Epidemiologic Trends and Distributions of Imported Infectious Diseases Among Travelers to Japan Before and During the COVID-19 Pandemic, 2016 to 2021: A Descriptive Study.

BACKGROUND: Little is known about the trends of imported infectious diseases among travelers to non-endemic countries during the novel coronavirus disease 2019 (COVID-19) pandemic. This article aimed to describe those among travelers to Japan. METHODS: This is a descriptive study based on national surveillance data. Imported infectious disease cases were defined as those with a reported overseas source of infection among 15 diseases pre-selected based on the probability and impact of importation. The number of notified cases from April 2016 to March 2021 were described by disease and time of diagnosis. The relative ratio and absolute difference in case counts-both by number and per arrival-were calculated by disease comparing those from the pandemic period (April 2020-March 2021) to the pre-pandemic period (April 2016-March 2020). RESULTS: A total of 3,524 imported infectious disease cases were diagnosed during the study period, including 3,439 cases before and 85 cases during the pandemic. The proportionate distribution of diseases changed but notification counts of all 15 diseases decreased during the pandemic. Accounting for arrivals, however, seven diseases showed a two-fold or greater increase, with a notable absolute increase per million arrivals for amebiasis (60.1; 95% confidence interval [CI], 41.5-78.7), malaria (21.7; 95% CI, 10.5-33.0), and typhoid fever (9.3; 95% CI, 1.9-16.8). CONCLUSION: The epidemiology of imported infectious diseases changed during the pandemic. While the number of imported infectious disease cases decreased, the number of cases per arrivals increased considerably both in relative and absolute terms for several diseases of public health and clinical importance.

Factors affecting the sensitivity of quantitative severe acute respiratory syndrome coronavirus 2 antigen test.

INTRODUCTION: The accuracy of nucleic acid amplification tests (NAATs) is affected by various factors; however, studies examining the factors affecting the accuracy of quantitative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test (QAT) are limited. METHODS: A total of 347 nasopharyngeal samples were collected from patients with coronavirus disease 2019 (COVID-19), and the date of onset was obtained from the electronic medical records. The SARS-CoV-2 antigen level was measured using Lumipulse Presto SARS-CoV-2 Ag (Presto), while NAAT was performed using the Ampdirect 2019-nCoV Detection Kit. RESULTS: Presto had a sensitivity rate of 95.1% (95% confidence interval: 92.8-97.4) in detecting the SARS-CoV-2 antigen in 347 samples. The number of days from symptom onset to sample collection was negatively correlated with the amount of antigen (r = -0.515) and sensitivity of Presto (r = -0.711). The patients' age was lower in the Presto-negative samples (median age, 39 years) compared with that in the Presto-positive samples (median age, 53 years; p < 0.01). A significant positive correlation was observed between age (excluding teenagers) and Presto sensitivity (r = 0.764). Meanwhile, no association was found between the mutant strain, sex, and Presto results. CONCLUSION: Presto is useful for the accurate diagnosis of COVID-19 owing to its high sensitivity when the number of days from symptom onset to sample collection is within 12 days. Furthermore, age may affect the results of Presto, and this tool has a relatively low sensitivity in younger patients.

Analysis of diagnostic performance and factors causing nonspecific reactions in SARS-CoV-2 rapid antigen detection tests.

INTRODUCTION: Early diagnosis and appropriate infection control are important to prevent the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we aimed to assess the diagnostic performance of SARS-CoV-2 rapid antigen detection (RAD) tests and the factors that cause nonspecific reactions. METHODS: Nasopharyngeal swab specimens (n = 100), sputum specimens (n = 10), and lithium-heparin plasma samples (n = 100) were collected. We evaluated Espline®SARS-CoV-2 (Espline) and SARS-CoV-2 Rapid Antigen Test that also known as STANDARD Q® (STANDARD Q), with reverse transcription-polymerase chain reaction (RT-PCR) and Lumipulse® Presto SARS-CoV-2 Ag as reference tests. In addition, we investigated the effects of inadequate pretreatment methods and five potential causes of nonspecific reactions. RESULTS: The sensitivities of Espline and STANDARD Q were 60% and 57%, respectively, and their specificity was 100%. It was confirmed that the judgment line for the positive insufficiently mixed specimens was faint. A false-positive result was observed with STANDARD Q when sputum was used as a specimen to investigate judgment the effect of viscosity. CONCLUSIONS: Espline and STANDARD Q show good sensitivity for specimens with Ct values less than 25, but specimens collected within 9 days of symptom onset may still give false negatives. The test should be performed carefully, and the results should be judged comprehensively, taking into account clinical symptoms and patient background.

Performance analysis among multiple fully automated anti-SARS-CoV-2 antibody measurement reagents: A potential indicator for the correlation of protection in the antibody titer.

BACKGROUND: To evaluate the performance of various reagents in automated analyzers for antibody detection against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Using 100 serum samples from 100 individual patients diagnosed with SARS-CoV-2 infection, the precision, linearity, determination agreement, and correlation of five qualitative reagents (Elecsys Anti-SARS-CoV-2, ARCHITECT SARS-CoV-2 IgG, ARCHITECT SARS-CoV-2 IgM, Access SARS-CoV-2 IgM, and SARS-CoV-2 IgM) and four quantitative reagents (Elecsys Anti-SARS-CoV-2 S, ARCHITECT SARS-CoV-2 IgG II, Access SARS-CoV-2 IgG 1st IS, and SARS-COV-2 IgG S) were analyzed. A surrogate virus-neutralizing test (sVNT) kit was used to evaluate the measurement value of each quantitative reagent corresponding to the amount of neutralizing antibody, similar to that of patients in the late stage of infection. RESULTS: Precision and linearity were found to be sufficient for clinical use. Five discrepant samples were observed in the positive and negative judgments of the qualitative reagents for IgG, and one discrepant sample was observed in the qualitative reagent for IgM. Although the measurement values of the quantitative reagents were different, they were correlated with each reagent. The reference values inferred from the sVNT were Elecsys Anti-SARS-CoV-2: 71.8 U/L, ARCHITECT SARS-CoV-2 IgGⅡ: 2976.3 AU/mL, Access SARS-CoV-2 IgG 1st IS: 689.6 IU/mL, and SARS-CoV-2 IgG S: 19.3 U/L. CONCLUSIONS: The performance observed for each anti-SARS-CoV-2 antibody detection reagent was sufficient. The reference values based on the inhibition rate of sVNT have potential as indicators of the correlation of protection and are expected to be leveraged in automated antibody tests.

Delayed dexamethasone treatment at initiation of oxygen supplementation for coronavirus disease 2019 is associated with the exacerbation of clinical condition.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) frequently causes inflammatory lung injury as its symptoms progress. While dexamethasone reportedly reduces inflammation and prevents progression to respiratory failure, the appropriate time to administer dexamethasone in patients with COVID-19 remains unclear. METHODS: This was a single-center, retrospective cohort study, where we consecutively enrolled patients hospitalized with COVID-19 who received oxygen and oral dexamethasone (n = 85). We assessed the association between the number of days to the initiation of dexamethasone and the cumulative rate of exacerbation defined as death or initiation of mechanical ventilation within 28 days of symptom onset. RESULTS: The optimal cut-off value from the initiation of oxygen supplementation to that of dexamethasone administration was two days (sensitivity, 85%; specificity, 59%), whereas that from oxygen saturation (SpO2) < 95% to the initiation of dexamethasone administration was five days (sensitivity, 78%; specificity, 59%). adjusting for age, sex, body mass index, Charlson comorbidity index score, time of oxygen supplementation (two or more days), and SpO2 < 95% (five or more days), Cox regression analysis results showed that delayed dexamethasone administration since the initiation of oxygen supplementation was significantly associated with a higher risk of death or greater need for mechanical ventilation (hazard ratio: 5.51, 95% confidence interval, 1.79-16.91). CONCLUSIONS: In patients with COVID-19 and hypoxemia, early administration of dexamethasone, preferably less than two days from initiation of oxygen supplementation, may be required to improve clinical outcomes.

Does the timing of saliva collection affect the diagnosis of SARS-CoV-2 infection?

We evaluated the optimal timing of saliva sample collection to diagnose the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We obtained 150 saliva samples at four specific time points from 13 patients with confirmed SARS-CoV-2 infection. The time points were (1) early morning (immediately after waking), (2) immediately after breakfast before tooth brushing, (3) 2 h after breakfast, and (4) before lunch. On the 2nd hospital day, patients collected saliva at the four time points by themselves. We collected samples at two time points, (1) and (3), from the 3rd hospital day to day 9 following symptom onset. In 52 samples collected at the four time points, there was no significant difference. Meanwhile, there was no significant difference in the positive proportion or the viral load between the two time points in both analyses by the day from symptom onset and by all samples. In this study, there was no difference in the positive proportions in saliva collected at various time points within 9 days after symptom onset. The timing of saliva collection was not affected by the diagnosis of SARS-CoV-2 infection.

Comparative study of rapid antigen testing and two nucleic acid amplification tests for influenza virus detection.

INTRODUCTION: This study aimed to evaluate rapid antigen detection (RAD) and rapid nucleic acid amplification tests (NAATs) to detect influenza virus (IV). METHODS: The conventional RAD test (Quick Chaser Flu A, B: QC), using silver amplified immunochromatography (Quick Chaser Auto Flu A, B: QCA), as well as two NAATs (Xpert Xpress Flu/RSV: Xpert, cobas Influenza A/B & RSV: cobas) were evaluated using nasopharyngeal swabs from suspected cases of influenza. A reference method was performed using real-time reverse transcription polymerase chain reaction according to the manual of the Japanese National Institute of Infectious Disease (NIID). RESULTS: From a total of 177 samples, 51 were positive according to the NIID assay. The kappa (κ) coefficient in Xpert and cobas for influenza A virus (IAV)/influenza B virus (IBV) was 1.00, which was the highest among the four detection assays. However, the κ coefficients in QC and QCA for IAV/IBV were 0.71-0.77 and 0.87-0.89, respectively. The sensitivities of the RAD tests were 41.7% in QC and 50.0% in QCA at < 6 h after onset, and 100.0% in both QC and QCA at 24-48 h after onset. The cycle threshold (Ct) values were significantly lower in the group in which all detection assays were positive for IAV. CONCLUSIONS: Xpert and cobas have comparable analytical performances and are highly useful as influenza virus detection assays. QC and QCA could show false negatives frequently in the early stage of infection and when viral load is low.

Viral load may impact the diagnostic performance of nasal swabs in nucleic acid amplification test and quantitative antigen test for SARS-CoV-2 detection.

INTRODUCTION: Compared to nasopharyngeal swabs (NPS), there has been insufficient evaluation of the diagnostic performance of nasal swabs (NS) for the detection of severe acute respiratory coronavirus 2 (SARS-CoV-2) in the nucleic acid amplification test (NAAT) and quantitative SARS-CoV-2 antigen test (QAT). METHODS: We prospectively compared healthcare worker-collected and flocked NS within nine days after symptom onset to paired NPS to detect SARS-CoV-2 in NAAT and QAT on the fully automated Lumipulse system. The agreement between sample types was evaluated, and cycle threshold (Ct) values and antigen levels were used as surrogate viral load measures. RESULTS: Sixty sets of NPS and NS samples were collected from 40 patients with COVID-19. The overall agreements between NAAT and QAT samples were 76.7% and 65.0%, respectively. In NAAT, the Ct value of NS was significantly higher, 5.9, than that of NPS. Thirty-nine (95.1%) NS tested positive in 41 positive-paired NPS with Ct ≤ 30. The negative correlation was observed between antigen levels of NS in QAT and Ct values of NS in NAAT (r = -0.88). In QAT, the antigen level of NS was significantly lower than that of NPS. Thirty-six (90.0%) NS tested positive in 40 positive-paired NPS with antigen levels >100 pg/mL, which were collected significantly earlier than those with antigen levels ≤100 pg/mL. CONCLUSIONS: In NAAT and QAT, NS had limited performance in detecting SARS-CoV-2 compared to NPS. However, NS may be helpful for patients with COVID-19 with high viral loads or those in the early stages of the illness.

Survival case of rhinocerebral and pulmonary mucormycosis due to Cunninghamella bertholletiae during chemotherapy for acute myeloid leukemia: a case report.

A 42-year-old man diagnosed with acute myeloid leukemia complained of progressive swelling of the right side of his face with pain 11 days after the third cycle of consolidation therapy with high-dose arabinosylcytosine-cytarabine. Head and neck magnetic resonance imaging showed a mass lesion in his right maxillary sinus with parapharyngeal involvement, which included the right masseter muscle, intraorbital involvement, and an abscess in his brain. Chest computed tomography revealed peribronchial small nodules in his right upper lobe and a necrotic tumor in his right lower lobe. Molds identified as Cunninghamella bertholletiae were isolated from the necrotic ulcer. According to these results, chemotherapy for leukemia was discontinued. High-dose liposomal amphotericin (10 mg/kg/day) was initiated. Because renal dysfunction occurred, the dosage was decreased to 6 mg/kg and combined with 150 mg/day micafungin. Debridement of necrotic tissue in the right maxillary sinus and establishment of the fenestration between the sinus and oral cavity were performed. Subsequently, brain and lung lesions were surgically removed. Rhinocerebral mucormycosis was successfully treated without relapse over 3 years by a 112-day course of intravenous anti-fungal therapy and 223-day course of terbinafine and partial surgical removal, respectively, to maintain masticatory and ocular functions. To our knowledge, there has been no other report of a long-term survival case of rhinocerebral mucormycosis due to C. bertholletiae.

Evaluating a novel, highly sensitive, and quantitative reagent for detecting SARS-CoV-2 antigen.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is rapidly spreading all over the world. A new quantifying reagent for detecting SARS-CoV-2 antigen was developed for early and accurate detection. We evaluated the novel quantitative reagent for detecting SARS-CoV-2 antigen using an automated laboratory device. METHODS: One-hundred nasopharyngeal samples were collected from 47 SARS-CoV-2-infected patients, and 200 samples were collected from healthy donners. We measured the SARS-CoV-2 antigen and nucleic acid using Lumipulse Presto SARS-CoV-2 Ag and the 2019 Novel Coronavirus Detection Kit, respectively. RESULTS: The sensitivity and specificity of the SARS-CoV-2 antigen test were 75.7% (56/74) and 96.0% (192/200), respectively. The concordance rate in the positive group between the antigen and nucleic acid tests was 66% (66/100). In addition, the correlation coefficient between the concentration of SARS-CoV-2 antigen and the level of SARS-CoV-2 RNA was 0.74. There were 19 discrepant samples in which SARS-CoV-2 RNA was detected without SARS-CoV-2 antigen. There was significant difference between the discrepant and matched samples in terms of the time since symptom onset: the 19 discrepant samples were collected a median of 33 days after onset, while the 55 matched samples were collected a median of 19 days after onset. In addition, the 19 discrepant samples were collected from patients who were immune against SARS-CoV-2. CONCLUSIONS: This novel SARS-CoV-2 antigen detection assay is highly sensitive, rapid, accurate, easily diagnostic. It may be useful in both clinical diagnosis and in screening because it does not require special methods such as PCR.

Evaluation of two commercial molecular diagnostic assays: The Xpert Norovirus and the TRCReady NV.

INTRODUCTION: Norovirus is highly contagious, and a few particles of this virus are sufficient to make people sick. It is desirable to develop quick and accurate laboratory methods to detect norovirus. METHODS: We evaluated two commercial molecular diagnostic assays, the Xpert Norovirus and the TRCReady NV, using clinical fecal samples. A reference method was performed using in-house real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR). RESULTS: The results of the real-time RT-PCR analysis of 60 suspected cases of norovirus infection showed 5 cases of Genogroup I (GI) positives and 21 cases of GII positives, among which was 1 GI and GII coinfection. The viral titers of the norovirus-positive samples ranged from 1.54 × 101 to 3.14 × 108 copies/µL. Norovirus GII.17 (12 cases, 48%) was the most frequently detected genotype in this study, followed by GII.4 (6 cases, 24%), GII.13 (2 cases, 8%), GI.2 (2 cases, 8%), GI.3 (2 cases, 8%), GI.1 (1 case, 4%), and GII.2 (1 case, 4%). The kappa coefficient was 1.000 (95% CI: 1.000-1.000) for Xpert Norovirus and 0.966 (95% CI: 0.896-1.000) for TRCReady NV, indicating a strong agreement. CONCLUSIONS: Norovirus detection using Xpert Norovirus and TRCReady NV is highly useful for diagnosis and infection control because these assays are easy to operate, quick, and exhibit almost the same performance as that of real-time RT-PCR.

Invasive pneumococcal disease affected the fatal outcome in a COVID-19 patient.

A 68-year-old man experienced fever and cough and was referred to a hospital for day 4. He had a positive reverse transcription-polymerase chain reaction result for severe acute respiratory syndrome coronavirus-2. On day 12, his PaO2/FiO2 ratio worsened to 120 and he was transferred to Sapporo Medical University Hospital for treatment using extracorporeal membrane oxygenation. Venous blood cultures were positive for Streptococcus pneumoniae, which were serotype 3, mucoid-type, and penicillin susceptible. Coinfections with coronavirus disease-2019 and invasive pneumococcal disease are rare; however, they are associated with a higher case fatality than either of the conditions manifesting alone.

Determination of reactivation rate and risk factors for Hepatitis B virus reactivation in low-positive cases: A retrospective cohort study.

INTRODUCTION: In quantitative assays for hepatitis B virus (HBV) DNA, although the amplification reaction signal is detected for low-positive cases, quantification remains challenging. HBV reactivation has been reported in many studies, but only a few have focused on HBV low-positive cases. This study aimed to determine the reactivation rate and risk factors for HBV reactivation in low-positive cases. METHODS: In this retrospective cohort study, we analyzed 7498 patients who had their HBV DNA measured at Sapporo Medical University Hospital between April 2008 and November 2020. Patient selection criteria were defined as follows: hepatitis B surface antigen was negative; HBV DNA was detectable but not quantifiable at least once. HBV DNA was monitored according to the guidelines for HBV reactivation. RESULTS: In total, 49,086 HBV DNA quantitative tests were performed. HBV DNA levels of 2578 tests were detectable but not quantifiable. Eighty patients met the criteria in this study. The median observation period was 497 days, and the 2-year reactivation rate was 15%. Ten patients had low HBV DNA positivity at baseline. Malignant lymphoma was observed in 15 patients; chemotherapy was used to treat other solid tumors in 35 patients, and immunosuppressive therapy was used in 30 patients. Multivariate analysis revealed that HBV DNA detected below the quantification level at baseline was an independent risk factor for HBV reactivation (adjusted hazard ratio 5.82; P = 0.010). CONCLUSIONS: Patients with low HBV DNA positivity, especially at baseline, are at high risk for HBV reactivation and therefore require closer monitoring.

Early favipiravir treatment was associated with early defervescence in non-severe COVID-19 patients.

INTRODUCTION: The antiviral drug favipiravir has been shown to have in vitro antiviral activity against severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2). In this study, we investigated the clinical benefits and initiation of favipiravir treatment in patients with non-severe coronavirus-disease-2019 (COVID-19). METHODS: This study was a single-center retrospective cohort study. Receiver operating characteristic curves were drawn to calculate the area under the curve, and the optimal cut-off values for the time to initiate favipiravir treatment were calculated to predict defervescence within seven days. Univariate and multivariate Cox regression analyses were performed to identify potential influencing factors of defervescence. This was defined as a body temperature of less than 37 °C for at least 2 days. RESULTS: Data from 41 patients were used for the efficacy assessment. The days from the onset of fever to defervescence showed a positive correlation with the duration from the onset of fever to initiation of favipiravir treatment (r = 0.548, P < 0.001). The optimal cut-off value was the administration of favipiravir on day 4. Patients were assigned to two groups based on the optimal cut-off value from onset to initiation of favipiravir treatment: early treatment group (within 4-days) and late treatment group (more than 4-days). In the multivariate analysis, when adjusted for age, sex, and days from onset to initiation of favipiravir treatment, the significant factors were male sex and days of initiation of the favipiravir treatment. CONCLUSIONS: We recommend that if favipiravir is to be used for treatment, it should be initiated as early as possible.

Evaluation of false positives in the SARS-CoV-2 quantitative antigen test.

INTRODUCTION: Highly sensitive reagents for detecting SARS-CoV-2 antigens have been developed for accurate and rapid diagnosis till date. In this study, we aim to clarify the frequency of false-positive reactions and reveal their details in SARS-CoV-2 quantitative antigen test using an automated laboratory device. METHODS: Nasopharyngeal swab samples (n = 4992) and saliva samples (n = 5430) were collected. We measured their SARS-CoV-2 antigen using Lumipulse® Presto SARS-CoV-2 Ag and performed a nucleic acid amplification test (NAAT) using the Ampdirect™ 2019 Novel Coronavirus Detection Kit as needed. The results obtained from each detection test were compared accordingly. RESULTS: There were 304 nasopharyngeal samples and 114 saliva samples were positive in the Lumipulse® Presto SARS-CoV-2 Ag test. All positive nasopharyngeal samples in the antigen test were also positive for NAAT. In contrast, only three (2.6%) of all the positive saliva samples in the antigen test were negative for NAAT. One showed no linearity with a dilute solution in the dilution test. Additionally, the quantitative antigen levels of all the three samples did not decrease after reaction with the anti-SARS-CoV-2 antibody. CONCLUSIONS: The judgment difference between the quantitative antigen test and NAAT seemed to be caused by non-specific reactions in the antigen test. Although the high positive and negative predictive value of this quantitative antigen test could be confirmed, we should consider the possibility of false-positives caused by non-specific reactions and understand the characteristics of antigen testing. We recommend that repeating centrifugation before measurement, especially in saliva samples, should be performed appropriately.

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.

Epidemiology of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli in Japan: Characteristics of community-associated versus healthcare-associated ESBL E. coli.

Data on community-associated extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (CA-ESBLEC) infections in Japan are scarce. We compared the clinical and microbiological epidemiology of CA-ESBLEC infections with that of healthcare-associated-ESBLEC infections among 76 patients with ESBLEC infections. We identified a high prevalence (26%) of CA-ESBLEC infections in Japan; only a small proportion (15%) of patients with CA-ESBLEC infections had recent exposure to antibiotics.

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.