DENGUE HEMORRHAGIC FEVER

A 45-year-old woman presents to the emergency department with bleeding gums and bruises on both forearms for the last 2 days. For the preceding 10 days she had been experiencing a high fever (which has since broken) and rigors. In addition, she complains of a rash over both forearms, but she is unable to further characterize it. She noted severe pain in both legs during the febrile portion of her illness. There was no history of hematuria, melena, cough, or hemoptysis. She is not taking any routine prescription medications or using over-the-counter products or supplements. She has no known drug allergies. She is married with 5 children and is currently unemployed. She does not smoke or drink alcohol and has no history of drug abuse. There is no travel history or any history of sick contacts. She is a resident of Pakistan.
On physical examination, she is alert and apparently well developed and well nourished. The patient has a regular pulse of 90 bpm and a respiratory rate of 14 breaths/min. Her temperature is 98.2° F (36.8° C) and blood pressure is 110/70 mm Hg. The cardiac examination reveals a normal S1 and S2, with no murmur, gallop, or rub. Auscultation of the lungs is normal, and no palpable organomegaly or tenderness is found on abdominal examination. Examination of the extremities reveals large bruises and a petechial rash across both forearms and lower extremities (Figure 1; the image shown is an example of the rash seen). Conjunctival hemorrhages are noted bilaterally. Bruises are also apparent on her soft palate, and minor trauma from oral examination results in gingival hemorrhage.
The laboratory investigation reveals a hemoglobin of 8 g/dL (80 g/L), platelet count of 11 × 103/µL (11 × 109/L), and a white blood cell count of 1.8 × 103/µL (1.8 × 109/L). Her serum blood urea nitrogen, creatinine, liver function tests, albumin, and electrolytes are normal. Coagulation studies, including a prothrombin time, activated partial thromboplastin time, fibrin degradation products, and serum fibrinogen, are normal. Blood cultures do not show any growth. Urine analysis and urine culture result negative. Posteroanterior and lateral chest radiographs, as well as abdominal ultrasonography, are unrevealing.

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Figure 1.
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Figure 1.
This patient was diagnosed with dengue hemorrhagic fever (DHF), which is a complication of dengue fever (DF). The diagnosis was eventually confirmed by paired immunoglobulin M samples demonstrating an acute rise in antibodies.
Dengue virus belongs to the family Flaviviridae (genus Flavivirus) and has emerged as the most common arboviral disease in the world. The disease is endemic to tropical and subtropical areas of the world, with about 2.5 billion people (40% of the world's population) at risk of acquiring the infection.[1] Dengue virus is transmitted to humans through the bites of infective female Aedes mosquitoes (particularly A aegypti and A albopictus). Mosquitoes generally acquire the virus while feeding on the blood of an infected person. After an incubation period of 8-10 days, an infected mosquito is capable, during probing and blood feeding, of transmitting the virus to susceptible individuals for the rest of its life.[2] Unlike malaria, which is more prevalent in rural areas, DF is spread via mosquitoes that thrive in highly populated urban environments.[3]
Four distinct, but closely related, viruses (termed dengue virus types 1-4 [DENV 1-4]) cause DF. Humans are the main amplifying host of the virus.[4] Infection with 1 of the 4 serotypes of dengue virus causes a wide spectrum of clinical disease, including asymptomatic infection, undifferentiated fever, DF, and DHF. DHF occurs in a minority of patients and is characterized by bleeding and plasma leakage, which may lead to shock.[5] The major risk factor for DHF is prior immunity to a single dengue virus serotype. Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity (~6 months), but an individual can eventually be infected by more than one serotype. An individual could therefore experience a case of DENV-1 fever in one year, followed by a case of DENV-2 fever in the following year. Third infections are, however, very rare, and fourth infections have never been reported.[6] Several serotypes can be in circulation during a particular epidemic.[7]
Some people infected with DF are asymptomatic. Young children often have a fever with a rash, but other symptoms are minor. Older children and adults may also have mild symptoms; however, they are more likely to experience classic DF.[2] Symptoms of DF include a high fever (up to 105° F [40.5° C]), severe headache, retro-orbital pain, severe muscle and joint pain, swollen lymph nodes, general malaise, nausea, and vomiting; a macular erythematous rash with petechiae may also be observed.[7] The differential diagnosis for DF and DHF is broad and includes meningococcal meningitis, septicemia and disseminated intravascular coagulation, other hemorrhagic fevers (Crimean Congo hemorrhagic fever, Ebola, etc.), thrombotic thrombocytopenic purpura, falciparum malaria, leptospirosis, aplastic anemia, acute leukemia, and yellow fever.
Direct person-to-person transmission of dengue virus has not been documented. A few case reports have been published of transmission of DENV through exposure to dengue-infected blood, organs, or other tissues from blood transfusions; solid organ or bone marrow transplants; needle stick injuries; and mucous membrane contact with dengue-infected blood.[8]
Dengue or dengue-like epidemics were reported throughout the nineteenth and early twentieth centuries in America, Southern Europe, North Africa, the east Mediterranean, Asia, Australia, and on various islands in the Indian Ocean, the south and Central Pacific, and the Caribbean. DHF has increased both in incidence and distribution over the past 40 years, and, in 1996, 2.5-3.0 billion people lived in areas potentially at risk for dengue virus transmission. It is estimated that there are 20 million cases of dengue infection annually, resulting in around 24,000 deaths.[9] The geographic distribution of dengue viruses and their mosquito vectors has expanded, and DHF has emerged in the Pacific region and the Americas. In Southeast Asia, epidemic DHF first appeared in the 1950s, but by 1975 it had become a leading cause of hospitalization and death among children in many countries in that region.[10] In Europe, the last dengue epidemic dates from 1927-1928 in Greece, with high mortality. However, there continues to be imported cases of DF in travelers returning to Europe from endemic areas.[11]
In the 1980s, DHF began a second expansion into Asia when Sri Lanka, India, and the Maldives Islands had their first major DHF epidemics; Pakistan first reported an epidemic of DF in 1994. The recent epidemics in Sri Lanka and India were associated with multiple dengue virus serotypes. After an absence of 35 years, epidemic DF occurred in both Taiwan and the People's Republic of China in the 1980s. The People's Republic of China had a series of epidemics caused by all 4 serotypes, and its first major epidemic of DHF, caused by DENV-2, was reported on Hainan Island in 1985. Singapore also had a resurgence of DF/DHF from 1990 to 1994 after a successful control program had prevented significant transmission for over 20 years. In other countries in Asia where DHF is endemic, the epidemics have become progressively larger in the last 15 years.[10]
A recent outbreak of DF in Karachi occurred in 2005 when Aga Khan University reported 30 positive cases out of 100. A recent trend of DF in southeastern countries is that it has become endemic, causing cyclical epidemics every 2-3 years.[12]
A major challenge for public health officials in all tropical areas of the world is the development and implementation of sustainable prevention and control programs that will reverse the trend of emergent DHF.[13] Environmental controls, including solid waste management, decreasing vector breeding sites by eliminating standing water, improvement in public awareness by media, and the use of household insecticides and mosquito repellants can help prevent the spread of dengue virus. Active case surveillance is important for early detection and implementation of control programs in the setting of acute epidemics.[11] Unfortunately, there is no commercially available vaccine to prevent dengue.[14] Tetravalent vaccines are currently being studied.
Clinically, the diagnosis of DF is suggested by the presence of fever, severe headache, maculopapular skin rash, and myalgias associated with either the isolation or identification of DENV from either serum, plasma, or tissue specimens, or by demonstration of a 4-fold increase of DENV antibodies in paired serum samples. The diagnosis of DHF is based on similar clinical features associated with a bleeding diathesis and/or thrombocytopenia. In some patients, a shock syndrome (dengue shock syndrome) may be observed.
The treatment of DF and DHF is essentially supportive. Antipyretics as well as fluid resuscitation, monitoring, and support are often necessary. Monitoring of laboratory parameters and replenishment with blood products as necessary are indicated in severe cases of DHF. The World Health Organization has created a useful guide (Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control; available at the WHO Website[9]) that delineates recommended approaches to the identification and management of DHF patients.
The patient presented in this case was admitted to an inpatient medical ward for 10 days and managed with intravenous fluids as well as repeated platelet and packed red blood cell transfusions. She was discharged when her platelet count reached 60 × 103/µL (60 × 109/L). She returned to the outpatient department after 3 weeks for follow-up, at which time her bleeding, rash, and other symptoms had improved.You are examining 30-year-old man who presents with increased bruising following a short bout of febrile illness accompanied by severe headaches, a rash, and muscle pain. You suspect dengue hemorrhagic fever (DHF). Which of the following situations puts this patient at greatest risk of developing DHF?
Dengue fever is an acute, mosquito-transmitted viral disease caused by any 1 of 4 virus serotypes (DENV-1-4). Infection with any of these causes a wide spectrum of clinical disease, ranging from asymptomatic infection, undifferentiated fever, and dengue fever (DF) to dengue hemorrhagic fever (DHF). Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity, but each individual can eventually be infected by more than one serotype. It is thought that subsequent infections with different serotypes in individuals put patients at risk for more severe manifestations of disease, including DHF. This is thought to be due to partial immunity, which may cause an amplification rather than a mediation of illness. Ebola is one of the many diseases in the differential diagnosis of dengue fever. Visiting an area with an active Ebola outbreak should raise suspicion for Ebola.
The diagnosis of DHF is confirmed with paired immunoglobulin M samples in the patient above. What is the most appropriate treatment plan for this patient?The treatment of DF and DHF is essentially supportive. Antipyretics as well as fluid resuscitation, monitoring, and support are often necessary. Monitoring of laboratory parameters and replenishment with blood products are indicated as necessary in severe cases of DHF. Antibiotics and EGDT are indicated for patients with significant bacterial infections and should likely be started empirically for severely ill, undifferentiated patients. However, they do not have a role in confirmed DHF. Plasmapheresis is indicated for treating thrombotic thrombocytopenic purpura, an illness in the differential diagnosis of dengue fever. Acyclovir is a treatment for herpes virus but is not indicated for DF.