Response to Hepatitis A Vaccination in Immunocompromised Travelers.

BACKGROUND: Hepatitis A vaccines are highly immunogenic in healthy patients, but there is uncertainty about their immunogenicity in immunocompromised patients. METHODS: Our study included immunocompromised patients who received 1 or 2 hepatitis A vaccinations between January 2011 and June 2013. We assessed factors that influenced the serologic response to vaccination. We performed a literature review of previous studies on hepatitis A vaccination in immunocompromised patients. RESULTS: Of 85 immunocompromised patients, 65 used immunosuppressive drugs, 13 had received stem cell transplants, and 7 were infected with human immunodeficiency virus. After vaccination, 65 of 85 (76.5%) developed antibodies. Tumor necrosis factor α blocker use was associated with better serologic responses than other immunosuppressive drugs. Female patients were more compliant than male patients with postvaccination antibody titer measurements. In 11 relevant studies, antibody responses after the first and second vaccination averaged 37% and 82%, respectively. Factors that negatively influenced serologic response rates were high doses of immunosuppressive drugs, fewer hepatitis A vaccinations, and a short interval between vaccination and antibody measurement. CONCLUSIONS: Immunocompromised patients showed moderate to good serologic responses to hepatitis A vaccination, but may need more time to develop immunity. Tumor necrosis factor α blocker use was associated with better antibody responses than other drugs. Specifically, male patients should be motivated to return for antibody titer measurements.

Efficacy and safety of artemisinin combination therapy (ACT) for non-falciparum malaria: a systematic review.

BACKGROUND: Artemisinin combination therapy (ACT) is recommended as first-line treatment for uncomplicated Plasmodium falciparum malaria, whereas chloroquine is still commonly used for the treatment of non-falciparum species (Plasmodium vivax, Plasmodium ovale and Plasmodium malariae). A more simplified, more uniform treatment approach across all malaria species is worthwhile to be considered both in endemic areas and for malaria as an imported condition alike. METHODS: A PROSPERO-registered systematic review to determine the efficacy and safety of ACT for the treatment of non-falciparum malaria was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to November 2014. RESULTS: The literature search identified 986 reports; 40 publications were found eligible for inclusion, all of them on non-falciparum malaria in endemic areas. Most evidence was available for P. vivax (n = 35). Five clinical trials in total were identified evaluating ACT for P. ovale, P. malariae and Plasmodium knowlesi. Most ACT presentations have high efficacy against P. vivax parasites; artemisinin-based combinations have shorter parasite and fever clearance times compared to chloroquine. ACT is as effective as chloroquine in preventing recurrent parasitaemia before day 28. Artemisinin-based combinations with long half-lives show significantly fewer recurrent parasitaemia up to day 63. The limited evidence available supports both the use of chloroquine and an ACT for P. ovale and P. malariae. ACT seems to be preferable for optimal treatment of P. knowlesi. CONCLUSION: ACT is at least equivalent to chloroquine in effectively treating non-falciparum malaria. These findings may facilitate development of simplified protocols for treating all forms of malaria with ACT, including returning travellers. Obtaining comprehensive efficacy and safety data on ACT use for non-falciparum species particularly for P. ovale, P. malariae and P. knowlesi should be a research priority. TRIAL REGISTRATION: CRD42014009103.

Serum lipids and lipoproteins in malaria--a systematic review and meta-analysis.

BACKGROUND: Serum lipid profile changes have been observed during malaria infection. The underlying biological mechanisms remain unclear. The aim of this paper is to provide an overview on those serum lipid profile changes, and to discuss possible underlying biological mechanisms and the role of lipids in malaria pathogenesis. METHODS: A systematic review and meta-analysis to determine lipid profile changes during malaria was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to 11 July, 2013, that measured serum lipid parameters in malaria patients. Also, major trial registries were searched. Mean differences in lipid profile parameters were combined in fixed and random effects meta-analysis, with a separate analysis for different groups of controls (healthy, other febrile illnesses or very low parasitaemia). These parameters were also compared between severe malaria and uncomplicated malaria. Funnel plots were used to test for publication bias. RESULTS: Of 2,518 studies reviewed, 42 met the criteria for inclusion in the qualitative analysis, and of these, 15 reported the necessary data for inclusion in the meta-analysis for cholesterol; nine for high-density lipoprotein (HDL), eight for low-density lipoprotein (LDL), and nine for triglycerides, respectively. Total cholesterol, HDL and LDL concentrations were lower in malaria and other febrile diseases compared to healthy controls. The decline was more pronounced and statistically significant during malaria compared to other febrile diseases. These results were consistent across included studies. Triglycerides were raised compared to healthy controls, but not statistically significant when compared to symptomatic controls. CONCLUSIONS: This meta-analysis suggests that the observed lipid profile changes are characteristic for malaria. Although a definite link with the pathogenesis of malaria cannot yet be demonstrated, plausible hypotheses of biological mechanisms involving host lipid alterations and the pathogenesis of malaria exist. An increased research effort to elucidate the precise pathways is warranted, since this could lead to better understanding of malaria pathophysiology and consequently to novel treatment approaches.

Towards improved uptake of malaria chemoprophylaxis among West African travellers: identification of behavioural determinants.

BACKGROUND: Malaria is a potentially lethal illness for which preventive measures are not optimally used among all travellers. Travellers visiting friends and relatives in their country of origin (VFRs) are known to use chemoprophylaxis less consistently compared to tourist travellers. In this study, factors explaining the low use of chemoprophylaxis were pursued to contribute to improving uptake of preventive measures among VFRs. METHODS: Following in-depth interviews with Ghanaians living in Amsterdam, a questionnaire was developed to assess which behavioural determinants were related to taking preventive measures. The questionnaire was administered at gates of departing flights from Schiphol International Airport, Amsterdam (the Netherlands) to Kotoka International Airport, Accra (Ghana). RESULTS: In total, 154 questionnaires were eligible for analysis. Chemoprophylaxis had been started by 83 (53.9%) and bought by 93 (60.4%) travellers. Pre-travel advice had been obtained by 104 (67.5%) travellers. Those who attended the pre-travel clinic and those who incorrectly thought they had been vaccinated against malaria were more likely to use preventive measures. Young-, business- and long-term travellers, those who had experienced malaria, and those who thought curing malaria was easier than taking preventive tablets were less likely to use preventive measures. CONCLUSION: Almost half of the VFRs travelling to West Africa had not started chemoprophylaxis; therefore, there is room for improvement. Risk reduction strategies could aim at improving attendance to travel clinics and focus on young-, business and long term travellers and VFRs who have experienced malaria during consultation. Risk reduction strategies should focus on improving self-efficacy and conceptions of response efficacy, including social environment to aim at creating the positive social context needed.

Dengue in travellers: applicability of the 1975-1997 and the 2009 WHO classification system of dengue fever.

OBJECTIVES: The aim of this study was to assess the applicability and benefits of the new WHO dengue fever guidelines in clinical practice, for returning travellers. METHODS: We compared differences in specificity and sensitivity between the old and the new guidelines for diagnosing dengue and assessed the usefulness in predicting the clinical course of the disease. Also, we investigated whether hypertension, diabetes or allergies, ethnicity or high age influenced the course of disease. RESULTS: In our setting, the old classification, compared with the new, had a marginally higher sensitivity for diagnosing dengue. The new classification had a slightly higher specificity and was less rigid. Patients with dengue who had warning signs as postulated in the new classification were admitted more often than those who had no warning signs (RR, 8.09 [1.80-35.48]). We did not find ethnicity, age, hypertension, diabetes mellitus or allergies to be predictive of the clinical course. CONCLUSIONS: In our cohort of returned travellers, the new classification system did not differ in sensitivity and specificity from the old system to a clinically relevant degree. The guidelines did not improve identification of severe disease.

Serum Lipids and Lipoproteins During Uncomplicated Malaria: A Cohort Study in Lambaréné, Gabon.

AbstractThe serum lipid profile in malaria patients has been found to differ from that of healthy controls. We investigated serum lipid profile changes in malaria patients over time compared with patients with other febrile diseases. In total, 217 patients were included in the study (111 malaria patients and 106 symptomatic controls, defined as malaria-negative febrile patients). Serum lipid levels (mmol/L) were significantly lower in malaria patients compared with those with other febrile diseases (total cholesterol [TC] = 3.26 [standard deviation = 0.94] versus 3.97 [1.22; P < 0.001]; high-density lipoprotein cholesterol [HDL-C] = 0.43 [0.47] versus 1.05 [0.67; P < 0.001], low-density lipoprotein cholesterol [LDL-C] = 2.05 [0.76] versus 2.42 [0.90; P < 0.001]. Triglycerides (TGs) levels were higher in malaria patients (1.81 [1.02] versus 1.11 [0.82; P < 0.001]). No significant differences were found for apolipoprotein A1, apolipoprotein B, and lipoprotein(a). Cholesterol levels increased toward reference values on day 28 (TC = 3.26-3.98, P < 0.001; HDL-C = 0.43-0.96, P < 0.001; LDL-C = 2.05-2.60, P < 0.001). TG levels decreased from 1.81 on admission to 1.76 (day 3) and 0.88 (day 28; P = 0.130). Lipid profile changes were not correlated with parasitemia or Plasmodium falciparum histidine-rich protein 2 levels. This study confirms characteristic temporary lipid profile changes in malaria. Lipid profile changes demonstrated a good accuracy to discriminate between malaria and other febrile diseases (area under the curve = 0.80 (95% confidence interval = 0.742-0.863, P < 0.001). Several plausible hypotheses exist regarding the pathophysiology of lipid profile changes in malaria. Further studies to elucidate the precise pathways may lead to improved understanding of the underlying pathophysiology.

A Single 17D Yellow Fever Vaccination Provides Lifelong Immunity; Characterization of Yellow-Fever-Specific Neutralizing Antibody and T-Cell Responses after Vaccination.

INTRODUCTION: Prompted by recent amendments of Yellow Fever (YF) vaccination guidelines from boost to single vaccination strategy and the paucity of clinical data to support this adjustment, we used the profile of the YF-specific CD8+ T-cell subset profiles after primary vaccination and neutralizing antibodies as a proxy for potentially longer lasting immunity. METHODS AND FINDINGS: PBMCs and serum were collected in six individuals on days 0, 3, 5, 12, 28 and 180, and in 99 individuals >10 years after YF-vaccination. Phenotypic characteristics of YF- tetramer+ CD8+ T-cells were determined using class I tetramers. Antibody responses were measured using a standardized plaque reduction neutralization test (PRNT). Also, characteristics of YF-tetramer positive CD8+ T-cells were compared between individuals who had received a primary- and a booster vaccination. YF-tetramer+ CD8+ T-cells were detectable on day 12 (median tetramer+ cells as percentage of CD8+ T-cells 0.2%, range 0.07-3.1%). On day 180, these cells were still present (median 0.06%, range 0.02-0.78%). The phenotype of YF-tetramer positive CD8+ T-cells shifted from acute phase effector cells on day 12, to late differentiated or effector memory phenotype (CD45RA-/+CD27-) on day 28. Two subsets of YF-tetramer positive T-cells (CD45RA+CD27- and CD45RA+CD27+) persisted until day 180. Within all phenotypic subsets, the T-bet: Eomes ratio tended to be high on day 28 after vaccination and shifted towards predominant Eomes expression on day 180 (median 6.0 (day 28) vs. 2.2 (day 180) p = 0.0625), suggestive of imprinting compatible with long-lived memory properties. YF-tetramer positive CD8+ T-cells were detectable up to 18 years post vaccination, YF-specific antibodies were detectable up to 40 years after single vaccination. Booster vaccination did not increase titers of YF-specific antibodies (mean 12.5 vs. 13.1, p = 0.583), nor induce frequencies or alter phenotypes of YF-tetramer+ CD8+ T-cells. CONCLUSION: The presence of a functionally competent YF-specific memory T-cell pool 18 years and sufficient titers of neutralizing antibodies 35-40 years after first vaccination suggest that single vaccination may be sufficient to provide long-term immunity.

Comparison of the PRNT and an immune fluorescence assay in yellow fever vaccinees receiving immunosuppressive medication.

BACKGROUND: The 17D-yellow fever (YF) vaccination is considered contraindicated in immune-compromised patients; however, accidental vaccination occurs. In this population, measuring the immune response is useful in clinical practice. METHODS: In this study we compare two antibody tests (the Immune Fluorescence Assay and the Plaque Reduction Neutralization Test) in a group of Dutch immune-compromised travellers with a median of 33 days (IQR [28-49]) after primary YF vaccination. RESULTS: We collected samples of 15 immune-compromised vaccinees vaccinated with the 17D yellow fever vaccine between 2004 and 2012. All samples measured in the plaque reduction neutralization test yielded positive results (>80% virus neutralization with a 1:10 serum dilution). Immune Fluorescence Assay sensitivity was 28% (95% CI [0.12-0.49]). No adverse events were reported. CONCLUSIONS: All immune-compromised patients mounted an adequate response with protective levels of virus neutralizing antibodies to the 17-D YF vaccine. No adverse effects were reported. Compared to the plaque reduction neutralization test, the sensitivity of the Immune Fluorescence Assay test was low. Further research is needed to ascertain that 17D vaccination in immune-compromised patients is safe.

Risk factors and pre-travel healthcare of international travellers attending a Dutch travel clinic: a cross-sectional analysis.

BACKGROUND: The number of international travellers is currently estimated to exceed one billion annually. To address travel related health risks and facilitate risk reduction strategies, detailed knowledge of travellers' characteristics is important. METHOD: In this cross-sectional study, data of a 20% sample of travellers visiting the Academic Medical Center (AMC) travel clinic Amsterdam from July 2011 to July 2012 was collected. Itineraries and protection versus exposure rates of preventable infectious diseases were mapped and reported according to STROBE guidelines. RESULTS: 1749 travellers were included. South-Eastern Asia, South-America and West-Africa were most frequently visited. 26.2% of the population had pre-existing medical conditions (often cardiovascular). Young and VFR travellers had a longer median travel time (28 and 30 days) compared to the overall population (21 days). Young adult travellers were relatively often vaccinated against hepatitis B (43.9% vs. 20.5%, p < .001) and rabies (16.6% vs. 4.3%, p < .001). VFRs were less often vaccinated against hepatitis B (11.6% vs. 30.6%, p < .001) and rabies (1.3% vs. 9.0%, p .012) compared to non-VFR travellers. CONCLUSIONS: Pre-travel guidelines were well adhered to. Young adult travellers had high-risk itineraries but were adequately protected. Improvement of hepatitis B and rabies protection would be desirable, specifically for VFRs.

Health risks of travelers with medical conditions--a retrospective analysis.

BACKGROUND: Traveling the world may result in infection with tropical or other travel-associated diseases. This applies increasingly also to people with immune-compromising and other medical conditions, as well as to elderly individuals. To reduce exposure and susceptibility to health risks, there is a need for appropriate pre-travel advice for these particular groups of travelers. METHODS: In this observational study, we analyzed the overall risk of health problems among travelers with underlying medical conditions who attended the University of Amsterdam's Academic Medical Center's (AMC) travel clinic from January to October 2010. Telephone questionnaires were administered to 345 travelers with underlying conditions and 100 healthy travelers. RESULTS: The most common underlying medical conditions studied included: (1) diabetes mellitus; (2) impaired immunity due to use of immune-suppressing medication; (3) reduced gastric barrier; and (4) HIV infection. The overall incidence of travel-related diseases (TRDs) was higher among those patients with underlying medical conditions compared to healthy travelers [incidence rate ratio (IRR) 2.26, 95% CI (1.29-3.98)]. Of all diseases reported, gastrointestinal disease, fever, and respiratory problems were reported most frequently. Travel to Central America, South Central Asia, Northeast Asia, and North Africa was associated with increased risk of contracting TRD. Hepatitis B protection was absent or unknown in 75% of these travelers. CONCLUSIONS: Travelers with medical conditions had a higher risk of obtaining TRD, predominantly gastrointestinal in nature.

Molecular diagnostics of Rickettsia africae infection in travelers returning from South Africa to The Netherlands.

BACKGROUND: African tick-bite fever (ATBF) is frequently diagnosed in The Netherlands in travelers returning from South Africa. It is caused by Rickettsia africae and diagnosis is based on travel history and clinical presentation and usually confirmed by detecting serum antibodies against rickettsiae of the spotted fever group. However, these typically occur late in the course of the disease, and a mild clinical course or early antibiotic treatment can diminish antibody production. METHODS AND RESULTS: Four travelers presented with (sub)febrile temperatures and eschar(s), several days after returning from South Africa. R. africae DNA was amplified and sequenced from skin biopsies of the eschars of all patients. Initial immunofluorescence assays yielded no immunoglobulin M (IgM)/IgG antibodies directed against spotted fever group rickettsiae; however, serology in the convalescent phase-several weeks after the patients had fully recovered-was positive. CONCLUSIONS: ATBF should be considered in travelers returning from South Africa to The Netherlands with febrile illness and (multiple) skin lesions. The diagnosis can be confirmed by (paired) serology; however, polymerase chain reaction and sequencing on skin biopsies could be a (faster and more accurate) confirmatory test. Advantages of molecular methods over serology are species identification and high sensitivity early in the course of the disease.