Rescue of Severely Immunocompromised HIV‐Positive Persons. Part 2
The main finding is that although ritonavir‐boosted lopinavir results in a slightly slower decline in plasma HIV RNA level and a slightly greater increase in CD4 cell count, compared with efavirenz, the 2 regimens result in a very similar risk of AIDS and death. On the other hand, the infrequently tested combination of zidovudine and didanosine showed inferior HIV RNA and CD4 cell count responses, compared with the combination of stavudine and lamivudine. The study had to be interrupted prematurely and, hence, was not fully powered, but there also was a trend toward a higher risk of AIDS and death with zidovudine and didanosine.
Consistent with the findings of previous studies, this trial observed a more robust recovery of CD4 cell counts for patients receiving a ritonavir‐boosted PI versus patients receiving NNRTI as the third drug. Of note, this difference was not explained by differences in viral response and as such cannot necessarily be interpreted to imply a better clinical outcome. Consistent with this, the risk of clinical end points was similar in the current trial. Several studies have now been published that compare NNRTI‐ versus PI‐based primary ART in advanced HIV infection; none of them have been powered to assess clinical outcome. We suggest that the research groups that have performed these comparisons might combine their data sets and performed a meta‐analysis to further clarify that the better CD4 cell count improvement associated with the ritonavir‐boosted PI is indeed not associated with better clinical outcome.
New World Health Organization (WHO) recommendations for the treatment of HIV infection suggest using zidovudine or tenofovir with lamivudine in first‐line regimens. The inferior outcomes for zidovudine plus didanosine in this trial may well, of course, be partly related to the use of didanosine, so it is difficult to draw inferences for the decision by the WHO guidelines panel to emphasize zidovudine above stavudine. WHO recommendations on the use of stavudine have been revised recently because of a growing realization that although stavudine is inexpensive to produce and has a comparable virological efficacy relative to other drugs in its class, it is toxic to subcutaneous adipocytes and peripheral nerve fibers; hence, extended use leads to disfiguring lipoatrophy and peripheral neuropathy. Unfortunately, the report from the Phidisa project does not contain any particularly detailed information relating to the drug‐induced adverse effect profile. However, the reported findings are consistent with this revision of the WHO recommendations, given that 13% of the patients had to discontinue stavudine because of treatment‐limiting adverse effects over the 2‐year study period, and lipoatrophy and peripheral neuropathy predominated as the cause thereof. However, stavudine‐containing combinations remain very widely used, and the authors of this report make the important point that although recent data and guidelines recommend limiting stavudine use because of toxicity, stavudine was well tolerated in the trial by many participants for up to 36 months. The authors suggest that a reasonable approach would be to still consider the use of stavudine when no other options exist and closely monitor its use.
It is interesting to compare the death rates observed in the current trial with those observed in the DART trial of strategies for monitoring people receiving ART in 2 countries in sub‐Saharan Africa (Uganda and Zimbabwe). Eligibility criteria were similar in the 2 trials, although DART patients had a slightly lower median CD4 cell count (86 vs 106 cells/μL) and the proportion of people with clinical symptoms (tuberculosis or WHO stage 4 event) was slightly higher in DART. DART compared laboratory monitoring for toxicity and CD4 cell counts with clinical monitoring alone. In the current trial, laboratory monitoring for toxicity was used and, unlike in DART, viral load measures were used to determine treatment switches to second‐line therapy. DART used a regimen of zidovudine, lamivudine, and tenofovir. The overall death rate in DART was 2.6 per 100 person‐years, compared with 5.5 per 100 person‐years in the South African trial. Losses to follow‐up was particularly low in DART, so this is unlikely to explain the difference. Cross‐trial comparisons have to be interpreted with extreme caution (and there are differences in the regimens used and other differences between the trials), but the use of virological monitoring in the South African trial, which is standard in developed countries but was not used in DART, does not appear to have been markedly beneficial in reducing the death rate among people receiving ART. This could be partially related to the relatively high viral load threshold (>20,000 copies/mL) used for changing regimens in the trial.
The Phidisa investigators deserve applause for their conduct of a large‐scale controlled trial in what appears to have been a challenging research environment. There are shortcomings (eg, lower‐than‐projected enrollment and less emphasis on pharmacovigilence than on efficacy assessment), but the data are highly informative. Let us hope that this will be the first in a series of research projects that further improve the body of evidence regarding how to best manage HIV infection in a resource‐constrained environment.
Rescue of Severely Immunocompromised HIV‐Positive Persons
In asymptomatic human immunodeficiency virus (HIV)–infected individuals, the range of CD4 cell counts at which treatment initiation is considered currently ranges from 350 to >500 cells/μL; some will argue on the conservative side (ie, 350 cells/μL), others on the more aggressive side (500 cells/μL). Importantly, although the benefits of initiation (vs deferral) of antiretroviral therapy (ART) has been documented in randomized controlled trials conducted in situations where patients enter care with a CD4 cell count <350 cells/μL, no such evidence exists to inform the contemporary debate. A major public health issue throughout the world is that many patients enter care for their HIV infection too late. Recently, a European consensus was established to define a late presenter for care as an asymptomatic patient entering care with a CD4 cell count <350 cells/μL or a person who presents at any CD4 cell count with an AIDS‐defining condition. Applying this definition, reports from both North America and Europe consistently suggest that at least 50% of patients enter care too late. Therefore, even in resource‐rich areas major difficulties exist in ensuring broad access to state‐of‐the‐art care to those in need of it. Unfortunately, resource‐limited sections of world also have this public health problem, although the reasons for it are partly different. Estimates from the Joint United Nations Programme on HIV/AIDS suggest that in sub‐Saharan Africa only 40%–50% of persons in need of ART (with “need” determined on the basis of a CD4 cell count <200 cells/μL) actually receive this lifesaving treatment. Moreover, given that the disease burden in resource‐limited settings is usually worse than that in resource‐rich environments (eg, the prevalence of tuberculosis and malaria is higher) and that the number of persons affected is much greater, the impact in terms of lives lost is enormous and points to the fact that research aimed at determining the best approaches to reducing the effect of late diagnosis is warranted in all parts of the world. Late presentation raises a key research question, namely, how to best use ART to reduce the risk of deteriorating health to the maximum extent possible. When ART is initiated in patients early during the course of chronic HIV infection, the strategy of providing ART is entirely to prevent disease; the clinical consequences of providing a suboptimal regimen will appear several years thereafter, if at all. Conversely, in late presenters HIV has already caused harm (be it clinically detectable or latent at the time of entering care); hence, the clinical impact of suboptimal choices is more readily observed.
In resource‐limited settings, financial constraints do not allow physicians and health system officials the same multitude of drugs as the >20 that physicians elsewhere have to choose from. Additionally, the limited—or lack of—research infrastructure makes endeavors difficult to implement.
In this issue of the Journal, a unique collaboration is described between the South African Armed Forces and the US National Institutes of Health—the Phidisa project. Established around the time when South Africa decided to implement a national treatment program in 2003–2004, this collaboration has allowed the creation of an infrastructure that can provide proper HIV care to the armed forces and their relatives and that allows for the conduct of research. The present article describes the results of a randomized controlled trial that enrolled 1771 patients with advanced HIV disease (ie, the subgroup of late presenters presenting for care with a CD4 cell count <200 cells/μL) and that used 2‐by‐2 factorial design to compare 2 choices of nucleoside reverse‐transcriptase inhibitor pairs and 2 third drugs—a nonnucleoside reserve‐transcriptase inhibitor (NNRTI) and a protease inhibitor (PI). The trial is particularly significant because it is one of the largest drug‐drug comparison trials performed during the highly active ART era and uses clinical end points.
Hepatitis E Seroprevalence and Seroconversion. Part 6
Second, the populations under investigation in these studies, although all from the United States, may have distinct differences. The military population may have a reduced risk for HEV exposure compared with that of the general US population. Factors such as living on a military installation, having standardized food suppliers on that installation, and emphasis on personal hygiene and sanitation in the military may minimize a service member’s exposure to HEV. In addition, 65% of our subjects were <30 years of age, with 42% of subjects being <25 years of age. Since HEV seropositivity has been shown to be positively associated with age and to have a cohort effect with higher rates in the past, differences in ages and collection dates of samples between each of the studies may be an additional explanation for differences in seroprevalence. In addition to the study limitations mentioned above, we did not have access to morbidity data collected in a standardized manner during the deployment that may have identified deployed military members with symptoms consistent with HEV infection. A study targeted to service members with known illnesses with a clinical presentation for hepatitis may have yielded higher seroconversion rates. In addition, data were not available on other HEV risk factors, such as contact with animals, diet, and travel.
Our study has several strengths. First, we had nearly the entire population of US military service members deployed to Afghanistan from which to sample, which made our study population representative of the entire cohort. Second, because of Department of Defense requirements to obtain predeployment and postdeployment serum samples, we had access to paired samples. Finally, even though the WRAIR assay differed from other assays, the incidence of anti‐HEV among US forces deployed to Afghanistan should not have been affected because any of the published assays would have detected seroconverters.
This study is the first (to our knowledge) to assess the incidence of HEV exposure among US military service members deployed to Afghanistan. Our findings of low anti‐HEV seroconversion during the deployment are reassuring. In addition, an encouraging finding was that even though deployment spanned several years, with undoubtedly varying levels of military infrastructure in Afghanistan, we did not see increased numbers of seroconverters among early deploying US forces. However, these findings only provide an overall assessment of risk; there may be certain deployed populations at increased risk of HEV infection. Service members who are embedded within local populations may have increased exposure to contaminated water, contaminated food sources, and unsanitary conditions, all of which have been shown to be risk factors for HEV transmission. In addition, these findings may not be generalizable to all deployment settings. Rapid or highly mobile deployments, which may lack the infrastructure to provide sanitary food and water supplies, deployments to regions where the disease is endemic, and deployments requiring frequent, close contact with local populations may all have high risks of HEV exposure. However, continued surveillance of HEV exposures and clinical cases are essential within the military, especially during deployments to new locations or to an immature theater setting.
Hepatitis E Seroprevalence and Seroconversion. Part 5
A secondary objective of this study was to assess the predeployment prevalence of anti‐HEV among service members. Our finding of low anti‐HEV seroprevalence was surprising. Although this rate is consistent with initial reports of anti‐HEV prevalence in the United States, which were 0.4%–2.3%, our rate was considerably lower than those reported in more recent studies. Previous studies among US blood donors reported seroprevalence rates of 18.3% and 21.3%. A study by Kuniholm et al reported a seroprevalence of HEV of 21% among a general civilian noninstitutionalized US population from 1988 through 1994.
We postulate several reasons for this marked difference between the findings of recent studies among the general US population and those of our study. First, there is the possibility that the assays used in these other studies led to an overestimation of the prevalence of HEV in the US population or that the WRAIR assay underestimated this prevalence. The WRAIR assay was specifically developed to improve seroepidemiology and identification of hepatitis E infections and underwent multiple validation steps. It has been reported to have greater sensitivity to low levels of anti‐HEV than commercially available assays and to have 100% specificity in a healthy population. However, one study did find that in an outbreak setting, the sensitivity of the WRAIR test among asymptomatic and symptomatic individuals was less than that of some commercially available assays. In addition, there are differences between the WRAIR assay and other assays in the dilution of test samples and the resulting positive cutoff values. The assay used in the study by Kuniholm et al had a serum dilution of 1:200, compared with a serum dilution of 1:1000 for the WRAIR assay.
The WRAIR assay used a cutoff value that was 15–25 times higher than the cutoff values used with the other assays. If shifting of the WRAIR assay cutoff value from 20 WRAIR U/mL to 15, 10, 5, or 3 WRAIR U/mL was verified, then the resulting seroprevalence estimates in this study would be 1.7%, 2.9%, 8.0%, or 17.1%, respectively. Using a lower cutoff value of 15 or 10 did not result in meaningful increases in seroprevalence. However, when one‐quarter and approximately one‐sixth of the original cutoff value were used, the seroprevalence increased to those of similar estimates seen in other studies. This supports the idea that different cutoff values may be driving some of the differences we see between these assays, but without direct comparisons between the assays in a variety of settings, it is difficult to determine the true source of these differences.
Hepatitis E Seroprevalence and Seroconversion. Part 4
Entries on the Postdeployment Health Assessment Form were analyzed for symptoms, specifically vomiting and diarrhea, that were suggestive of enterically transmitted disease, possibly including hepatitis E. Comparison between the study subjects and the total Afghanistan‐deployed cohort revealed nearly identical rates of reporting of these symptoms; 28%, 8%, and 7% of service members had experienced diarrhea, vomiting, or diarrhea and vomiting, respectively, during deployment.
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Predeployment anti‐HEV prevalence.Predeployment samples from 16 subjects had detectable total anti‐HEV levels. This gave a predeployment seroprevalence of 1.1% (95% CI, 0.6%–1.7%). All 16 samples were nonreactive for IgM anti‐HEV.
Although higher percentages of seropositive subjects were male, were white, were officers, had attended college, or lived in an urban area prior to military entry, these differences could have been due to chance alone. An age of 35 years was also more frequent among seropositive subjects, although this difference did not reach statistical significance (odds ratio, 2.9 [95% CI, 0.9–8.8]; ). A statistically significant association between birth country and seropositivity was noted, but this was driven by the large number of subjects with missing data. When subjects with missing birth countries were removed from the analysis, the difference was not statistically significant.
Examination of the percentage of subjects with total anti‐HEV by home location when they entered the military found that subjects from the New England division had the highest percentage of seropositivity for anti‐HEV at 4.2% (95% CI, 0.5%–14.3%). Subjects from the East South Central division had the next highest percentage at 2.6% (95% CI, 0.3%–9.0%), followed by the Mountain, West North Central, and Mid‐Atlantic divisions all at 2% (95% CI, 0.3%–7.2%), the Pacific division at 1.1% (95% CI, 0.1%–4.0%), and the West South Central division at 0.6% (95% CI, 0.02%–3.4%). The remaining divisions (East North Central and South Atlantic) had no anti‐HEV–positive subjects.
Anti‐HEV seroconversion. Two subjects developed total anti‐HEV during the time period between the collection of their predeployment and postdeployment serum samples. However, the samples from both subjects were nonreactive for IgM anti‐HEV. This yielded a seroconversion rate of 0.1% (95% CI, 0.02%–0.5%). These 2 seroconverters were deployed in 2003 and 2004, respectively. The subject who was deployed in 2004 reported on the Postdeployment Health Assessment Form experiencing vomiting and diarrhea during the deployment. Neither subject had any hepatitis‐related medical encounters after their return from the deployment.
This study provides the first reported rates of anti‐HEV seroprevalence and seroconversion among US military personnel deployed to Afghanistan. The results of this study suggest a very low risk of anti‐HEV seroconversion during deployment. Our results did not support a hypothesized high risk of exposure of service members to HEV due to outbreaks among Afghan civilians and previously reported hepatitis outbreaks among the Soviet military in Afghanistan in the 1980s. Either the exposure risk was less than expected or the preventive measures implemented during deployments were effective in minimizing exposure to HEV. Food and water precautions were implemented among US forces. These included using only bottled water or water treated by reverse osmosis units. Food was imported and was subject to inspection and testing. In addition, other preventive practices such as encouraging good hygiene and discouraging consumption of local foods may have been effective at minimizing HEV exposures.
Hepatitis E Seroprevalence and Seroconversion. Part 3
Laboratory samples and methods.Aliquots of predeployment and postdeployment frozen serum from the 1500 subjects (3000 samples in total) were shipped on dry ice to the Armed Forces Research Institute of Medical Sciences for anti‐HEV testing. Samples were tested for total anti‐HEV by a noncommercial enzyme immunoassay developed at Walter Reed Army Institute of Research (WRAIR; Silver Spring, MD). To determine whether reactive samples were due to a recent infection (2–3 months prior to sample collection), samples were also tested for immunoglobulin M (IgM) anti‐HEV. Paired predeployment and postdeployment samples were tested simultaneously in duplicate on the same plate. Results were quantified in WRAIR units per milliliter (WRAIR U/mL) by comparing the test sample with the reference serum pool. The reference serum pool was a pool of samples collected from Nepalese donors who were known to have been infected with HEV. A total anti‐HEV level of 20 WRAIR U/mL was considered to be evidence of past infection unless the sample was also reactive for IgM anti‐HEV. Seroconversion was defined as a 4‐fold increase in the anti‐HEV level to 20 WRAIR U/mL. An IgM anti‐HEV level of >100 WRAIR U/mL was considered to be evidence of acute infection.
Statistical analysis.Seroprevalence and 95% confidence intervals (CIs) of total anti‐HEV levels before deployment were calculated. Anti‐HEV seroprevalence was also calculated for specific demographic, location, and service‐related strata. For intrastratum comparisons, because of the small numbers of samples, the Fisher exact test was used to generate P values and exact logistic regression was used to calculate odds ratios. The proportion and 95% CI of service members who seroconverted during deployment was also calculated on the basis of the seroconversion definitions given above. All 95% CIs were calculated using an exact binomial formula. SAS software (version 9.1; SAS Institute) was used for this analysis.
Scientific and human subjects research approvals.This study received scientific review from the WRAIR Scientific Review Committee and was additionally reviewed and approved by the US Army Medical Research and Materiel Command’s Human Subjects Research Review Board.
Study population. The characteristics of the random sample of study subjects with serum samples available were similar to those of the total deployed cohort. A large percentage of the study subjects and a large percentage of the total deployed cohort had missing birth countries (21.2% and 23.4%, respectively). Birth country is reported at the Military Entrance Processing Station and is often missing in the DMSS data.
Hepatitis E Seroprevalence and Seroconversion. Part 2
Although the seroprevalence of anti‐HEV in Afghanistan is not known, hepatitis E is considered to be endemic in that country. Large numbers of hospitalizations for hepatitis and other enterically transmitted diseases during Soviet operations in Afghanistan during the 1980s and a recent HEV outbreak in Laghman Province generated concern that US service members deployed to Afghanistan may be at risk for HEV infection. In addition, outbreaks of hepatitis E have been reported in several other military environments in Chad, Djibouti, Nepal, Ethiopia, Somalia, India, and Pakistan. In most of these outbreaks, contaminated drinking water was usually implicated. High attack rates in areas where hepatitis E is endemic and lengthy convalescent periods lasting 6 or more weeks contribute significantly to the loss of soldier duty days and seriously impact military operations. Sporadic and epidemic hepatitis E (likely caused by genotype 1) in Afghanistan has the potential to render combat troops combat ineffective for weeks.
To address these concerns, we conducted a retrospective cohort serosurvey of US service members who were deployed to Afghanistan as part of Operation Enduring Freedom. The survey was designed to estimate the baseline anti‐HEV prevalence, determine the incidence of HEV infections during deployment, and determine the risk factors for HEV seroprevalence and seroconverison.
Methods
Study population and design.The Defense Medical Surveillance System (DMSS) contains medical, demographic, occupational, service, and deployment data about US service members beginning at the time they apply and continuing for the duration of their military careers [39]. DMSS deployment rosters are provided by the Defense Manpower Data Center. Using DMSS, we identified the entire cohort of service members who were deployed to Afghanistan between 1 January 2002 and 31 December 2006, which consisted of 108,218 personnel.
The Department of Defense Serum Repository maintains serum samples collected from service members for the purpose of mandatory human immunodeficiency virus (HIV) testing and operationally required predeployment and postdeployment samples. The Department of Defense Serum Repository was queried to identify which service members from the cohort had at least 2 serum samples on file at the repository. The cohort was further restricted to the 40,162 personnel whose samples were collected within the 180 d preceding and following the deployment start and end dates, respectively. From this remaining cohort, we selected a random sample of 1500 subjects for the study.
Demographic, deployment, and medical encounter data for the 1500 subjects were obtained from DMSS. Specifically, data on age, race or ethnicity, education level, birth location, home location at entry, service, deployment history, military occupational history, and responses on the Postdeployment Health Assessment Form (form DD2796, which is completed within 30 d prior to or 90 d after the end of the deployment) were extracted from DMSS. Home locations at entry were categorized into 9 US divisions based on US census division categories. In addition, home locations at entry were categorized as urban or rural on the basis of the rural‐urban continuum codes developed by the US Department of Agriculture. Data on all possible hepatitis‐related medical encounters (ICD‐9‐CM codes 070.00–070.99 [hepatitis diagnosis], 009.00–009.99 [ill‐defined intestinal infections], 787.00–787.99 [symptoms involving the digestive system], 780.6 [fever], 783.0 [anorexia], and 789.1 [hepatomegaly]) that occurred before or after the deployment were also obtained from DMSS.
Hepatitis E Seroprevalence and Seroconversion
Hepatitis E virus (HEV) is an important agent of acute hepatitis in developing regions worldwide and is increasingly associated with infections that were acquired in regions where HEV infection had not been considered to be endemic. HEV is also a distinctive, nonenveloped, positive‐strand RNA virus; it represents the only species in genus Hepevirus, family Hepeviridae, and only 1 serotype is recognized. There are, however, 4 known genotypes that infect certain mammals; among humans, HEV genotypes 1 and 2 appear to differ clinically and epidemiologically from genotypes 3 and 4. HEV genotype 1 is the primary cause of epidemic and sporadic hepatitis among residents and travelers in many developing countries, where the primary mode of transmission is suspected to be fecal‐oral but indirect; genotype 2 infections are thought to have similar characteristics on the basis of fewer studies that represent several nations. In industrialized countries where hepatitis E (ie, disease caused by HEV) is very unusual, infections with genotype 3 or 4 are relatively common and transmission is postulated to have a zoonotic component.
Most reported outbreaks have occurred in South Asia, commonly following monsoon rains or flooding that resulted in contamination of well water or public water supplies. Epidemic and sporadic hepatitis E may account for half to nearly all of the cases of acute viral hepatitis among young adults in affected areas. Infection may manifest with a range of severity from subclinical to acute hepatitis to even death. Clinical features can include jaundice, anorexia, hepatomegaly, abdominal pain and tenderness, nausea and vomiting, and fever. Without laboratory confirmation, hepatitis E is indistinguishable from other types of hepatitis. Epidemics of HEV infection are common throughout nonindustrialized countries and may be responsible for up to half of all cases of acute viral hepatitis among young adults in affected areas. Although hepatitis E is generally self‐limited and the case‐fatality rate is low (estimated to be 0.5%–4%), morbidity from widespread outbreaks in large populations, including military populations, is well documented. In addition, pregnant women in their third trimester may have case‐fatality rates that exceed 20%, and immunosuppressed individuals may develop chronic hepatitis. It has been reported in developing countries that the ratio of subclinical to clinical infections is 2:1 for sporadic cases and 7:1 during epidemics. Therefore, seroprevalence studies are typically the best approach to determine the number of persons who have been infected with HEV.
The prevalence of antibodies to HEV (anti‐HEV) in the United States (US) was initially estimated to be 0.4%–2% and was thought to be almost exclusively associated with foreign travel. However, more recent studies among various US populations have found rates as high as 21%. HEV seroprevalence rates among United Nations Peacekeepers from several less industrialized countries were reported to be between 3% (among soldiers from Haiti) and 62% (among soldiers from Pakistan), whereas the seroprevalence rate among US soldiers was relatively low at 2%.
Severe Dengue Virus Infection in Travelers. Part 2
WHO definitions cause confusion when patients with otherwise uncomplicated dengue fever have severe thrombocytopenia or when patients suspected clinically to have DHF do not meet all 4 WHO criteria. Second, the DHF/DSS classification excludes severe dengue disease associated with “unusual manifestations.” Moreover, the term “dengue hemorrhagic fever” places undue emphasis on hemorrhage, when the most important “danger” sign that should be watched for and managed appropriately is plasma leakage leading to shock. Finally, the WHO classification is mainly based on studies in children and may therefore not be applicable to predominantly adult travelers. Shock and plasma leakage appear to be more common in children, whereas internal hemorrhage is more frequently a manifestation in adults. A new definition for severe dengue is now urgently needed. A large multicenter descriptive study is under way to obtain the evidence base to establish a more robust dengue classification scheme for use by clinicians, epidemiologists, public health authorities, vaccine specialists, and scientists involved in dengue pathogenesis research. The development of shock, altered consciousness, severe bleeding, unusual manifestations, or death would be considered an indication of severe dengue, the main outcome, and the data might then be used to construct an algorithm to predict this outcome.
Wichmann et al. also attempted to identify risk factors for more severe disease, because the risk factors and clinical findings in adult travelers may differ from those observed in the predominantly pediatric population in which dengue is endemic. They added laboratory parameters to their analysis to supplement the initial descriptive epidemiological studies by their network on dengue, published in 2002. The data are limited somewhat by the small number of travelers with serious complications—of 219 patients with imported dengue virus infections, only 17 had any spontaneous hemorrhage, the majority of which were epistaxis or gum bleeding, and none required blood or platelet transfusions. In addition, only 2 patients met the WHO criteria for DHF, and none had DSS. Despite these limitations, the data confirm previous studies suggesting that the secondary immune response increases the risk of more‐severe disease but is not the only factor associated with DHF.
In conclusion, dengue is increasingly a global problem that also affects international travelers. There are huge challenges—the clinical diagnosis is difficult; cocirculation of all 4 virus serotypes has increased the risk of more‐severe disease; vaccines remain a challenge; new hosts have appeared, with dengue having been transmitted to transplant recipients; nosocomial transmission without a mosquito vector has been reported; and there is the potential for increased spread with global climate change. Efforts such as those by TropNetEurop and GeoSentinel that allow for systematic aggregation of clinical and laboratory data on dengue in international travelers via formal data collection are to be commended, and it is hoped that similar efforts will arise in Asia. This will allow for greater collaboration in terms of surveillance, identification of risk factors, improved treatment, and, potentially, vaccine studies.
Severe Dengue Virus Infection in Travelers
Dengue has become one of the most important emerging disease problems among international travelers. This comes as no surprise, because dengue is now the most common arboviral disease in the tropics and subtropics—areas that have become popular tourist destinations. In some case series, dengue is the second most frequent cause of hospitalization (after malaria) among travelers returning from the tropics. GeoSentinel is a global provider‐based surveillance network of travel medicine providers; in its most recent update, dengue was the most frequent cause of systemic febrile illness in travelers to Asia.
The World Health Organization (WHO) classifies symptomatic dengue virus infections into 3 categories: undifferentiated fever, classic dengue fever, and dengue hemorrhagic fever (DHF). Dengue fever is defined clinically as an acute febrile illness with 2 manifestations (headache, retroorbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, or leukopenia). DHF is defined by 4 criteria: fever or history of fever lasting 2–7 days, a hemorrhagic tendency shown by a positive tourniquet test or spontaneous bleeding, thrombocytopenia (platelet count 100×109 cells/L), and evidence of plasma leakage shown either by hemoconcentration with substantial changes in serial measurements of packed‐cell volume (hematocrit) or by the development of pleural effusions or ascites; or both. Hemorrhagic manifestations without capillary leakage do not constitute DHF. The term “dengue shock syndrome” (DSS) refers to a condition in which shock is present as well as all 4 DHF‐defining criteria.
Solely on the basis of on this classification, however, it would be wrong to conclude that “classic dengue fever” is a mild disease. Hemorrhagic manifestations such as gum bleeding, epistaxis, menorrhagia, and gastrointestinal hemorrhage may be associated with dengue fever, as well as rare complications such as myocarditis, fulminant hepatitis, encephalopathy, and neuropathies. Classic dengue fever in travelers, although mostly self‐limiting and rarely fatal, can be incapacitating, may halt travel, and may require hospitalization and even evacuation and a return home.
Wichmann et al., in this issue of the Journal, report the results of an intensified surveillance of dengue in travelers within the European Network on Surveillance of Imported Infectious Diseases. Such networks are important in quantifying the risk of severe dengue in travelers. On the basis of strict WHO criteria, only 0.9% of the 219 travelers had DHF in this case series. The low incidence of DHF in these travelers, compared with 2%–6% in populations in which dengue is endemic, is most likely because most travelers do not have preexisting antibodies to dengue, given their lack of previous exposure. Secondary infection is thought to be one of the risk factors for DHF because of postulated antibody‐enhanced infection. However, although only 0.9% met the criteria for DHF, 11% of travelers had severe clinical manifestations (internal hemorrhage, plasma leakage, shock, or marked thrombocytopenia). The authors correctly point out that severe dengue is not uniformly defined and may be missed if the WHO classification is strictly applied. Indeed, the WHO classification of dengue is increasingly being criticized for several reasons. First, as clinicians who treat dengue know, the disease exists as a continuous spectrum rather than as distinct clinical entities listed in the WHO classification. There is considerable overlap among the 3 conditions.