG titers.

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Patients with hemodialysis-induced hypoxemia had a poor prognosis of COVID-19

Toda M., Yoshifuji A., Fujii K., Komatsu M., Kato A., Tamura I., Sugi W., Ryuzaki M.

Renal Replacement Therapy （Renal Replacement Therapy） 8 （ 1 ） 2022年12月

Background: We experienced that some hemodialysis (HD) patients with coronavirus disease 2019 (COVID-19) exacerbated hypoxemia during HD. Though HD-induced hypoxemia has been reported, there have been no reports of HD-induced hypoxemia in patients with COVID-19 and its effect on prognosis of COVID-19. Methods: Eleven HD patients admitted with COVID-19 from August 2020 to April 2021 were classified into the patients whose oxygen demand increased by more than 3 L/min with mask during HD (worsened group, n = 5) and others (not-worsened group, n = 6). The background, laboratory findings, severity of COVID-19 and prognosis were compared between the two groups. In addition, blood gases were measured before and after dialysis among HD patients admitted with COVID-19 on April 2021 (n = 3). Results: There were no significant differences in backgrounds, except for a higher proportion of diabetes mellitus in worsened group (p = 0.04). Although laboratory findings were not significantly different on admission day, albumin and LDH levels 7 days after admission were significantly lower and higher in worsened group, respectively (p = 0.03 and < 0.01). The severity of COVID-19 and survival rate were significantly worse in worsened group (p = 0.01 and 0.03). The alveolar-arterial oxygen pressure difference (Aa-DO2) opened during HD in a patient with HD-induced hypoxemia, but did not open in patients without HD-induced hypoxemia. Conclusions: There is a close relationship among HD-induced hypoxemia and poor prognosis of COVID-19. The HD-induced hypoxemia of patients with COVID-19 may be caused by ventilation/perfusion mismatching.

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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

Wang Q.S., Edahiro R., Namkoong H., Hasegawa T., Shirai Y., Sonehara K., Tanaka H., Lee H., Saiki R., Hyugaji T., Shimizu E., Katayama K., Kanai M., Naito T., Sasa N., Yamamoto K., Kato Y., Morita T., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Ichikawa M., Nakamura A., Harada S., Sandhu Y., Kabata H., Masaki K., Kamata H., Ikemura S., Chubachi S., Okamori S., Terai H., Morita A., Asakura T., Sasaki J., Morisaki H., Uwamino Y., Nanki K., Uchida S., Uno S., Nishimura T., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Tagaya E., Kawana M., Arimura K., Takahashi K., Anzai T., Ito S., Endo A., Uchimura Y., Miyazaki Y., Honda T., Tateishi T., Tohda S., Ichimura N., Sonobe K., Sassa C.T., Nakajima J., Nakano Y., Nakajima Y., Anan R., Arai R., Kurihara Y., Harada Y., Nishio K., Ueda T., Azuma M., Saito R., Sado T., Miyazaki Y., Sato R., Haruta Y., Nagasaki T., Yasui Y., Hasegawa Y., Mutoh Y., Kimura T., Sato T.

Nature Communications （Nature Communications） 13 （ 1 ） 2022年12月

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

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Committee report: Questionnaire survey on the treatment of COVID-19 in patients receiving dialysis therapy

Yoshifuji A., Ryuzaki M., Uehara Y., Ohmagari N., Kawai T., Kanno Y., Kikuchi K., Kon H., Sakai K., Shinoda T., Takano Y., Tanaka J., Hora K., Nakazawa Y., Hasegawa N., Hanafusa N., Hinoshita F., Morikane K., Wakino S., Nakamoto H., Takemoto Y.

Renal Replacement Therapy （Renal Replacement Therapy） 8 （ 1 ） 2022年12月

Background: Patients with coronavirus disease 2019 (COVID-19) who receive dialysis therapy develop more severe disease and have a poorer prognosis than patients who do not. Although various data on the treatment of patients not receiving dialysis therapy have been reported, clinical practice for patients on dialysis is challenging as data is limited. The Infection Control Committee of the Japanese Society for Dialysis Therapy decided to clarify the status of treatment in COVID-19 patients on dialysis. Methods: A questionnaire survey of 105 centers that had treated at least five COVID-19 patients on dialysis was conducted in August 2021. Results: Sixty-six centers (62.9%) responded to the questionnaire. Antivirals were administered in 27.7% of facilities treating mild disease (most patients received favipiravir) and 66.7% of facilities treating moderate disease (most patients with moderate or more severe conditions received remdesivir). Whether and how remdesivir is administered varies between centers. Steroids were initiated most frequently in moderate II disease (50.8%), while 43.1% of the facilities initiated steroids in mild or moderate I disease. The type of steroid, dose, and the duration of administration were generally consistent, with most facilities administering dexamethasone 6 mg orally or 6.6 mg intravenously for 10 days. Steroid pulse therapy was administered in 48.5% of the facilities, and tocilizumab was administered in 25.8% of the facilities, mainly to patients on ventilators or equivalent medications, or to the cases of exacerbations. Furthermore, some facilities used a polymethylmethacrylate membrane during dialysis, nafamostat as an anticoagulant, and continuous hemodiafiltration in severe cases. There was limited experience of polymyxin B-immobilized fiber column-direct hemoperfusion and extracorporeal membrane oxygenation. The discharge criteria for patients receiving dialysis therapy were longer than those set by the Ministry of Health, Labor and Welfare in 22.7% of the facilities. Conclusions: Our survey revealed a variety of treatment practices in each facility. Further evidence and innovations are required to improve the prognosis of patients with COVID-19 receiving dialysis therapy.

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Ceftazidime encephalopathy developed without the elevation of cerebrospinal fluid concentration of ceftazidime: A case report of two cases

Toda M., Yoshifuji A., Hosoya K., Taguchi K., Komatsu M., Kobayashi E., Fujii K., Kato A., Hasegawa N., Matsumoto K., Ryuzaki M.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 28 （ 12 ） 1667 - 1671 2022年12月

ISSN 1341321X

Background: Ceftazidime encephalopathy is reported to be caused by the repeated administration of ceftazidime in patients with renal impairment because of the high serum concentration of ceftazidime. Ceftazidime encephalopathy has been considered to be caused by the elevation of the cerebrospinal fluid (CSF) concentration. However, as no reports have measured CSF concentrations, the relationship with ceftazidime encephalopathy and CSF concentration has not been clarified. Case presentation: Case 1: An 80-year-old Japanese man under a combination therapy with peritoneal dialysis and hemodialysis, who had been treated for a cellulitis with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was only under 0.1 μg/mL. Case 2: An 88-year-old Japanese man with chronic kidney disease, who had been treated for a urinary tract infection with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was within the therapeutic range. However, his serum and CSF concentration of quinolinic acid was markedly increased. Conclusions: Patients with renal failure are more likely to develop ceftazidime encephalopathy. We need to pay attention to the dosage of ceftazidime and to the appearance of neurological symptoms. Ceftazidime encephalopathy was considered to be caused by the high CSF concentration, but it could be caused by quinolinic acid as neurotoxic substance.

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DOCK2 is involved in the host genetics and biology of severe COVID-19

Namkoong H., Edahiro R., Takano T., Nishihara H., Shirai Y., Sonehara K., Tanaka H., Azekawa S., Mikami Y., Lee H., Hasegawa T., Okudela K., Okuzaki D., Motooka D., Kanai M., Naito T., Yamamoto K., Wang Q.S., Saiki R., Ishihara R., Matsubara Y., Hamamoto J., Hayashi H., Yoshimura Y., Tachikawa N., Yanagita E., Hyugaji T., Shimizu E., Katayama K., Kato Y., Morita T., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Aoki R., Nakamura A., Harada S., Sasano H., Kabata H., Masaki K., Kamata H., Ikemura S., Chubachi S., Okamori S., Terai H., Morita A., Asakura T., Sasaki J., Morisaki H., Uwamino Y., Nanki K., Uchida S., Uno S., Nishimura T., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Tagaya E., Kawana M., Arimura K., Takahashi K., Anzai T., Ito S., Endo A., Uchimura Y., Miyazaki Y., Honda T., Tateishi T., Tohda S., Ichimura N., Sonobe K., Sassa C.T., Nakajima J., Nakano Y., Nakajima Y., Anan R., Arai R., Kurihara Y., Harada Y., Nishio K.

Nature （Nature） 609 （ 7928 ） 754 - 760 2022年09月

ISSN 00280836

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

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A case of Bacillus subtilis var. natto bacteremia caused by ingestion of natto during COVID-19 treatment in a maintenance hemodialysis patient with multiple myeloma

Kato A., Yoshifuji A., Komori K., Aoki K., Taniyama D., Komatsu M., Fujii K., Yamada K., Ishii Y., Kikuchi T., Ryuzaki M.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 28 （ 8 ） 1212 - 1215 2022年08月

ISSN 1341321X

A 70-year-old woman, who started on hemodialysis 7 months before for end-stage renal disease due to diabetic nephropathy and was diagnosed with symptomatic multiple myeloma 1 month before, was admitted to our hospital with critical coronavirus disease 2019 and treated with long-term immunosuppressive therapy such as steroids and tocilizumab. During treatment, Bacillus subtilis was detected in the blood cultures. We could not exclude the association of natto (fermented soybeans) with B. subtilis var. natto, which the patient had been eating every day from 8 days after admission. She was prohibited from eating natto and treated with vancomycin. Later, B. subtilis detected in the blood culture was identified as B. subtilis var. natto, which was identical with those contained in the natto that the patient consumed daily using a next-generation sequencer. Gut dysbiosis due to old age, malignant tumor, diabetes mellitus, end-stage renal disease, and intestinal inflammation caused by severe acute respiratory syndrome coronavirus 2 increased intestinal permeability and the risk of bacterial translocation, causing B. subtilis var. natto bacteremia. Therefore, careful consideration might be given to the intake of fermented foods containing live bacteria in patients with severe immunocompromised conditions.

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Factors associated with SARS-CoV-2 antibody titers and prognosis of breakthrough infection in hemodialysis patients

Toda M., Yoshifuji A., Kikuchi K., Koinuma M., Komatsu M., Fujii K., Kato A., Kikuchi T., Nakazawa A., Ryuzaki M.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 26 （ 6 ） 571 - 580 2022年06月

ISSN 13421751

Background: The mortality rate of Coronavirus disease 2019 (COVID-19) is extremely high in hemodialysis patients (HDP). These patients also develop lower antibody titers after vaccination. Therefore, factors associated with antibody titers and vaccine efficacy in HDP with breakthrough infection need to be investigated. Methods: We measured anti-S1 antibody titers in HDP (n = 104) and controls (n = 35), evaluating the influence of background on HDP by multivariable regression analysis. We classified 26 HDP patients admitted with COVID-19 into the unvaccinated (n = 15) and breakthrough infection group (n = 11), performing between-group comparisons of laboratory findings and prognosis. Vaccinated COVID-19 patients were classified into HDP and non-HDP controls, and compared the relationship between antibody titer and severity, and the prognosis of breakthrough infection. Results: The antibody titer was significantly lower in the HDP group than in the control group. Among HDP, age and smoking history were significantly independent factors associated with antibody titer. The breakthrough infection group had significantly better laboratory findings (KL-6 and LDH), severity, and hospitalization period than the unvaccinated group even if antibody titers were lower than the known threshold for neutralization (p < 0.05). There was no significant difference in prognosis between the HDP and non-HDP with breakthrough infection. Severity of COVID-19 tended to be higher with lower antibody titer in non-HDP, but not in HDP. Conclusion: Vaccines improved the severity of COVID-19 and hospitalization period of breakthrough infection in HDP, although HDP, especially in elderly smokers had lower antibody titers than control. There was no significant association between antibody titer and severity in HDP.

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Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

Joseph C.B., Mariniello M., Yoshifuji A., Schiano G., Lake J., Marten J., Richmond A., Huffman J.E., Campbell A., Harris S.E., Troyanov S., Cocca M., Robino A., Thériault S., Eckardt K.U., Wuttke M., Cheng Y., Corre T., Kolcic I., Black C., Bruat V., Concas M.P., Sala C., Aeschbacher S., Schaefer F., Bergmann S., Campbell H., Olden M., Polasek O., Porteous D.J., Deary I.J., Madore F., Awadalla P., Girotto G., Ulivi S., Conen D., Wuehl E., Olinger E., Wilson J.F., Bochud M., Köttgen A., Hayward C., Devuyst O.

Journal of the American Society of Nephrology （Journal of the American Society of Nephrology） 33 （ 3 ） 511 - 529 2022年03月

ISSN 10466673

Background Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. Methods We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. Results Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. Conclusions Common variants in KRT40,WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

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COVID-19 vaccine induced interstitial lung disease

Yoshifuji A., Ishioka K., Masuzawa Y., Suda S., Murata S., Uwamino Y., Fujino M., Miyahara H., Hasegawa N., Ryuzaki M., Hoshino H., Sekine K.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 28 （ 1 ） 95 - 98 2022年01月

ISSN 1341321X

A 60-year-old man presented with dyspnea four days after the second dose of the coronavirus disease (COVID-19) vaccine. Imaging revealed extensive ground-glass opacification. Blood tests were notable for elevated KL-6 levels. Bronchoalveolar lavage fluid analysis showed increased lymphocyte-dominant inflammatory cells and decreased CD4/CD8 ratio. These findings were consistent with the diagnosis of drug-induced interstitial lung disease (DIILD). To the best of our knowledge, this has never been reported in previous literature. Treatment with glucocorticoids relieved his symptoms. This paper highlights that although extremely rare, COVID-19 vaccine could cause DIILD, and early diagnosis and treatment are crucial to improve patient outcomes.

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Clinical efficacy and safety of combination therapy of tocilizumab and steroid pulse therapy for critical COVID-19 in HD patients

Toda M., Fujii K., Yoshifuji A., Kondo Y., Itoh K., Sekine K., Kikuchi T., Ryuzaki M.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 26 （ 1 ） 75 - 85 2022年01月

ISSN 13421751

Background: Critical coronavirus disease 2019 (COVID-19) has a high fatality rate, especially in hemodialysis (HD) patients, with this poor prognosis being caused by systemic hyperinflammation; cytokine storms. Steroid pulse therapy or tocilizumab (TCZ) have insufficient inhibitory effects against cytokine storms in critical cases. This study evaluated the clinical effects and safety of combining steroid pulse therapy and TCZ. Methods: From September 2020 to May 2021, 201 patients with COVID-19 were admitted to our hospital. Before February 2021, patients with an oxygen demand exceeding 8 L/min were intubated and treated with standard therapy (dexamethasone and antiviral therapy). After February 2021, patients underwent high-flow nasal cannula oxygen therapy and were treated with TCZ (8 mg/kg) and methylprednisolone (mPSL) (500 mg/day [≤ 75 kg], 1000 mg/day [> 75 kg]) for 3 days. We compared background characteristics, laboratory findings, and prognosis between non-HD and HD patients and between patients who received and did not receive TCZ and mPSL pulse therapy. Results: Among non-HD patients, the TCZ + mPSL pulse group had significantly higher survival rates and lower secondary infection rates (p < 0.05), than the standard therapy group. All HD patients in the standard therapy group with oxygen demand exceeding 8 L/min died. Contrastingly, all patients in the TCZ + mPSL pulse group survived, with their oxygen demand decreasing to 0–1 L/min within 3 weeks post-administration. Conclusion: TCZ combined with mPSL pulse therapy improved the survival rate without significant adverse events in critical HD and non-HD patients with COVID-19 by strongly suppressing systemic hyperinflammation.

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Nafamostat Mesylate Monotherapy in Patients with Moderate COVID-19: a Single-Center, Retrospective Study

Soma T., Fujii K., Yoshifuji A., Maruki T., Itoh K., Taniyama D., Kikuchi T., Hasegawa N., Nakamura M.

Japanese Journal of Infectious Diseases （Japanese Journal of Infectious Diseases） 75 （ 5 ） 484 - 489 2022年

ISSN 13446304

Coronavirus disease (COVID-19) has spread dramatically worldwide. Nafamostat mesylate inhibits intracellular entry of the novel severe acute respiratory syndrome coronavirus 2 and is believed to have therapeutic potential for treating patients with COVID-19. In this study, patients with moderate COVID-19 who were admitted to our hospital were retrospectively analyzed. Thirty-one patients received monotherapy with nafamostat mesylate, and 33 patients were treated conservatively. Nafamostat mesylate was administered with continuous intravenous infusion for an average of 4.5 days. Compared with the conservative treatment, nafamostat mesylate did not improve outcomes or laboratory data 5 days after admission. In addition, no significant differences in laboratory data 5 days after admission and outcomes in high-risk patients were observed. The incidence of hyperkalemia was significantly higher in the nafamostat mesylate group; however, none of the patients required additional treatment. In conclusion, monotherapy with nafamostat mesylate did not improve clinical outcomes in patients with moderate COVID-19. This study did not examine the therapeutic potential of combining nafamostat mesylate with other antiviral agents, and further investigation is required. Because of the high incidence of hyperkalemia, regular laboratory monitoring is required during the use of nafamostat mesylate.

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Glomerulonephritis caused by bartonella spp. infective endocarditis: The difficulty and importance of differentiation from anti-neutrophil cytoplasmic antibody-related rapidly progressive glomerulonephritis

Yoshifuji A., Hibino Y., Komatsu M., Yasuda S., Hosoya K., Kobayashi E., Baba Y., Hirose S., Hashiguchi A., Kanno Y., Ryuzaki M.

Internal Medicine （Internal Medicine） 60 （ 12 ） 1899 - 1906 2021年

ISSN 09182918

A 65-year-old man with valvular disorder presented to his physician because of widespread purpura in both lower extremities. Blood tests showed elevated serum creatinine levels and proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) with hematuria, suggesting ANCA-related rapidly progressive glomerulonephritis (RPGN). Although multiple blood cultures were negative, transthoracic echocardiography revealed warts in the valves, and a renal biopsy also showed findings of glomerular infiltration by mononuclear leukocytes and C3 deposition in the glomeruli, suggesting infection-related glomerulonephritis. Later, Bartonella antibody turned positive. Antimicrobial treatment improved the purpura and renal function without any recurrence. ANCA-positive RPGN requires the exclusion of infective endocarditis, especially that induced by Bartonella spp.

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