Varicella in Adult Foreigners at a Referral Hospital, Central Tokyo, Japan, 2012-2016.

We report a case series of varicella among adult foreigners at a referral hospital in central Tokyo, Japan, during 2012-2016. This series highlights differences in varicella vaccination schedules by country and epidemiology by climate and identifies immigrants and international students as high-risk populations for varicella.

Rabies post-exposure prophylactic vaccination for returning travelers to Japan.

BACKGROUND: Rabies post-exposure prophylaxis (PEP) in Japan is administered using 6 subcutaneous doses (on days 0, 3, 7, 14, 30, and 90), which is not in line with international recommendations of 4 or 5 intramuscular doses. For reducing dose frequency, we evaluate the immunogenicity of PEP with a regimen of 6 subcutaneous doses. METHOD: This prospective single-center cross-sectional study was performed between September 2013 and December 2014. We included patients underwent rabies PEP by purified chick embryo-cultured rabies vaccine Kaketsuken (PCEC-K) at our clinic, and excluded patients with a history of pre-exposure prophylaxis or PEP using rabies immunoglobulin. The rabies virus-neutralizing antibody tests were performed at the first visit to our office (doses 1-4) and at the fifth and sixth doses. RESULTS: Data were available for 43 of 59 enrolled patients. Thirty-two patients did not start PEP within 48 h after exposure to animals. The seroprotection rates (≥0.5 IU/mL) were 90.7% and 75.7%, at days 30 and 90, respectively. Despite receiving a fifth dose, 85.3% of the patients exhibited decreasing antibody titers during days 30-90 (p < 0.001). CONCLUSIONS: The seroprotection rates of PCEC-K induced subcutaneously were insufficient to prevent rabies at day 30 and 90.

Wohlfahrtiimonas chitiniclastica Bacteremia Hospitalized Homeless Man with Squamous Cell Carcinoma.

We report a case of Wohlfahrtiimonas chitiniclastica bacteremia in an elderly man in Japan who had squamous cell carcinoma. Blood cultures were initially negative for W. chitiniclastica but were positive on day 20. Careful attention needs to be paid to this organism in patients who have chronic wounds with maggots.

Imported Leptospira licerasiae Infection in Traveler Returning to Japan from Brazil.

We describe a case of intermediate leptospirosis resulting from Leptospira licerasiae infection in a traveler returning to Japan from Brazil. Intermediate leptospirosis should be included in the differential diagnosis for travelers with fever returning from South America. This case highlights the need for strategies that detect pathogenic and intermediate Leptospira species.

Amoxicillin and Ceftriaxone as Treatment Alternatives to Penicillin for Maternal Syphilis.

There is no proven alternative to penicillin for treatment of maternal syphilis. We report 2 case-patients with maternal syphilis who were successfully treated without penicillin. We used amoxicillin and probenecid for the first case-patient and amoxicillin, probenecid, and ceftriaxone for the second case-patient.

Chikungunya Fever in Traveler from Angola to Japan, 2016.

Simultaneous circulation of multiple arboviruses presents diagnostic challenges. In May 2016, chikungunya fever was diagnosed in a traveler from Angola to Japan. Travel history, incubation period, and phylogenetic analysis indicated probable infection acquisition in Angola, where a yellow fever outbreak is ongoing. Thus, local transmission of chikungunya virus probably also occurs in Angola.

A fatal case of melioidosis with pancytopenia in a traveler from Indonesia.

Melioidosis, an infectious disease with high mortality, caused by Burkholderia pseudomallei, is endemic in southeast Asia and northern Australia. In Indonesia, autochthonous cases have been rarely reported, with most cases being sporadic and occurring in travelers. Herein, we report a fatal case of neurological melioidosis in a traveler from Indonesia presenting with septic shock.

A case of consecutive infection with Zika virus and Chikungunya virus in Bora Bora, French Polynesia.

Chikungunya fever (CHIK) and Zika virus (ZIKV) infection have similar endemic areas and clinical manifestations. We report a case of CHIK at 1 year after a ZIKV infection in Bora Bora (French Polynesia), which we diagnosed based on IgM to the CHIK virus and neutralizing antibodies to ZIKV.

[A Case of Blackwater Fever after Treatment for Plasmodium falciparum Malaria].

Blackwater fever (BWF), which causes massive intravascular hemolysis and the passage of black-colored urine, is a poorly understood condition that is rarely seen during the course of malaria. Here, we present a case of BWF that developed after treatment for falciparum malaria complicated by hyperparasitemia in a Japanese traveler. A 29-year-old woman returning from Ghana visited our travel clinic with complaints of sudden fever and headache on the third day of illness. She had taken anti-malarial drugs for intermittent malaria prophylaxis and the treatment of malaria while in Ghana. Falciparum malaria was diagnosed based on the results of a blood smear and was confirmed using PCR. She was successfully treated with a single artesunate suppository and one dose of intravenous quinine followed by artemether-lumefantrin for 3 days. She was discharged without complications on the 11th day of illness. However, she was re-admitted for fever and headache on the 16th day of illness. The recrudescence of malaria was excluded by peripheral blood smear results. BWF was diagnosed based on the presence of fever, black-colored urine, and laboratory findings suggesting intravascular hemolysis. She was treated with supportive care, including the transfusion of 10 packs of red blood cells and the maintenance of fluid and electrolyte balance, and she gradually improved within two weeks. BWF is a rare but severe complication induced by severe falciparum malaria and/or the use of the aryl-amino alcohol group of antimalarial drugs. Thus, consideration of BWF is particularly important for a rapid and accurate diagnosis.

[Unexpected Diseases in Two Patients with False-Positive Dengue Immunoglobulin M Antibody Test Results].

In 2014, an outbreak of 162 domestic dengue fever infections occurred in Tokyo, Japan; the first outbreak of its kind in 70 years. Nineteen of these cases were confirmed in our center. Advancements in diagnostic methods have enabled an earlier diagnosis of dengue fever; however, unfamiliarity with the clinical course and characteristics of diagnostic tests for dengue fever can lead to misdiagnosis. We herein describe 2 cases of Japanese patients with false-positive dengue immunoglobulin M antibody test results, who were finally diagnosed as having dermatomyositis and acute hepatitis A infection, respectively.

The first case of adult-onset PFAPA syndrome in Japan.

A 26-year-old woman presented with fever and pharyngitis. She previously experienced four periodic febrile episodes at 30- to 40-day intervals. We suspected periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, and prescribed predisolone, thereby her fever rapidly subsided. Her febrile episodes improved after daily cimetidine treatment. Genetic testing results of genomic DNA for periodic fever syndromes were negative, although she was heterozygous for p.Glu148Gln variation in MEFV, supporting the diagnosis of PFAPA syndrome.

Autochthonous dengue fever, Tokyo, Japan, 2014.

After 70 years with no confirmed autochthonous cases of dengue fever in Japan, 19 cases were reported during August-September 2014. Dengue virus serotype 1 was detected in 18 patients. Phylogenetic analysis of the envelope protein genome sequence from 3 patients revealed 100% identity with the strain from the first patient (2014) in Japan.

Comparison of clinical characteristics and laboratory findings of malaria, dengue, and enteric fever in returning travelers: 8-year experience at a referral center in Tokyo, Japan.

BACKGROUND: Without specific symptoms, diagnosis of febrile illness in returning travelers is challenging. Dengue, malaria, and enteric fever are common causes of fever in returning travelers and timely and appropriate treatment is important. However, differentiation is difficult without specific diagnostic tests. METHODS: A retrospective study was conducted at the National Centre for Global Health and Medicine (NCGM) from April 2005 to March 2013. Febrile travelers returning from overseas who were diagnosed with dengue, malaria, or enteric fever were included in this study. Clinical characteristics and laboratory findings were compared for each diagnosis. RESULTS: During the study period, 86 malaria, 85 dengue, and 31 enteric fever cases were identified. The mean age of the study cohort was 33.1 ± 12 years and 134 (66.3%) study participants were male. Asia was the most common area visited by returning travelers with fevers (89% of dengue, 18.6% of malaria, and 100% of enteric fever cases), followed by Africa (1.2% of dengue and 70.9% of malaria cases). Clinical characteristics and laboratory findings were significantly different among each group with each diagnosis. Decision tree models revealed that returning from Africa and CRP levels <10 mg/L were factors specific for diagnosis of malaria and dengue fever, respectively. CONCLUSION: Clinical manifestations, simple laboratory test results, and regions of travel are helpful to distinguish between dengue, malaria, and enteric fever in febrile returning travelers with non-specific symptoms.

Travel-related leptospirosis in Japan: a report on a series of five imported cases diagnosed at the National Center for Global Health and Medicine.

Leptospirosis is one of the most common travel-related infections. We report 5 cases of travel-related leptospirosis who presented at our clinic between January 2008 and December 2013. Patients were included in the study if they presented with a clinical profile that was compatible with the disease within 21 days of their return from traveling, which were laboratory-diagnosed as leptospirosis by blood culture, rise in antibody titers in paired sera using the microscopic agglutination test (MAT), and/or DNA detection using flaB-nested PCR. Five leptospirosis cases were evaluated, all of which contracted the disease after exposure to fresh water in Southeast Asian countries. All of the cases had fevers, headaches, conjunctival injections, and relative bradycardia. The pertinent laboratory findings included elevated C-reactive protein levels, elevated creatinine levels, and sterile pyuria. All 5 cases had serum MAT titers that increased by ≥ 4 times in the interval between specimens taken during the acute phase and those taken during the convalescence phase, and leptospiral DNA was detected in plasma and/or urine specimens in 4 cases. Leptospira interrogans was isolated from one patient's blood sample. Patients were treated with penicillin G, minocycline, or doxycycline. One case was cured without antibiotics. A diagnosis of leptospirosis should be considered for febrile travelers who return from Southeast Asian countries to Japan after being exposed to freshwater while traveling.

Comparison of clinical characteristics and laboratory findings of malaria, dengue, and enteric fever in returning travelers: 8-year experience at a referral center in Tokyo, Japan.

BACKGROUND: Without specific symptoms, diagnosis of febrile illness in returning travelers is challenging. Dengue, malaria, and enteric fever are common causes of fever in returning travelers and timely and appropriate treatment is important. However, differentiation is difficult without specific diagnostic tests. METHODS: A retrospective study was conducted at the National Centre for Global Health and Medicine (NCGM) from April 2005 to March 2013. Febrile travelers returning from overseas who were diagnosed with dengue, malaria, or enteric fever were included in this study. Clinical characteristics and laboratory findings were compared for each diagnosis. RESULTS: During the study period, 86 malaria, 85 dengue, and 31 enteric fever cases were identified. The mean age of the study cohort was 33.1 ± 12 years and 134 (66.3%) study participants were male. Asia was the most common area visited by returning travelers with fevers (89% of dengue, 18.6% of malaria, and 100% of enteric fever cases), followed by Africa (1.2% of dengue and 70.9% of malaria cases). Clinical characteristics and laboratory findings were significantly different among each group with each diagnosis. Decision tree models revealed that returning from Africa and CRP levels < 10 mg/L were factors specific for diagnosis of malaria and dengue fever, respectively. CONCLUSION: Clinical manifestations, simple laboratory test results, and regions of travel are helpful to distinguish between dengue, malaria, and enteric fever in febrile returning travelers with non-specific symptoms.

Case report: failure under azithromycin treatment in a case of bacteremia due to Salmonella enterica Paratyphi A.

BACKGROUND: Limited information is available regarding the clinical efficacy of azithromycin for the treatment of enteric fever due to fluoroquinolone-resistant Salmonella Typhi and Salmonella Paratyphi among travelers returning to their home countries. CASE PRESENTATION: We report a case of a 52-year-old Japanese man who returned from India, who developed a fever of 39°C with no accompanying symptoms 10 days after returning to Japan from a 1-month business trip to Delhi, India. His blood culture results were positive for Salmonella Paratyphi A. He was treated with 14 days of ceftriaxone, after which he remained afebrile for 18 days before his body temperature again rose to 39°C with no apparent symptoms. He was then empirically given 500 mg of azithromycin, but experienced clinical and microbiological failure of azithromycin treatment for enteric fever due to Salmonella Paratyphi A. However, the minimum inhibitory concentration (MIC) of azithromycin was not elevated (8 mg/L). He was again given ceftriaxone for 14 days with no signs of recurrence during the follow-up. CONCLUSION: There are limited data available for the treatment of enteric fever using azithromycin in travelers from developed countries who are not immune to the disease, and thus, careful follow-up is necessary. In our case, the low azithromycin dose might have contributed the treatment failure. Additional clinical data are needed to determine the rate of success, MIC, and contributing factors for success and/or failure of azithromycin treatment for both Salmonella Typhi and Salmonella Paratyphi infections.

Immunogenicity of single-dose Vero cell-derived Japanese encephalitis vaccine in Japanese adults.

In Japan, intensive immunization against Japanese encephalitis (JE) was performed from 1967 to 1976, and regular JE immunization was performed thereafter. However, for Japanese adults facing JE risk, dates of vaccination with new inactivated Vero cell-derived JE vaccine are unavailable. This study investigated how a single dose of Vero cell-derived JE vaccine affects Japanese adults. Neutralizing antibodies were measured pre- and post-JE vaccination in 79 participants (age 40.7 ± 9.4 years), enrolled between October 2009 and March 2011, whose JE-vaccination data were gathered from vaccination records and history taking. Before vaccination, the participants' seroprotection rate (SPR) was 51.9%, whereas SPR after vaccination was 93.7%. The seroconversion rate (SCR), which measures seronegative cases that turn seropositive after vaccination, was 86.8%. The geometric mean titer (GMT) was 14.7 before vaccination and 70.1 after vaccination. Age was a significant difference between seroprotected (42.8 years) and non-seroprotected (38.7 years) groups before vaccination. Then the difference of age, SCR, pre-vaccination GMT, post-vaccination GMT and sex ratio were also significant in participants aged 25-39 years and ≥40 years, who represent generations born when Japan's JE-vaccination policy changed. SCR was 100% in participants aged 25-39 years with a vaccination recorded 55.6% in participants aged 25-39 without a vaccination record, and 96.0% in participants aged ≥40 years. Thus, more participants aged 25-39 years were seroprotected before vaccination, but SCR was higher in those aged ≥40 years. Most Japanese adults can be protected after one-dose vaccination, but this may be insufficient for people aged 25-39 years without recorded JE vaccination.

[Malaria cases treated with artemether/lumefantrine in Japanese travelers].

Artemisinin-based combination therapy (ACT) has been the standard treatment for uncomplicated malaria. Although not licensed in Japan, artemether/lumefantrine (AL), one type of ACT, has been administered to patients with malaria since 2002 by the Research Group on Chemotherapy of Tropical Diseases. Herein, we reviewed malaria cases treated with AL in Japanese travelers. A retrospective study was conducted at the National Center for Global Health and Medicine from October 2005 to March 2013. There were 19 malaria patients treated with AL, and 10 falciparum malaria patients treated with AL only. In these 10 patients treated with AL only, the median time of fever clearance was 25.0 hours (range:14-66 hours), and the median time of parasite clearance was 36.0 hours (range:16-62 hours). There was a positive correlation between parasitemia and time from the start of therapy to the disappearance of the parasites. Parasitemia was higher (4.05% vs. 0.24%; p = 0.044) and parasite clearance time was longer (55.5 hours vs. 31.5 hours; p = 0.044) in the cases of recrudescence than non-recrudescence, respectively. Three of the 19 malaria patients showed recrudescence of malaria after treatment with AL. The reason that treatment failure was more frequently observed in this study than in previous reports may be related to poor absorption of lumefantrine owing to gastrointestinal symptoms, insufficiently ingested fatty foods, or high parasitemia on admission. The World Health Organization recommends that intravenous antimalarials should be administered in cases of severe malaria however, this is not applicable in Japan. Further studies are needed to distinguish patients with malaria who are treatable with ACT from those who should be treated initially with other intravenous antimalarials.

First case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia.

This is the first case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia. In September 2012, a previously healthy 35-year-old Japanese man presented to National Center for Global Health and Medicine in Tokyo with a two-day history of daily fever, mild headaches and mild arthralgia. Malaria parasites were found in the Giemsa-stained thin blood smear, which showed band forms similar to Plasmodium malariae. Although a nested PCR showed the amplification of the primer of Plasmodium vivax and Plasmodium knowlesi, he was finally diagnosed with P. knowlesi mono-infection by DNA sequencing. He was treated with mefloquine, and recovered without any complications. DNA sequencing of the PCR products is indispensable to confirm P. knowlesi infection, however there is limited access to DNA sequencing procedures in endemic areas. The extent of P. knowlesi transmission in Asia has not been clearly defined. There is limited availability of diagnostic tests and routine surveillance system for reporting an accurate diagnosis in the Asian endemic regions. Thus, reporting accurately diagnosed cases of P. knowlesi infection in travellers would be important for assessing the true nature of this emerging human infection.

[Clinical experience of primaquine use for treatment of vivax and ovale malaria in Japanese travelers].

Primaquine phosphate has been used to prevent relapse as a radical cure after the acute-phase treatment of vivax and ovale malaria however. Many vivax malaria relapses have been reported following a standard dose of primaquine (15 mg/day for 14 days). A higher dose of primaquine (30 mg/day for 14 days) decreases the relapse rate, and the concomitant risk of gastrointestinal side effects tends to disappear when the drug is administered with food. G6PD deficiency is rare in the Japanese population. Although the relapsed phenomenon is reported globally, the higher dose of primaquine is currently recommended in Japan only for those returning from Southeast Asia or Papua New Guinea. Cases of 18 Japanese, including 13 vivax malaria and 5 ovale malaria, prescribed primaquine at a referral center in Japan, were analyzed retrospectively from 2007-2011. Data on diagnosis, treatment, and outcome were extracted from medical records. Of the 18, 10 with vivax malaria were administered the higher dose of primaquine. We found that only one suffered relapse-a vivax malarial case returning from Brazil and treated with the standard dose of primaquine. No ovale malarial case suffered relapse. None, including the 10 prescribed the higher primaquine dose, experienced any adverse side effects. Based on our findings, we recommend a higher dose of primaquine be used to prevent relapse when treating Japanese suffering from vivax malaria.