Dengue (Dengue Fever, Breakbone Fever)

Are You Confident of the Diagnosis?

Dengue is a disease caused by a virus of the Flavivirus genus and is transmitted by an arthropod. The prevalence is increasing worldwide.

  • Characteristic findings on physical examination

Classically, patients will complain of sudden onset of fever lasting 2-5 days, severe headache, intense myalgia, arthralgia, and retro-orbital pain. Careful physical examination detects lesions that may be transient. Erythema and an erythematous mottled rash can be observed on the face, neck, chest, and legs. The presence of islands of healthy skin is very peculiar.

In the second to the sixth day of illness, the erythema gives place to a morbiliform rash initially on the trunk, which spreads to the legs, arms, and face (Figure 1, Figure 2). This rash may be pruritic and heals with desquamation after 2-3 days. Petechiae can be seen soon after the disappearance of fever, especially in the lower limbs, ocular mucosa, hard palate, and soft palate.

  • Expected results of diagnostic studies

At the beginning of classical dengue, neutropenia can be observed in addition to atypical lymphocytosis. In about 50-90% of the patients with classical dengue, leukopenia and thrombocytopenia were reported in about 35-50% of confirmed cases, even without hemorrhage. Normally, hematocrit, hemoglobin, and coagulation tests are normal throughout the convalescence period.

In cases of hemorrhagic dengue, initially there is a normal lymphocyte count or even leukopenia with about 15-20% of atypical lymphocytes. In dengue hemorrhagic fever (DHF), the patients present with moderate to severe thrombocytopenia and an increased hematocrit level, reflecting plasma extravasation. This is related to the severity of the disease. Increased glutamic pyruvic and oxalacetic transaminase, hypoproteinemia, and hypoalbuminemia are common and in approximately two-thirds of patients, reversal of the albumin/globulin ratio can be observed.

Radiologic examination shows a unilateral or bilateral pleural effusion.

Serologic assays can detect antibodies both in dengue or hemorrhagic dengue fever, and virus-specific nucleic acid sequences can be detected with PCR. Laboratory diagnosis of dengue in travelers depends principally on serological testing of serum immunoglobulins. IgM testing by enzyme-linked immunosorbent assay (ELISA) is the preferred method of testing. This assay is 95% sensitive when serum specimens are collected 7-10 days after the onset of illness. A positive tourniquet test is usually present in dengue patients, even with mild clinical symptoms, although it is not a specific finding.

  • Diagnosis confirmation

The differential diagnosis includes malaria, typhoid fever, hemorrhagic viral fevers, viral hepatitis, poisonings, influenza, the non-jaundice form of leptospirosis, pharyngitis, endocarditis, rickettsiosis, sepsis, meningitis and meningococcal disease, chikungunya, and Zika virus. Purpuric lesions and circulatory shock usually occur only in serious forms of dengue after the first 48 hours. In the case of meningococcal disease and meningococcal meningitis, such signs generally occur during the first 2 days.

Epidemiologic history is very important to distinguish dengue from malaria, yellow fever, and leptospirosis. Often, dengue is underdiagnosed or diagnosed as flu or measles due to the rash. Significant leukocytosis should lead to the diagnosis of a bacterial disease such as leptospirosis and practically discards dengue. In acute leukemia and aplastic anemia, severe cytopenia, fever, and moderate and severe anemia can be observed.

Clinical manifestations of dengue are similar to Zika and chikungunya infections, with fever, exanthema, conjunctivitis, retro-orbital headache, and arthralgia as the main signs/symptoms. In cases of chikungunya infection, the high prevalence of chronic arthralgia should be taken into account. In the presence of Zika, potential sexual and maternal-fetal transmission (with risk of congenital microcephaly if viral infection was acquired in the first trimester of pregnancy) should always be investigated. A very useful algorithm for this differential diagnosis was released earlier this year by Moulin and collaborators.

Who is at Risk for Developing this Disease?

Dengue occurs as an epidemic disease in tropical and subtropical regions of Asia and Africa, but transmission has been geographically increasing during the past few decades. Successive introduction of new serotypes into the Caribbean and Central and South America has occurred since 1977. One hundred million cases of dengue fever are reported yearly, making it one of the most important viral diseases in the world. Some 2.5 billion people are now at risk from dengue. The World Health Organization (WHO) currently estimates there may be 50 million cases of dengue infection worldwide every year. Not only is the number of cases increasing as the disease is spreading to new areas, but explosive outbreaks are occurring.

What is the Cause of the Disease?

  • Etiology

  • Pathophysiology

A biting mosquito transmits dengue (horizontal transmission) and can also pass the virus via infected eggs to its offspring (vertical transmission). Therefore, the mosquito is the true reservoir and also the vector for the disease. The main vector, Aedes aegypti, can also transmit yellow fever and presents a broad ecologic range and spread throughout the world, mostly via ships.

After being inoculated into humans through the bite of the arthropod vector, the initial viral population multiplies within regional lymph nodes and subsequently enters the bloodstream. Generally, the clearance of the virus happens during the period of 5-8 days when the body temperature rises. The second replication cycle occurs inside circulating monocytes. Its tropism to monocytes, macrophages, and muscle cells explains the intense myalgia that may be observed during the course of the disease.

The production of cytokines by macrophages is directly stimulated by viral replication. The release of tumor necrosis factor alpha and interleukin 6 is probably related to the development of febrile framework. Anti-dengue IgM antibodies can be observed from the fourth day of the disease, with a peak at the end of the first week. Anti-dengue IgG antibodies may be found in the blood for years and are responsible for immunity against a particular virus serotype.

DHF is generally observed in patients that have already had an infection of a particular serotype and, years later, acquire dengue again, this time by a different serotype of the virus. DEN-2 is considered the most virulent, followed by DEN-3, 4, and 1, in descending order. During the primary infection, neutralizing antibodies are produced against the first serotype inoculated and are able to protect the body against the other serotypes during a short period of time. This is known as cross-immunity and lasts for a few months or a few years. The theory of Halstead, or the theory of immunologic amplification, is based on these observations.

Systemic Implications and Complications

DHF is the most severe form of the disease and is characterized by high fever and hemorrhagic phenomena, often accompanied by hepatosplenomegaly and circulatory collapse. It occurs mainly in children under 16 years. The initial clinical picture resembles classical dengue fever, with the emergence of multiple petechiae and bruises.

Hemorrhagic manifestations and effusions are observable from the second or third day of the disease, but may be missing. The main characteristics that determine its severity and distinguish it from classical dengue are the increase in vascular permeability leading to extravasation of plasma and abnormal hemostasis. The selective loss of plasma volume to the peritoneal and pleural cavities is responsible for hypovolemic shock.

Abnormal hemostasis, including thrombocytopenia, change in platelet function, disseminated vascular coagulation, and increased capillary fragility is related to the emergence of hemorrhagic manifestations (Figure 3). There is clear evidence of extravasation of plasma and bleeding in various organs such as the gastrointestinal tract, lungs, brain, and esophagus. Hepatomegaly is seen more commonly in DHF than in classical dengue and can be associated with massive liver necrosis and splenomegaly. The signs and symptoms of DHF are summarized in Table I.

Table I.
Signs and Symptoms
GRADE I Thrombocytopenia + hemoconcentration. Absence of spontaneous bleeding.
GRADE II Thrombocytopenia + hemoconcentration. Presence of spontaneous bleeding.
GRADE III Thrombocytopenia + hemoconcentration. Hemodynamic instability: filiform pulse, narrowing of the pulse pressure ( >20 mmHg), cold extremities and mental confusion.
GRADE IV Thrombocytopenia + hemoconcentration. Declared shock, patient pulseless and with arterial blood pressure = 0 mmHg (dengue shock syndrome).

Treatment Options

Treatment options for DHF are summarized in Table II.

Table II.
Classic Dengue Oral hydratation, antipyretics, pain relievers (not aspirin or non-steroidal anti-inflammatory drugs), antiemetics.
DHF GRADES I and II Intravenous hydration (saline, ringer, albumin, blood transfusion), antipyretics, pain relievers, antiemetics.
DHF GRADES III and IV Intensive care

Optimal Therapeutic Approach for this Disease

The initial treatment for dengue fever is nonspecific and supportive. It is important to find out whether the patient shows signs of dehydration and to check out his/her ability to ingest liquids. Often in the first 3 days of disease, the treatment of choice is symptomatic with antipyretics, pain relievers, gastric protectors, and antiemetics. Bed rest and oral hydration are also important. Paracetamol is the medication of choice for treatment of fever and analgesia. The non-steroidal anti-inflammatory drugs should be avoided, as well as aspirin, because they can be related to Reye’s syndrome and exacerbate hemorrhagic manifestations.

Dehydrated patients may need intravenous hydration based on physiologic saline or ringer, or even human albumin. The critical period is between the third and the eighth day, when the first signs of evolution to DHF/dengue shock syndrome can be observed. The use of high doses of corticosteroid in the treatment of shock has not been shown to alter mortality rates. The majority of patients with dengue fever get better in a week. Patients with hypotension and disseminated intravascular coagulation have indication for hospitalization in the intensive care unit.

Patient Management

Criteria for hospitalization:

  • The patient refuses liquids and food intake.

  • Warning signs: mental confusion, filiform pulse, narrowing of the pulse pressure, cold extremities.

  • Platelet count below 20,000/mm3, regardless of hemorrhagic manifestations.

  • Respiratory impairment: difficulty breathing, chest pain, decreased lung function, or other signs of severity including acute respiratory distress syndrome (ARDS).

  • Follow-up difficulties.

Criteria for leaving hospital (all six following criteria must be present):

  • Normality and stability of hematocrit for 24 hours.

  • Platelet levels ascending above 50,000 mm3.

  • Visible clinical improvement.

  • No fever for 24 hours, without medications.

  • Hemodynamic stability for 24 hours.

  • Pleural or peritoneal effusions in the process of reabsorption.

Prevention and control of the arthropod vector relies on insecticides, barrier measures, protective clothing, bed netting, and insect repellents. In the United States, Wolbachia has been regulated as a biopesticide since 2011 by the Environmental Protection Agency (EPA) Office of Pesticide Programs, Biopesticides and Pollution Prevention Division. A wMel strain of this endosymbiotic bacterium, estimated to chronically infect between 40-75% of all arthropod species, has been used by the Eliminate Dengue Program to reduce dengue transmission. The World Health Organisation (WHO) recommended the deployment of Wolbachia in March 2016 to counter the recent escalating healthcare burden of Aedes-transmitted viruses.

Patients should be warned that A. aegypti breeds primarily in man-made containers like earthenware jars, metal drums, and concrete cisterns used for domestic water storage, as well as discarded plastic food containers, used automobile tires, and other items that collect rainwater. It also breeds extensively in natural habitats such as tree holes and leaf axils.

Unusual Clinical Scenarios to Consider in Patient Management

There is strong evidence demonstrating the association between dengue and Reye’s syndrome in adults and in children. During an epidemic of DEN-4 in Puerto Rico, there was a case of liver failure assigned to Reye’s syndrome. Reye’s syndrome is characterized by a viral condition, such as flu or chicken pox (and is now related to dengue), the use of salicylates for symptom control, and then progressive metabolic encephalopathy, cerebral edema, and intracranial hypertension (vomiting, headache, altered level of consciousness, and coma), and is associated with microvesicular steatosis with hepatic impairment. It can lead to neurologic and hepatic failure followed by multiple organ failure and death.

What is the Evidence?

Lupi, O, Tyring, SK. “Tropical dermatology: viral tropical diseases”. J Am Acad Dermatol. vol. 49. 2003. pp. 979-1000. (Resume of viral tropical diseases, including the main topics of dengue and its cutaneous manifestations.)

Lupi, O, Spinelli, L, Tyring, S, Lupi, O, Hengge, U. “Tropical dermatology”. Dengue. 2005. (Cutaneous and systemic manifestations of dengue fever and supportive treatment.)

Lupi, O, Carneiro, CG, Castelo Branco, I. “Manifestações mucocutâneas da dengue”. An Bras Dermatol. vol. 82. 2007. pp. 291-305. (Reviews all cutaneous and systemic manifestations of dengue fever and laboratorial findings. Gives directions for patients' management.)

Moulin, E, Selby, K, Cherpillod, P, Kaiser, L. “Simultaneous outbreaks of dengue, chikungunya and Zika virus infections: diagnosis challenge in a returning traveller with nonspecific febrile illness”. New Microbes New Infect.. vol. 11. 2016. pp. 6-7. (Report of the first Zika virus infection imported to Switzerland and diagnostic algorithm of all three Aedes-borne viruses, which have caused simultaneous outbreaks with similar clinical manifestations, which represents a diagnostic challenge in ill, returning travellers.)

O’Neill, SL. “Wolbachia mosquito control: Tested”. Science. vol. 352. 2016. pp. 526

Dobson, SL, Bordenstein, SR, Rose, RI. “Wolbachia mosquito control: Regulated”. Science. vol. 352. 2016. pp. 526-527. (Both are discussions regarding Wolbachia to counter Aedes-transmitted viruses and WHO recommendations.)