Rationale:

• Like those of many other viral syndromes, the symptoms of dengue are nonspecific. The index of suspicion for dengue must be high.
• Dengue can be excluded if symptoms begin more than 2 to 3 weeks after the patient has left an endemic area or if the fever lasts for more than 2 weeks.

Evidence:

• Clinical features of dengue vary with the age of the patient. Several population-based studies have found an increased severity of clinical features of dengue fever with increased patient age and with repeated infections (32; 33; 34; 35).
• A retrospective study analyzed 66 elderly (aged 65 years or older) and 241 nonelderly adults (aged 19 to 64 years) with dengue hemorrhagic fever. Compared to the nonelderly patients, the elderly individuals had significantly lower incidences of fever, abdominal pain, bone pain, and skin rashes and higher frequencies of concurrent bacteremia, gastrointestinal bleeding, acute renal failure, and pleural effusion. The elderly patients also had a higher incidence of prolonged prothrombin time, lower mean hemoglobin level, and longer hospitalization and a higher mortality rate. Five elderly patients with dengue hemorrhagic fever died. Multivariate analysis showed that only dengue shock syndrome (OR, 77.3; P=0.001) was an independent risk factor for death in elderly patients (36).
• Most dengue infections are clinically unapparent. From December 1997 to January 1998, a random, age-stratified serum sample was taken from 1151 persons in 40 residential clusters in Santiago, Cuba. Sera were tested for dengue-1 and dengue-2 neutralizing antibodies. Dengue fever and dengue hemorrhagic fever/dengue shock syndrome attack rates were calculated from estimated total primary and secondary dengue-2 infections. Three percent of 13,116 primary infections were found to be overt (32). However, generalizing from Cuba may be problematic due to the fact that dengue may be less severe in blacks. In addition, the disease tends to occur in the form of epidemics in Cuba, whereas in many places where dengue is found, it is endemic, with multiple circulating virus serotypes.
• Clinical reviews and prospective clinical studies report that dengue can present clinically as nonspecific febrile illness, classic dengue fever, dengue hemorrhagic fever, and dengue hemorrhagic fever with shock syndromes and other unusual syndromes, such as encephalopathy and fulminant liver failure (23; 37).
• Prospective, population-based studies have found that most persons, particularly young children, with dengue infections in areas where the disease is endemic are asymptomatic or present with mild febrile illness (33; 38).
• A study on the incidence of dengue virus infections in a cohort of adult Dutch short-term travelers to dengue-endemic areas in Asia from 1991 to 1992 found the ratio of asymptomatic to symptomatic cases to be 1:3.3 (8). Among 104 Israeli young adults who traveled to tropical countries for at least 3 months, this ratio was 0.8:1 (6).
• Two clinical reviews on dengue state that the incubation period can vary from 3 to 14 days (typically between 5 and 7 days) (38; 39).
• Dengue viremia was found to persist for up to 12 days (typically 4 to 5 days) when measured in serial plasma samples from 168 children with acute dengue virus infection enrolled in a prospective study at two hospitals in Thailand (40).
• An analysis of the epidemiology, clinical manifestations, and virologic results in patients with imported acute dengue infection who presented at a travel clinic in Frankfurt am Main, Germany, between September 1998 and November 2000 was conducted. Dengue fever was confirmed in 13 patients, making it the second most common tropical infection after malaria in patients with fever and a history of travel to a tropical country. Most patients had only spent a short time abroad, either in South, Central, or Southeast Asia or in the Caribbean (41).
• A retrospective analysis of the medical records of 93 patients with imported dengue in Vienna, Austria, between 1990 and April 2005 identified 48 patients (52%) with confirmed dengue infections and 45 patients (48%) with probable dengue infections. The infections were acquired in Southeast Asia (56%), the Indian subcontinent (18%), Africa (10%), and Oceania (3%). The main symptoms were fever, headache, arthralgia, myalgia, nausea, vomiting, diarrhea, chills, extreme fatigue, and dizziness. Forty-three percent of patients had a rash, and 22% had lymphadenopathy. Eighteen patients showed hemorrhagic manifestations, and 7 fulfilled the criteria for dengue hemorrhagic fever (1 of whom had dengue shock syndrome). No fatalities were seen (42).
• In a review of 696 consecutive returned travelers managed at an Australian tertiary care hospital for an illness acquired overseas, 19 cases of dengue fever and 20 cases of dengue-like illness were diagnosed. Eighty-five percent of the cases were acquired in Asia. The main presenting features of dengue were fever (100%), myalgia (79%), rash (74%), headache (68%), nausea (37%), and diarrhea (37%). Compared to patients with malaria, typhoid fever, and rickettsial infections, patients with dengue were significantly more likely to have myalgia and a temperature below 39°C (102.2°F). Compared to other illnesses in the returned travelers, dengue fever was 18 times more likely if fever and leukopenia were present, 71 times more likely if fever and rash were present, and 230 times more likely if fever, rash, and leukopenia were present (43).
• Clinical manifestations, epidemiologic information, and laboratory findings were described for 18 Israeli travelers who tested serologically positive for dengue. All of the patients contracted the disease in Southeast Asia, mostly in Thailand; 30% had to be evacuated due to severe morbidity. The clinical symptoms of dengue in travelers differ somewhat from the classic description among indigenous populations. High fever, chills, extreme fatigue, and severe headaches were prevalent. Other symptoms considered to be typical of dengue fever, such as myalgia, arthralgia, rash, and biphasic fever, were uncommon. Laboratory findings included marked leukopenia, usually accompanied by lymphopenia, thrombocytopenia, liver function impairment, and hyponatremia. Some hemorrhagic phenomena were manifest, but there were no deaths (44).
• Of 26 patients with serologically confirmed dengue fever diagnosed in Norway from 1991 to 1996, 21 (81%) were infected in Asia. Typical exanthem, leukopenia, and thrombocytopenia were seen in 71%, 79%, and 84% of patients, respectively. One woman developed grade I dengue hemorrhagic fever after a visit to New Delhi, India, and the other 25 patients had classic dengue fever (45).
• During a dengue-2 epidemic in Cuba in 1997, 3012 serologically confirmed cases were reported, with 205 dengue hemorrhagic fever/dengue shock syndrome cases and 12 fatalities. The main signs and symptoms observed among fatal adult dengue hemorrhagic fever cases were fever (100%), vomiting (100%), hepatomegaly (67%), abdominal pain (83%), ascites (92%), pleural effusion (58%), shock (100%), hemorrhagic manifestations (100%), petechiae (42%), hematemesis (58%), melena (25%), vaginal bleeding (43%), hemoconcentration (92%), and thrombocytopenia (83%) (46).
• In a prospective clinical study of 37 travelers suspected to have dengue infection upon returning from dengue-endemic areas, anti-dengue antibodies were found in 24 patients (14 with recent infections and 10 undetermined). The most common clinical findings among patients with a recent infection were fever (100%), thrombocytopenia (61.5%), rash (53.8%), and abnormal liver function test results (61.5%). One patient had grade III dengue hemorrhagic fever (47).
• Based on data on 483 confirmed and probable cases of dengue fever (including 13 cases of dengue hemorrhagic fever) reported to the European Network on Surveillance of Imported Infectious Diseases and the German Surveillance Network on Imported Infectious Diseases between January 1999 and December 2002, the signs and symptoms of travel-acquired dengue virus infections were fever (91%), headache (63%), myalgia or arthralgia (52%), fatigue (42%), rash (34%), diarrhea (23%), vomiting (12%), lymphadenopathy (7%), respiratory symptoms (6%), otolaryngologic symptoms (6%), neurologic symptoms (3%), psychologic symptoms (2%), and other symptoms (15%) (13).
• A prospective study in Puerto Rico analyzed 145 laboratory-positive and 293 laboratory-negative dengue cases to define the early clinical features of dengue infection in children and adults and to identify the clinical features that predict laboratory-positive dengue infection. Among children, rash and age were independently associated with laboratory-positive dengue infection. Rash in the absence of cough had a positive predictive value of 100% and a negative predictive value of 82.4% as a pediatric dengue screen. Among adults, eye pain, diarrhea, and absence of upper respiratory symptoms were independently associated with laboratory-positive dengue infection. No useful early predictors of dengue infection among adults were found (48).
• A case series was reported from three tertiary care hospitals in Karachi, Pakistan, from November 2006 to February 2007 and included 100 patients with dengue fever and positive anti-dengue IgM serologic results. All of the patients had low leukocyte and platelet counts. Common presenting symptoms were high-grade fever with or without rigors, headache, body aches, backache, vomiting, sore throat with cough, and generalized weakness (seen in 86% of patients). Uncommon features included diarrhea, abdominal pain, bleeding from gums, and nosebleeds (seen in 14% of patients). Sixty-eight patients (68%) had skin lesions. The most common skin presentation was generalized macular blanchable erythema involving the trunk and limbs, which was seen in 44 patients (65%). Discrete petechial lesions were seen on various body areas in 24 patients (35%). Palmar erythema was seen in 20 patients (30%). Generalized itching was seen in 16 patients (23%), and isolated itching of the palms and soles was seen in 20 patients (30%). Twenty-eight patients (28%) had abnormal liver function test results; 4 of these patients had an increased serum bilirubin level, whereas the remaining 24 patients had an increased ALT level (49).
• Investigators collected data on dengue in travelers from 14 European clinical referral centers within the European Network on Surveillance of Imported Infectious Diseases between 2003 and 2005. A total of 219 dengue virus infections were noted. Twenty-three patients (11%) had severe clinical manifestations (internal hemorrhage, plasma leakage, shock, marked thrombocytopenia). Secondary dengue occurred in 17% (50).
• Fatal dengue associated with fulminant hepatic failure (51) or subarachnoid hemorrhage (52) has been reported in travelers.
• During 1995, all patients with suspected CNS infections admitted to a referral hospital in southern Vietnam were studied, and 4.2% of 378 patients with suspected CNS infections were found to be infected with the dengue virus (53).
• A prospective study conducted to determine the etiology and outcome of acute hepatic failure in Thai children aged 1 to 15 years found dengue infection to be a major cause. The case-fatality rate was 68.6%. Eight of the 24 deaths were caused by dengue infection (54).
• In consultation with experts on dengue, the WHO has established case definitions for dengue fever, dengue hemorrhagic fever, and dengue shock syndrome (55).

Comments:

• Symptoms of fever, myalgia, and retro-orbital pain are characteristic of but not specific for dengue fever. The triad of fever, exanthem, and leukopenia is helpful in diagnosis.
• Classic dengue fever in travelers, although self-limiting and rarely fatal, can be incapacitating, may halt travel, and may require hospitalization and even evacuation and return home (56).
• Occasionally dengue may occur in persons who have never visited a dengue-endemic area, e.g., those who are bitten by local Aedes mosquitoes that have acquired the virus from an immigrant or visitor from a dengue-endemic country or by infected mosquitoes transported into a non-dengue region (“airport dengue”).
• Some clinical manifestations of dengue in pregnant patients can be confused with primary obstetric or other medical conditions (57). When occurring near term, dengue can cause severe bleeding complications during delivery, as well as perinatal dengue infection in infants.