Christoph Hatz

Illness in Travelers Visiting Friends and Relatives: A Review of the GeoSentinel Surveillance Network

Travelers returning to their country of origin to visit friends and relatives (VFRs) have increased risk of travel-related health problems. We examined GeoSentinel data to compare travel characteristics and illnesses acquired by 3 groups of travelers to low-income countries: VFRs who had originally been immigrants (immigrant VFRs), VFRs who had not originally been immigrants (traveler VFRs), and tourist travelers. Immigrant VFRs were predominantly male, had a higher mean age, and disproportionately required treatment as inpatients. Only 16% of immigrant VFRs sought pretravel medical advice. Proportionately more immigrant VFRs visited sub-Saharan Africa and traveled for >30 days, whereas tourist travelers more often traveled to Asia. Systemic febrile illnesses (including malaria), nondiarrheal intestinal parasitic infections, respiratory syndromes, tuberculosis, and sexually transmitted diseases were more commonly diagnosed among immigrant VFRs, whereas acute diarrhea was comparatively less frequent. Immigrant VFRs and traveler VFRs had different demographic characteristics and types of travel-related illnesses. A greater proportion of immigrant VFRs presented with serious, potentially preventable travel-related illnesses than did tourist travelers.

Meta-analysis: accuracy of rapid tests for malaria in travelers returning from endemic areas

Context What is the accuracy of rapid tests for detecting malaria? Contribution This meta-analysis of 21 studies in nonimmune travelers with suspected malaria summarizes the accuracy of various rapid tests compared with expert microscopic examination or polymerase chain reaction tests. Histidine-rich protein-2 (HRP-2) tests had high sensitivities (range, 88% to 99%) and specificities (range, 95% to 100%) for detecting Plasmodium falciparum malaria. Positive 3-band HRP-2 test results detected malaria better than 2-band HRP-2 tests. Negative HRP-2based test results excluded malaria better than parasite lactate dehydrogenasebased tests. Cautions Few studies evaluated 3-band HRP-2 tests for malaria species other than P. falciparum. The Editors Imported malaria is an increasing problem and causes considerable morbidity in the United States and other industrialized countries. Few travelers use recommended chemoprophylaxis and insect protection measures (1), which means that malaria needs to be ruled out in febrile patients who have recently returned from an endemic country. Microscopic examination of thick blood smears is the diagnostic gold standard, but it is accurate only if performed by experienced microscopists. In a Canadian survey (1), community-based microscopic diagnosis provided incorrect species identification in 64% of cases. Polymerase chain reaction (PCR) is a highly sensitive alternative to microscopy, but the infrastructure and expertise required preclude its routine use in many health care settings (2). The time until results from microscopic examinations become available can substantially delay provision of appropriate therapy to patients with malaria who are treated in centers without expertise in tropical medicine (1). Such delays may be detrimental, particularly in infections caused by Plasmodium falciparum, which can be rapidly fatal (3, 4). Tests that allow bedside diagnosis of malaria have been introduced in recent years (5). By using immunochromatographic methods, these tests detect parasite antigens in lysed blood from a fingerprick blood sample and can be performed in approximately 15 minutes without special equipment (2). Two-band tests target histidine-rich protein-2 (HRP-2) and detect P. falciparum only, while the more recent 3-band tests also detect other malaria parasites (P. vivax, P. malariae, and P. ovale) by using HRP-2 and aldolase combined or parasite lactate dehydrogenase (LDH) as targets. Licensing authorities in Canada and some European countries, but not the United States, have approved rapid diagnostic tests. Currently, it is unclear whether rapid tests are an accurate alternative to established laboratory-based methods in industrialized countries and whether diagnostic accuracy differs among different types of tests. We performed a systematic review and meta-analysis of test accuracy studies to determine the ability of different rapid tests to rule out malaria in nonimmune individuals with suspected malaria. Methods Identification and Selection of Studies We searched MEDLINE, EMBASE, CAB Health, and CINAHL (1988 to September 2004), combining free-text terms (plasmodi* OR malaria* OR falcipar* OR vivax* OR ovale*) with a search strategy for diagnostic studies described elsewhere (6); hand-searched conference proceedings; checked references of obtained papers; and contacted experts and manufacturers. Details on the search strategy are available from the authors. We included diagnostic accuracy studies in nonimmune individuals with suspected malaria (that is, travelers returning from malaria-endemic areas), which compared rapid tests with microscopic examination or PCR as the reference standard and presented 2 2 contingency tables or data allowing their construction. We excluded studies in which more than 10% of individuals were immune and studies that determined the accuracy of self-administered rapid tests. We applied no language restrictions (7). If more than 1 test based on the same target antigen had been evaluated in the same patient population for diagnosis of the same parasite, we avoided duplication of data by applying predefined rules: We gave precedence to 3-band tests over 2-band tests and to the evaluation that was based on more patients if only 2-band tests had been evaluated. If sample sizes were identical, we selected the more recently developed test. Data Extraction and Quality Assessment Two observers independently extracted data on test characteristics, study setting, and patients and assessed the components of methodologic quality that may be associated with bias in test accuracy studies (8): prospective design; relevant clinical population (as opposed to diagnostic casecontrol study); enrollment of a series of consecutive patients with suspected malaria; all patients undergoing reference testing; performance and interpretation of the index test without knowledge of the reference test results; and performance and interpretation of the reference test without knowledge of the index test results. We used a piloted, standardized data extraction sheet and resolved disagreements by consensus. Definition of Reference Test and Main Outcome The reference standard consisted of a combination of results from microscopic examination and PCR, with patients considered positive if 1 of the 2 test results was positive. We gave PCR results precedence over microscopic examination if combined results were unavailable. In some studies, additional tests, such as quantitative buffy coat, were performed when microscopy results were unclear. We considered patients with pure gametocytemia to be positive. We defined a priori the likelihood ratio for a negative test result (negative likelihood ratio) for P. falciparum infection as the primary measure of accuracy. The negative likelihood ratio indicates how much less likely it is to find a negative result in individuals with malaria as compared with those without infection (9). Conversely, the positive likelihood ratio specifies how much more likely it is to find a positive test result in individuals with malaria as compared with individuals without malaria. In our main analysis, we considered individuals infected with a Plasmodium species other than P. falciparum to be negative. We excluded individuals infected with P. falciparum in analyses restricted to 3-band tests and calculated the negative likelihood ratio for infections with P. vivax and for infections with P. malariae or P. ovale. We also calculated positive likelihood ratios and plotted the sensitivity of tests against 1 specificity. Statistical Analysis We used a random-effects model to combine estimates of likelihood ratios (10). We planned analyses stratified by the antigen targeted by index tests (HRP-2 or parasite LDH) and by test generation (2-band tests, first-generation 3-band tests, or second-generation 3-band tests). We also analyzed subgroups of relevant studies to determine the association between the negative likelihood ratio and parasite density. For the diagnosis of P. falciparum, we examined funnel plots (11) of negative likelihood ratios by plotting likelihood ratios against total sample size (12, 13). In addition, we used meta-regression models (14) to quantify the association of the negative likelihood ratio with the type of target antigen, components of methodologic quality, and study size. We calculated the I2 statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance (15): I2 = 100% (Q df)/Q, where Q is Cochrans heterogeneity statistic and df is the degrees of freedom. Mild heterogeneity will account for less than 30% of the variation, and pronounced heterogeneity will account for substantially more than 50%. Four studies included direct comparisons of HRP-2 and parasite LDH tests (16-19). We separately compared negative likelihood ratios of HRP-2 and parasite LDH tests for each of these studies and subsequently pooled these comparisons by using a random-effects model. Finally, we determined pretest probabilities for individuals returning from different continents on the basis of prevalences found in test accuracy studies and malaria surveillance data from the Centers for Disease Control and Prevention (CDC) (20). We used the programs meta and metareg in Stata, version 8.2 (Stata Corp., College Station, Texas), for random-effects meta-analysis and meta-regression analysis. Role of the Funding Source The Swiss Federal Office of Public Health had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Results Literature Search We screened 5689 citations and identified 308 potentially eligible reports. We excluded 165 articles on the basis of their abstracts and obtained the full-text articles for the remaining 143 reports. Of these, we excluded 118 reports. The most common reasons for exclusion were immune study populations and ineligible study designs (Figure 1). We analyzed 22 published reports (2, 16-19, 21-37) and 3 unpublished reports (38); Hernandez E, unpublished; de Monbrison F, unpublished) on 21 studies and 5747 individuals with suspected malaria. Figure 1. Identification of 21 eligible test accuracy studies. Characteristics of Studies and Tests Table 1 presents the characteristics of included studies. Three studies were unpublished (38; Hernandez E, unpublished; de Monbrison F, unpublished), 3 were published in French (17, 22, 24), 1 was published in Italian (34), and the remaining studies were published in English. Four studies were from North America (21, 25, 36, 37), 1 study was from Australia (19), and the other studies were from Europe. Travel destinations were available for 3 Canadian studies, which reported that 58% to 64% of individuals had traveled in Africa, 18% to 21% in Asia, and 14% to 19% in Central and South America, and from 1 French study (18), which reported that 75% of patients had returned from Af

Efficacy and Safety of Mefloquine, Artesunate, Mefloquine-Artesunate, and Praziquantel against Schistosoma haematobium: Randomized, Exploratory Open-Label Trial

BACKGROUND Morbidity control of schistosomiasis relies on a single drug, praziquantel. The antimalarial drug mefloquine possesses interesting antischistosomal properties, yet no clinical studies have been performed. METHODS We conducted a randomized, exploratory open-label trial to assess the efficacy and safety of mefloquine (25 mg/kg), artesunate (3 doses of 4 mg/kg), mefloquine-artesunate (3 doses of 100 mg artesunate plus 250 mg mefloquine), and praziquantel (40 mg/kg) against Schistosoma haematobium. The effects on Schistosoma mansoni, malaria parasitemia, soil-transmitted helminths, and intestinal protozoa were also determined. RESULTS A total of 83 S. haematobium-infected schoolchildren were included in the study. Cure rates of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against S. haematobium at day 26 after treatment were 21%, 25%, 61%, and 88%, respectively. Both mefloquine-artesunate and praziquantel resulted in egg reduction rates >95%. Significantly lower egg reduction rates were seen in the artesunate (85%) and mefloquine groups (74%). In children coinfected with S. mansoni, praziquantel and mefloquine-artesunate, but not mefloquine and artesunate alone, resulted in high cure rates and egg reduction rates. Mefloquine, artesunate, and mefloquine-artesunate completely cured infections due to Plasmodium falciparum. No effects were found against soil-transmitted helminths and intestinal protozoa. Abdominal pain was the most frequent adverse event, with a higher incidence among children treated with mefloquine (89%), mefloquine-artesunate (83%), and artesunate (60%) than among children treated with praziquantel (46%). CONCLUSIONS The high efficacy of mefloquine-artesunate against S. haematobium warrants further investigation. Individuals coinfected with Plasmodium and Schistosoma who were treated with a mefloquine-artesunate combination against malaria might have a dual benefit: clearance of malaria parasitemia and reduction of schistosomiasis-related morbidity. CLINICAL TRIALS REGISTRATION Current Controlled Trials identifier: ISRCTN06498763.

Immunogenicity and adverse effects of inactivated virosome versus alum-adsorbed hepatitis A vaccine: a randomized controlled trial

Immunogenicity and adverse effects of a novel inactivated hepatitis A vaccine based on virosomes (IRIV-HAV) was compared with a standard vaccine adsorbed to aluminium (Al-HAV). Seronegative volunteers (n = 301) were randomly allocated to one injection of IRIV-HAV or to two injections of Al-HAV, followed by a booster injection at 12 months. Two hundred and ninety-eight (99%) completed the first month and 215 (71%) could be evaluated at 1 year. Geometric mean antibody concentrations at days 0, 14 and at 12 months were similar in the two vaccine groups. Lower antibody concentrations were recorded with IRIV-HAV at day 28 (P < 0.0001) and at 13 months (P = 0.02). Seroconversion to protective antibody levels, however, was similar (98% at day 28, 94% at 12 months, 100% at 13 months). Local adverse effects were reported in 17% with IRIV-HAV but in 66% with Al-HAV (P < 0.0001) after the initial vaccination and in 32% and 42% following the booster vaccination (P = 0.05). In conclusion, IRIV-HAV may provide similar protection but cause less local adverse effects.

Efficacy and safety of CGP 56697 (artemether and benflumetol) compared with chloroquine to treat acute falciparum malaria in Tanzanian children aged 1–5 years

A randomized, open trial involving 260 Tanzanian children, aged 1–5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven‐day parasitological cure rates were 94% (95% CI 88–97.5) for CGP 56697 and 35.4% (95% CI 25.9–45.8) for chloroquine. Using the same definition, the 14‐day parasitological cure rates were 86.4% (95% CI 78.5–92.2) for CGP 56697 and 10.3% (95% CI 5.1–18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first‐line drug in an area of high malaria transmission and very high levels of chloroquine resistance.

Immunogenicity and Safety of Yellow Fever Vaccination for 102 HIV-Infected Patients

BACKGROUND Yellow fever vaccine (17DV) has been investigated incompletely in human immunodeficiency virus (HIV)-infected patients, and adequate immunogenicity and safety are of concern in this population. METHODS In the Swiss HIV Cohort Study, we identified 102 patients who received 17DV while they were HIV infected. We analyzed neutralization titers (NTs) after 17DV administration using the plaque reduction neutralization test. NTs of 1:>or=10 were defined as reactive, and those of 1:<10 were defined as nonreactive, which was considered to be nonprotective. The results were compared with data for HIV-uninfected individuals. Serious adverse events were defined as hospitalization or death within 6 weeks after receipt of 17DV. RESULTS At the time of 17DV administration, the median CD4 cell count was 537 cells/mm(3) (range, 11-1730 cells/mm(3)), and the HIV RNA level was undetectable in 41 of 102 HIV-infected patients. During the first year after vaccination, fewer HIV-infected patients (65 [83%] of 78; P = .01) than HIV-uninfected patients revealed reactive NTs, and their NTs were significantly lower (P < .001) than in HIV-uninfected individuals. Eleven patients with initially reactive NTs lost these reactive NTs <or= 5 years after vaccination. Higher NTs during the first year after vaccination were associated with undetectable HIV RNA levels, increasing CD4 cell count, and female sex. We found no serious adverse events after 17DV administration among HIV-infected patients. CONCLUSION Compared with HIV-uninfected individuals, HIV-infected patients respond to 17DV with lower reactive NTs, more often demonstrate nonprotective NTs, and may experience a more rapid decline in NTs during follow-up. Vaccination with 17DV appears to be safe in HIV-infected individuals who have high CD4 cell counts, although rate of serious adverse events of up to 3% cannot be excluded.

Sushi Delights and Parasites: The Risk of Fishborne and Foodborne Parasitic Zoonoses in Asia

Because of the worldwide popularization of Japanese cuisine, the traditional Japanese fish dishes sushi and sashimi that are served in Japanese restaurants and sushi bars have been suspected of causing fishborne parasitic zoonoses, especially anisakiasis. In addition, an array of freshwater and brackish-water fish and wild animal meats, which are important sources of infection with zoonotic parasites, are served as sushi and sashimi in rural areas of Japan. Such fishborne and foodborne parasitic zoonoses are also endemic in many Asian countries that have related traditional cooking styles. Despite the recent increase in the number of travelers to areas where these zoonoses are endemic, travelers and even infectious disease specialists are unaware of the risk of infection associated with eating exotic ethnic dishes. The aim of this review is to provide practical background information regarding representative fishborne and foodborne parasitic zoonoses endemic in Asian countries.

A review of the literature on the use of ultrasonography in schistosomiasis with special reference to its use in field studies: 1. Schistosoma haematobium

This paper gives a brief description of the pathology resulting from Schistosoma japonicum infection, and ways in which it can be investigated. It then reviews reports of the application of ultrasound in investigating lesions in schistosomiasis japonica, including papers published in Chinese and Japanese. Ultrasonography has been widely used for the diagnosis of schistosomiasis and for the investigation of pathological changes resulting from the infection. Marked and characteristic changes are observed in the structure of the liver parenchyma in advanced disease. Chronic pathology may be seen as a result of past infection. Animal studies have been used to compare ultrasound images with actual pathological changes. Ultrasonography can also be used to detect early changes, for example periportal fibrosis, which can indicate the development of portal hypertension. The problem of differential diagnosis is discussed.

DengueTools: innovative tools and strategies for the surveillance and control of dengue

Dengue fever is a mosquito-borne viral disease estimated to cause about 230 million infections worldwide every year, of which 25,000 are fatal. Global incidence has risen rapidly in recent decades with some 3.6 billion people, over half of the worlds population, now at risk, mainly in urban centres of the tropics and subtropics. Demographic and societal changes, in particular urbanization, globalization, and increased international travel, are major contributors to the rise in incidence and geographic expansion of dengue infections. Major research gaps continue to hamper the control of dengue. The European Commission launched a call under the 7th Framework Programme with the title of ‘Comprehensive control of Dengue fever under changing climatic conditions’. Fourteen partners from several countries in Europe, Asia, and South America formed a consortium named ‘DengueTools’ to respond to the call to achieve better diagnosis, surveillance, prevention, and predictive models and improve our understanding of the spread of dengue to previously uninfected regions (including Europe) in the context of globalization and climate change. The consortium comprises 12 work packages to address a set of research questions in three areas: Research area 1 Develop a comprehensive early warning and surveillance system that has predictive capability for epidemic dengue and benefits from novel tools for laboratory diagnosis and vector monitoring. Research area 2 Develop novel strategies to prevent dengue in children. Research area 3 Understand and predict the risk of global spread of dengue, in particular the risk of introduction and establishment in Europe, within the context of parameters of vectorial capacity, global mobility, and climate change. In this paper, we report on the rationale and specific study objectives of ‘DengueTools’. DengueTools is funded under the Health theme of the Seventh Framework Programme of the European Community, Grant Agreement Number: 282589 Dengue Tools.

Enteric (Typhoid) Fever in Travelers

The incidence of enteric (typhoid) fever in travelers is estimated to be approximately 3-30 cases per 100,000 travelers to developing countries. Recently, it is become clear that travelers who are visiting friends and relatives, especially travelers to the Indian subcontinent, seem to be the most vulnerable to enteric fever and require special attention for prevention. Recent concerns are the increasing incidence of paratyphoid fever in Asia, which is not covered by available typhoid vaccines, and the emergence of infections caused by antibiotic-resistant strains (including strains resistant to fluoroquinolones). Typhoid vaccination is recommended for most travelers to moderate- to high-risk countries. Because of the nonspecific clinical presentation of enteric fever, a high index of suspicion is important in febrile travelers who have traveled to areas of endemicity.