Background
Rabies is a viral disease that affects the CNS. The genus Lyssavirus contains more than 80 viruses. Classic rabies, the focus of this article, is the prototypical human Lyssavirus pathogen. Ten viruses are in the rabies serogroup, most of which only rarely cause human disease. The genus Lyssavirus, rabies serogroup, includes the classic rabies virus, Mokola virus, Duvenhage virus, Obodhiang virus, Kotonkan virus, Rochambeau virus, European bat Lyssavirus types 1 and 2, and Australian bat Lyssavirus. In 1997, an unusual bat Lyssavirus caused a brief outbreak of a rabieslike illness in Australia.
The fatal madness of rabies has been described throughout recorded history, and its association with rabid canines is well known. For centuries, dog bites were treated prophylactically with cautery, unfortunately, with predictable results. In the 19th century, Pasteur developed a vaccine that successfully prevented rabies after inoculation and launched a new era of hope in the management of this uniformly fatal disease. Rabies is recognized as a zoonosis worldwide. Animal-control and vaccination strategies currently supersede postexposure prophylaxis in preventing the spread of rabies. Through such programs, rabies has been eliminated in several nations and some areas in the US territories.
Human rabies reflects the prevalence of animal infection and the extent of contact this population has with humans. Less than 5% of cases in developed nations occur in domesticated dogs; however, unvaccinated dogs serve as the main reservoir worldwide. Undomesticated canines, such as coyotes, wolves, jackals, and foxes, are most prone to rabies and serve as reservoirs. These reservoirs allow rabies to remain an indefinite public health concern, and ongoing public health measures are critical to its control. Raccoons, skunks, and insect-eating bats remain the prime vectors in the United States, followed by cats and cattle. Increasingly in the United States, the source of exposures cannot be identified, but the risk of death from rabies is exceedingly low, with fewer than 5 cases documented per year. Opossums are rarely infected and are not considered a likely risk for exposure.
Other very rare sources of exposure have included neurally derived tissues (eg, transplanted corneas) and laboratory aerosols. Recently, the first US instance of human rabies transmission via solid organ transplantation was documented in 3 recipients of a donor unsuspected of having rabies; transmission via organ transplantation has also been documented in other countries.1, 2
The rabies virus is a bullet-shaped virion with a single-stranded RNA nucleocapsid core and lipoprotein envelope. Its nucleocapsid material comprises the Negri bodies observed in the cytoplasm of infected neurons. The virus is transmitted in saliva or in aerosolized secretions from infected animals, typically via a bite. The virus is not hardy and is quickly inactivated by drying, ultraviolet rays, x-rays, trypsin, detergents, and ether.
Pathophysiology
Rabies is a highly neurotropic virus that evades immune surveillance by its sequestration in the nervous system. Upon inoculation, it enters the peripheral nerves. A prolonged incubation follows, the length of which depends on the size of the inoculum and its proximity to the CNS. Amplification occurs until bare nucleocapsids spill into the myoneural junction and enter motor and sensory axons. At this point, prophylactic therapy becomes futile, and rabies can be expected to follow its fatal course, with a mortality rate of 100%.
The rabies virus travels along these axons at a rate of 12-24 mm/d to enter the spinal ganglion. Its multiplication in the ganglion is heralded by the onset of pain or paresthesia at the site of the inoculum, which is the first clinical symptom and a hallmark finding. From here, the rabies virus spreads quickly, at a rate of 200-400 mm/d, into the CNS, and spread is marked by rapidly progressive encephalitis. Thereafter, the virus spreads to the periphery and salivary glands.
Frequency
United States
The prevalence of rabies varies by location depending on animal-control effectiveness and immunization programs. The largest number of human deaths annually was recorded during the first half of the 20th century, with an average of 50 documented cases per year. Most were related to rabid-dog exposure. Since 1940, when canine rabies vaccination programs began, the average number of documented cases declined to 2 per year. From 2001-2005, 15 cases of human rabies were reported in the United States. In 2006, 3 cases of human rabies were reported in California, Indiana, and Texas. Bat rabies virus variants were implicated in the rabies cases in Texas and Indiana, whereas exposure to a dog in the Philippines was responsible for the case in California.3 Approximately 16,000-39,000 people receive rabies postexposure prophylaxis each year.
Some concern exists regarding occupational transmission of rabies from patients to health care workers. Despite the lack of proven occupational transmission, approximately 30% of health care worker contacts exposed to known cases of rabies have been treated with postexposure prophylaxis in the United States, some of which may have been unnecessary. The delivery of health care to a patient with rabies is not an indication for postexposure prophylaxis unless mucous membranes or open wounds are contaminated by saliva, tears, cerebrospinal fluid (CSF), or neurologic tissue. Adherence to standard infection-control precautions recommended by the US Centers for Disease Control and Prevention (CDC) is expected to minimize the risk for exposure to rabies in caregivers.
International
Rabies is more prevalent in the developing world than in the developed world. The World Health Organization (WHO) estimates that rabies is responsible for 35,000-50,000 deaths annually worldwide and that gross underreporting is likely. An estimated 10 million people receive postexposure prophylaxis each year after being exposed to animals with suspected rabies.
Mortality/Morbidity
If rabies treatment is not initiated before the onset of symptoms, death is imminent. Five cases of survival of human rabies have been documented in individuals who had been previously vaccinated or received postexposure prophylaxis. The survival of a teenaged girl from Wisconsin received substantial attention in October 2004 as the first case of human survival of rabies in the absence of preceding vaccination or postexposure prophylaxis.4 Notably, she received an investigational regimen of ribavirin, amantadine, and a ketamine-midazolam–induced coma; however, assessing whether this therapy was genuinely efficacious, whether other factors may have been involved, or whether these results are in fact reproducible is difficult.
In addition, bat rabies virus (isolated from the Wisconsin survivor) may be less neurovirulent than canine or other variants that are responsible for most human cases of rabies. The case, wherein the victim did not seek medical attention after handling a bat and being bitten, underscores the potentially long incubation period (in this case, 1 mo) and the need for ongoing public awareness of the risk of contracting this almost uniformly fatal infection.
Race
Rabies has no known racial predilection.
Sex
Rabies has no known sexual predilection.
Age
Rabies has no known age predilection.
History
Incubation period
The rabies virus transfers from peripheral areas to the CNS.
The infected individual remain asymptomatic.
The average duration of incubation is 20-90 days. Rarely, incubation lasts as long as 19 years. In more than 90% of cases, incubation is less than 1 year.
The incubation period is less than 50 days if the patient is bitten on the head or neck or if a heavy inoculum is transferred through multiple bites, deep wounds, or large wounds. A person with a scratch on the hand may take longer to develop symptoms of rabies than a person who receives a bite to the head.
The rabies virus is segregated from the immune system during this period, and no antibody response is observed.
Patients may not recall exposure because of the prolonged incubation period.
Prodromal period
The virus enters the CNS.
The duration of this period is 2-10 days.
Nonspecific symptoms and signs develop.
Paresthesia or pain at the inoculation site is pathognomonic for rabies and occurs in 50% of cases during this phase; this may be the individual's only presenting sign.
Symptoms may include malaise, anorexia, headaches, fever, chills, pharyngitis, nausea, emesis, diarrhea, anxiety, agitation, insomnia, and depression.
Acute neurologic period
This period is associated with objective signs of developing CNS disease.
The duration is 2-7 days.
Furious rabies may develop in this period. Patients develop agitation, hyperactivity, restlessness, thrashing, biting, confusion, or hallucinations. After several hours to days, this becomes episodic and interspersed with calm, cooperative, lucid periods. Furious episodes last less than 5 minutes. Episodes may be triggered by visual, auditory, or tactile stimuli or may be spontaneous. Seizures may occur. This phase may end in cardiorespiratory arrest or may progress to paralysis.
Paralytic rabies is also known as dumb rabies or apathetic rabies because the patient is relatively quiet compared with a person with the furious form.
Twenty percent of patients do not develop the furious form.
Paralysis occurs from the outset.
Fever and headache are prominent.
Coma
This begins within 10 days of onset; the duration varies.
Without intensive supportive care, respiratory depression, arrest, and death occur shortly after coma.
Recovery
This is unlikely. A few reports indicate that persons who survived had preexposure or postexposure prophylaxis.
Most US cases result in death within 14 days because of complications, despite intensive supportive care.
Physical
Incubation period: The virus transfers from peripheral areas to the CNS. Physical findings are not present.
Prodromal period: The virus enters the CNS. Signs include fever, agitation, emesis, or diarrhea.
Neurologic period
Furious rabies
Patients present with episodic delirium, psychosis, restlessness, thrashing, muscular fasciculations, seizures, and aphasia.
Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. Attempting to drink or having air blown in the face produces severe laryngeal or diaphragmatic spasms and a sensation of choking. This may be related to a violent response of the airway irritant mechanisms. Even the suggestion of drinking may induce hydrophobic spasm.
Autonomic instability is observed, including fever, tachycardia, hypertension, hyperventilation, drooling, anisocoria, mydriasis, lacrimation, salivation, perspiration, and postural hypotension.
Other neurologic signs include cranial nerve involvement with diplopia, facial palsy, and optic neuritis.
Paralytic rabies
Fever and nuchal rigidity may occur.
Paralysis is symmetric and may be either generalized or ascending and may be mistaken for Guillain-Barré syndrome. The sensory system is usually spared.
Calm clarity gradually progresses to delirium, stupor, and then coma.
Coma: Respiratory failure occurs within one week of neurologic symptoms. Hypoventilation and metabolic acidosis predominate. Acute respiratory distress syndrome is common. Wide variations in blood pressure, cardiac arrhythmias, and hypothermia ensue. Bradycardia and cardiac arrest occur.
Causes
High-risk exposures consist of contact with saliva or infected CNS tissue, including corneal transplants, via the following:
The bite of an rabid animal
Contact with broken skin
Contact with mucous membranes
Exposure to aerosolized secretions from an rabid animal
Contact with unpasteurized milk from dairies: Each year since 1990, approximately 150 rabid cattle are been reported to the CDC.
Transplant patients: The innate state of immunosuppression in this population often provides a favorable environment for viral replication.
Corneal transplants: Currently, donated corneas are not accepted if the donor died from an encephalitis that may be consistent with rabies.
Kidney and liver transplants: In 2004, organs were inadvertently transplanted from a donor from Texas with rabies that had gone undiagnosed. The recipients developed clinical rabies within 30 days, resulting in 100% mortality.
Organ donation: Clinical screening of potential organ donors should include a history of animal bites, presence of clinical features of rabies, and a travel history (within a period of months) to areas where rabies is endemic. Pre-exposure rabies immunization of potential organ recipients is being evaluated as an alternative approach to prevent transmission associated with organ transplantation.
High-risk animal species in the United States include the following:
Bats
Bat bites, if noticed by the patient, are generally thought to be trivial injuries because of the small size of most temperate-zone species (eg, silver-haired bats, eastern pipistrelles). In addition, bat bites can go completely unrecognized by the patient; consequently, appropriate postexposure prophylaxis is not administered.
One third of rabies cases occur in children, and most have no known exposure to a rabid animal. Because children may not be able to recall contact with a bat, if a bat is found in a room where a child has been sleeping, the bat should be captured and submitted for examination to the county or state health authorities. In 60% of cases, testing of the bat can avoid the need for rabies immunization.6 (For additional information on pediatric rabies, see the eMedicine article Rabies in the Pediatrics: General Medicine volume.)
In September 2005, a previously healthy 10-year-old boy in Mississippi died from encephalitis later attributed to rabies. Upon further questioning after the patient's death, family members recalled that bats were commonly seen outside the home. On two occasions, dead bats also were discovered inside the home. Several family members and friends who possibly had contact with the patient's saliva received postexposure prophylaxis.
At least 30 of the more than 39 species of bats in the United States have been reported as rabid at some time.
Raccoons: Raccoons have been recognized a reservoir for rabies in the southeastern United States since the 1950s.7 Currently, the risk of raccoon transmission exists in all of the eastern coastal states and Alabama, Pennsylvania, Vermont, West Virginia, and Ohio.
Skunks: Three areas are associated with skunk-borne rabies. These areas include the north-central United States, the south-central United States, and California.
Foxes
Dogs and cats along the Mexican border: Because of limited resources and minimal public health infrastructure in the bordering communities, efforts to maintain animal control through dog-vaccination programs are hindered. Viral studies of human cases reported from US border states implicate an urban canine rabies strain and a link to coyote rabies in southern Texas.8
Lower-risk animal species in the United States include dogs, cats, and ferrets in areas not near a border. No person in the United States has ever contracted rabies from a dog, cat, or ferret held in quarantine for 10 days.
The vaccinia-rabies glycoprotein virus used to bait wild animals is a self-replicating agent. Only one case has been documented of a pregnant woman developing a skin infection and needing surgery after she was bitten by her dog. Her history findings revealed that she was bitten when she took a vaccinia-rabies virus vaccine out of her dog's mouth.9 This oral animal vaccine may cause adverse effects, particularly in hosts with altered immunocompetence and in persons in whom smallpox vaccination is contraindicated (eg, pregnant women, patients with an exfoliative skin condition).
Lab Studies
Microbiology: The results of saliva culture for rabies virus are positive in low yield within 2 weeks of illness onset.
Serology:
Serum rapid fluorescent focus inhibition test (RFFIT) titer results are positive in 50% of rabies cases.
Results of the CSF RFFIT are antibody-positive (2-25% of serum titer) after the first week of illness.
Detection of viral RNA from saliva using polymerase chain reaction (PCR) and viral antigen from brain biopsy specimens yield 100% specificity.
Viral antigen assessment involving nuchal skin and corneal touch impressions have sensitivities of 67% and 25%, respectively.
Blood gas: Respiratory alkalosis resulting from hyperventilation develops in the prodromal and early acute neurologic phases of rabies, which is followed by respiratory acidosis as respiratory depression progresses.
Cerebrospinal fluid
After the first week of illness, 80% monocytosis is observed.
Protein and glucose test results are normal.
Hematology: Results of the WBC count range from normal to elevated, with 6-8% atypical monocytes.
Urinalysis: Albuminuria and sterile pyuria may be observed.
Future tests
The nucleic acid sequence-based amplification (NASBA) technique on urine samples may be used in the future.10, 11
The NASBA technique on saliva and CSF can be used for rapid diagnosis as early as 2 days after symptom onset.
Imaging Studies
As the neurologic phase of rabies progresses, chest radiographs may reveal infiltrates due to aspiration, nosocomial pneumonia, acute respiratory distress syndrome, or congestive heart failure.
Findings from MRI and CT scanning of the brain often indicate that no abnormalities are present.
Other Tests
Electroencephalography findings include encephalopathic changes but no findings specific for rabies.
Supraventricular tachycardia may be observed during cardiac monitoring.
Eventually, bradycardia and cardiac arrest occur.
Procedures
Skin biopsy
Results from nuchal skin punch biopsy for immunofluorescent antibody staining are 50% positive within the first week.
Obtain a full-thickness punch biopsy from the nape of the neck and include hair follicles. Place the specimen in a sterile container with saline-soaked sterile gauze. Store at -70°C; then, obtain shipping instructions for a laboratory that performs the examination.
Nuchal skin biopsy is the most reliable test of rabies infection during the first week.
Histologic Findings
Eosinophilic cytoplasmic inclusions (Negri bodies) are observed in 70% of rabies cases and are pathognomonic (see Image 1). Neuronal cell death is uncommon histopathologically.
Medical Care
Before the onset of rabies symptoms, both passive and active immunizations are effective for preventing progression to full-blown rabies.
Vaccines commonly available in the United States are discussed further in Deterrence/Prevention.
Human diploid cell vaccine (HDCV, Pasteur Merièux)12
Rabies vaccine, adsorbed (RVA, Michigan State Department of Health)
Optimal results require the following:
Immediate vigorous wound cleansing with a solution of 1 part soap and 4 parts water
Passive immunization
No prior vaccination with HDCV or RVA - Human rabies immunoglobulin (HRIG)
Prior vaccination - No HRIG
Active immunization
No prior vaccination with HDCV or RVA - Primary series HDCV or RVA
Prior vaccination - Booster series HDCV or RVA
A neutralizing antibody (NAb) titer greater than or equal to 0.5 IU/mL (or complete neutralization at a serum dilution of 1:5) is considered an acceptable antibody response for protection against rabies. Of 7 patients infected with HIV who had CD4 counts less than 200 cells/µL, 3 had a poor or even undetectable NAb response to vaccination. Patients infected with HIV who had higher CD4 lymphocyte counts had a good antibody response to postexposure rabies vaccination.13 If an acceptable antibody response is not achieved, a second double-dose series of rabies vaccine should be administered in an attempt to successfully mount an adequate antibody response.
Elderly patients (>50 y) produce antibody titer levels 52% lower than younger patients. Whether this equates to reduced protective efficacy remains unclear.
Do not administer immunoglobulin and vaccine with the same syringe or in the same site.
Passive antibody provides protection for 1-2 weeks until the vaccine elicits protective antibody.
In exposures to high-risk species, initiate treatment immediately pending laboratory examination of the animal, if it is caught.
Therapy can be stopped if results from the animal's brain examination are negative.
The median duration of rabies illness in dogs, cats, and ferrets is less than 10 days, and viral shedding in saliva occurs within a few days of onset of illness and death. Because of the exceedingly low prevalence of rabies in domestic animals in the United States, healthy unvaccinated domestic dogs, cats, and ferrets may be observed for 10 days for signs of illness. If the animal remains healthy, administer no treatment; otherwise, begin treatment on the exposed individual pending necropsy results of the animal. Treatment can be discontinued if examination of the animal's brain is negative for rabies. Vaccinated animals in the United States have not transmitted rabies; outside the United States, rare instances of transmission occur. Species other than the above should be managed in conjunction with the local health department, taking into account whether viral shedding periods are known for the species, the animal's history and risk for rabies exposure, and local epidemiology.
Consult the local health department because the risk of rabies differs geographically based on local endemicity and immunization practices. Some countries and limited areas in US territories are considered rabies-free, and no prophylaxis is administered.
Note that an assessment of whether a bite was provoked is subjective and does not significantly affect the chances that the animal is rabid. Therefore, this is probably not helpful in determining the need for prophylactic treatment.
Intensive cardiopulmonary supportive care is the only treatment available for patients with symptomatic rabies.
Regardless of treatment, symptomatic rabies is invariably fatal, resulting from autonomic dysfunction that leads to cardiac arrhythmia and hypotension. Only 6 recorded cases of survivors exist, 5 of whom received some level of preexposure or postexposure prophylaxis in the asymptomatic phase and subsequently developed rabies. The use of ribavirin and induced coma has yet to be reproduced or validated in the one survivor who did not receive preexposure or postexposure prophylaxis; however, some role for combination therapies including ribavirin, interferon, ketamine, and immunomodulatory therapies has been proposed and may be considered in future cases under investigational protocols. The rarity of human rabies hinders timely testing for effective therapies. Immunomodulatory therapies such as rabies immunoglobulin, rabies vaccine, and interferon have not altered outcomes in trials.
Pregnancy is not a contraindication to postexposure prophylaxis against rabies, which is warranted to protect the life of the fetus and mother. No adverse pregnancy outcomes have been documented with postexposure prophylaxis. No mother-to-fetus transmission has been described; thus, neither rabies exposure nor diagnosis of rabies in the mother is an indication for pregnancy termination.
Steroids, which are usually indicated in the treatment of local vaccine reactions or cerebral edema, are contraindicated because of increased mortality noted in animal studies and because they reduce the response to the vaccine.
Consultations
Local health department personnel
Infectious diseases specialist
Neurologist
MEDICATION
Before the onset of rabies symptoms, both passive and active immunizations are effective in preventing progression to full-blown rabies. Optimal results require immediate vigorous wound cleansing, passive immunization, and active immunization.
In developing countries, nerve tissue vaccines are still the most widely used type for prophylaxis of rabies worldwide. They are dangerous in terms of induction of autoimmune CNS disease, require multiple injections, and are not always effective. Two types exist, the Semple type (STV) and the suckling mouse brain vaccine (SMBV).
STV is obtained from inactivated virus prepared on adult animal nerve tissue. It is inexpensive and relatively easy to produce. In India, 3 million people receive postexposure courses of STV each year. STV may produce neurological reactions, including postvaccination encephalomyelitis, in up to 1 in 220 courses, with a 3% mortality rate.
SMBV is cultured on immature mouse brain tissue, which contains little myelin. It is the most widely used rabies postexposure vaccine in Vietnam. Rare neurologic reactions occur, with complications in 1 in 27,000 treated people, with a 22% mortality rate.
Both SMBV and STV are widely used throughout the developing world and are the vaccines administered to US travelers exposed to animal bites in such countries.
Drug Category: Immunizing agents (passive)
Rabies immunoglobulin is recommended as part of the rabies postexposure regimen for persons not previously immunized against rabies.
In the United States, passive immunization consists of administration of HRIG pooled from the sera of immunized human donors. Two products are available in the United States, BayRab and Imogam.
In developing countries, equine rabies immunoglobulin (ERIG) is sometimes used but has a higher incidence of adverse effects. ERIG is no longer produced by large pharmaceutical companies. When produced by smaller pharmaceutical firms, quality cannot be ensured.
A US Investigational New Drug Application has been submitted for a new-generation purified ERIG.
A human rabies virus–specific monoclonal antibody is in development, theoretically to decrease the possibility of anaphylaxis.14
Because of cost, ERIG and HRIG are not readily available throughout much of the developing world, areas in which rabies is more common than in the United States.
If HRIG is available only after more than a week after vaccination has started, then it is probably unnecessary because an active antibody response has already begun.
Vaccine and antiserum should never be mixed or injected in the same limb.
Drug Name Rabies immune globulin-Human (BayRab, Imogam)
Description Has been licensed since 1975, and, unlike its predecessor, ERIG, is not associated with significant adverse reactions, anaphylaxis, or serum sickness. Purified ERIG is still used in some developing nations because of cost or availability and is associated with an adverse effect rate of 0.8-6%, which usually involves minor reactions. HRIG is not associated with transmission of viral hepatitis or HIV. Experimentally, infiltration of HRIG at site of exposure is more protective than IM administration. Previously, half the dose was administered at the site and half IM; however, current recommendation is that the entire dose be infiltrated, if possible, in and around the site, with any remaining solution administered IM in the gluteus.
Adult Dose 20 IU/kg; most or all of solution is infiltrated around the wound; any remaining solution should be administered IM in the gluteus; not to exceed 20 IU/kg
Pediatric Dose Administer as in adults, except inject into anterolateral thigh
Contraindications Documented hypersensitivity; to prevent interference with a maximum active immunity from rabies vaccine, do not administer in repeated doses once rabies vaccine treatment initiated; >20 IU/kg is associated with reduced antibody response to HDCV and should not be used
Interactions Through an antigen-antibody antagonism, RIG may diminish antibody response to MMR vaccine; should administer live virus vaccines 14-30 d before or 6-12 wk after immune globulin administration; antibody response to rabies vaccine may be delayed if administered simultaneously with RIG
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Caution in thrombocytopenia or bleeding disorders; do not administer immunoglobulin and vaccine using same syringe or in same site
Drug Category: Rabies vaccines (United States)
These agents promote immunity by inducing an active immune response.
Advantages of HDCV include freedom from heterologous protein, a high level of immunogenicity that permits a rational dosing schedule, and efficacy demonstrated in trials. The disadvantage of these vaccines is the cost of production.
The CDC only recommends postexposure prophylaxis with IM injections.
The WHO released guidelines for ID use of HDCV, purified chick embryo cell vaccine, and purified duck embryo cell vaccine in 1998.15 In areas where cost and vaccine supply are limiting factors, this may be the most feasible treatment option. IM regimens based on US Food and Drug Administration (FDA) approval and manufacturer's recommendations are included below, with WHO regimens listed as alternatives.
Booster immunization is for individuals at continuous or frequent risk of rabies, who should undergo periodic rabies antibody testing and who have serum rabies titer <1:5>30 d).
The WHO recommends 2 doses of cell-culture vaccine administered intramuscularly or intradermally on days 0 and 3 for booster dosing. A study published in 2001 found that a 4-site intradermal booster regimen had a more rapid NAb response than the series traditionally recommended by the WHO.16 The NAb was also shown to be consistently high 1 year after the booster vaccination.
Nervous-tissue vaccine is commonly used in developing countries and is associated with many neurologic complications, including acute demyelinating encephalomyelitis.
Complications
Regardless of treatment, symptomatic rabies is invariably fatal because autonomic dysfunction leads to cardiac arrhythmia and hypotension.
Prognosis
The prognosis of rabies is fair if postexposure prophylaxis is administered exactly as recommended and in a timely fashion.
Coordination with local health authorities is crucial.
Death is almost certain if rabies treatment is not started before the onset of prodromal symptoms.
Patient Education
The need for adherence to local public health recommendations regarding the control and vaccination of domestic animals and the vaccination of individuals who may be exposed to rabies in their occupation cannot be stressed enough.
Counsel patients regarding the subjective nature of provocative behavior toward animals. Especially stress avoiding contact with unfamiliar or wild animals.
Prompt vigorous cleansing of any injury or bite from any animal is critical and may reduce the risk of rabies transmission.
Provide extensive reassurance after any injury that may be related to rabies transmission. Fear of rabies is primal and is known to induce hysterical reactions that mimic the disease manifestations.
For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Rabies.
Medical/Legal Pitfalls
Failure to administer prophylaxis appropriately to patients at risk for rabies
Failure to involve local public health authorities, which is critical in determining whether an injury requires prophylaxis
Special Concerns
The following are from the American Veterinary Medical Association Compendium of Animal Rabies Prevention and Control, 2004 recommendations for owners of unvaccinated livestock exposed to rabid animals:18
If the animal is slaughtered within 7 days of being bitten, its tissues may be eaten without risk of infection, provided that liberal portions of the exposed area are discarded. US federal meat inspectors must reject for slaughter any animal known to have been exposed to rabies within 8 months.
Neither tissues nor milk from a rabid animal should be used for human or animal consumption. Pasteurization temperatures inactivate the rabies virus; therefore, drinking pasteurized milk or eating cooked meat does not constitute a rabies exposure.
The presence of more than one rabid animal in a herd or herbivore-to-herbivore transmission is uncommon; therefore, isolating the rest of the herd if a single animal has been exposed to or infected by rabies might not be necessary.
Wednesday, January 7, 2009
Sunday, January 4, 2009
DENGUE
Background
Dengue, the most common arboviral illness transmitted worldwide, is caused by infection with 1 of the 4 serotypes of dengue virus. Dengue is transmitted by mosquitoes of the genus Aedes, which are widely distributed in subtropical and tropical areas of the world, and is classified as a major global health threat by the World Health Organization (WHO).
Initial dengue infection may be asymptomatic, may result in a nonspecific febrile illness, or may produce the symptom complex of classic dengue fever (DF). A small percentage of persons who have previously been infected by one dengue serotype develop bleeding and endothelial leak upon infection with another dengue serotype. This syndrome is termed dengue hemorrhagic fever (DHF). Some patients with dengue hemorrhagic fever develop shock (dengue shock syndrome [DSS]), which may cause death.
Dengue virus transmission follows two general patterns—epidemic dengue and hyperendemic dengue. Epidemic dengue transmission occurs when dengue virus is introduced into a region as an isolated event that involves a single viral strain. If the number of vectors and susceptible pediatric and adult hosts is sufficient, explosive transmission can occur, with an infection incidence of 25-50%. Mosquito-control efforts, changes in weather, and herd immunity contribute to the control of these epidemics. This is the current pattern of transmission in parts of Africa and South America, areas of Asia where the virus has reemerged, and small island nations. Travelers to these areas are at increased risk of acquiring dengue during these periods of epidemic transmission.
Hyperendemic dengue transmission is characterized by the continuous circulation of multiple viral serotypes in an area where a large pool of susceptible hosts and a competent vector (with or without seasonal variation) are constantly present. This is the predominant pattern of global transmission. In these populations, antibody prevalence increases with age and most adults are immune. Hyperendemic transmission appears to be a major risk for dengue hemorrhagic fever. Travelers to these areas are more likely to be infected than are travelers to areas that experience only epidemic transmission.
Dengue fever–like illnesses were described in Chinese medical writings dating back to 265 AD. Outbreaks of febrile illnesses compatible with dengue fever have been recorded throughout history. In 1789, Benjamin Rush, MD, published an account of a probable dengue fever epidemic that had occurred in Philadelphia in 1780. Rush coined the term breakbone fever to describe the intense symptoms reported by one of his patients. Probable outbreaks of dengue fever occurred sporadically every 10-30 years until after World War II. The socioeconomic disruptions caused by World War II resulted in increased worldwide spread of dengue viruses.
The first epidemic of dengue hemorrhagic fever was described in Manila in 1953. After that, outbreaks of dengue fever became more common. A pattern developed in which dengue fever epidemics occurred with increasing frequency and were associated with occasional dengue hemorrhagic fever cases. Subsequently, dengue hemorrhagic fever epidemics occurred every few years. Eventually, dengue hemorrhagic fever epidemics occurred yearly, with major outbreaks occurring approximately every 3 years. This pattern has repeated itself as dengue fever has spread to new regions.
Although initial epidemics were located in urban areas, increased dengue spread has involved suburban and rural locales in Asia and Latin America. The only continents that do not experience dengue transmission include Europe and Antarctica. In the 1950s, 9 countries reported dengue outbreaks; today, the geographic distribution includes more than 100 countries worldwide. Several of these countries had not previously reported dengue, and many had not reported dengue in 20 years.
Dengue transmission spread from Southeast Asia into surrounding subtropical and tropical Asian countries, southern China and southern Taiwan, the Indian subcontinent and Sri Lanka, and down the island nations of Malaysia, the Philippines, New Guinea, northeastern Australia, and several Pacific islands, including Tahiti, Palau, Tonga, and the Cook Islands. Nepal has not reported dengue transmission. Hyperendemic transmission is reported in Vietnam, Thailand, Indonesia, Pakistan, India, Malaysia, and the Philippines.
Currently, dengue hemorrhagic fever is one of the leading causes of hospitalization and death in children in many Southeast Asian countries, with Indonesia reporting the majority of dengue hemorrhagic fever cases. Of interest and significance in prevention and control, 3 surveillance studies in Asia report an increasing age among infected patients and increasing mortality rate. Since 1982 in Singapore, more than 50% of deaths have occurred in individuals older than 15 years. In Indonesia, young adults in Jakarta and provincial areas make up a larger percentage of infected patients. During the 2000 epidemic in Bangladesh, up to 82% of hospitalized patients were adults, and all deaths occurred in patients older than 5 years.
The epidemiology of dengue fever in Africa is more poorly characterized. Aedes aegypti is present in a large portion of the Middle East and sub-Saharan Africa. Dengue fever is present in 19 countries on the African continent. In a 1993 epidemic in the Comoros, an estimated 60,000 persons were infected with dengue. Of note, no major dengue hemorrhagic fever epidemics have occurred in Africa, despite the fact that all 4 dengue serotypes circulate in the continent. This may be explained by a genetic factor in these populations.
In the Americas, dengue epidemics were rare postwar because Aedes mosquitoes had been eradicated from most of the region through coordinated vector-control efforts. Systematic spraying was halted in the early 1970s because of environmental concerns. By the 1990s, A aegypti mosquitoes repopulated most of the countries in which they had been eliminated.
The first dengue hemorrhagic fever epidemic in the Americas occurred in Cuba in 1981, with 24,000 cases of dengue hemorrhagic fever, 10,000 cases of dengue shock syndrome, and 158 reported deaths. Since then, dengue fever and dengue hemorrhagic fever cases have progressively increased. A aegypti is abundant year-round in most countries in the Caribbean basin. Significant outbreaks of dengue have been reported in 2005 and 2006 in Puerto Rico, the US Virgin Islands, the Dominican Republic, Barbados, Curacao, Cuba, Guadeloupe, and Martinique.
Aedes albopictus, originally from Asia, is now found in limited areas of Brazil, Bolivia, Colombia, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Cuba, and the Cayman Islands. A aegypti is present in all countries in South America except Chile. Hyperendemic circulation of all 4 dengue serotypes is present in the northern countries of South America. Brazil (700,000 cases in 2002), Colombia, and Venezuela report the most cases of dengue and dengue hemorrhagic fever, with low-level transmission occurring year-round but with most occurring during periods of epidemic transmission.
In 1986, the first clearly identified local transmission of dengue in the United States occurred in Texas. Carriers of the virus were believed to have crossed the border from Mexico; the local vector population was then infected. Since then, seasonal autochthonous infection has been reported in both Texas and Hawaii.
Two competent vectors, A aegypti and A albopictus, are currently seasonally abundant in some areas of the southwestern and southeastern United States, including Texas, Arizona, New Mexico, Louisiana, Mississippi, Alabama, Georgia, and mid to south Florida. A aegypti has also been reported sporadically in portions of North Carolina, South Carolina, Tennessee, Arkansas, Maryland, and New Jersey. The range of A albopictus extends almost as far north as the Great Lakes. Since many cases of dengue in US citizens occur as a result of endemic transmission in some US territories, the Centers for Disease Control and Prevention (CDC) currently conducts laboratory-based surveillance in Puerto Rico.
Dengue fever does not naturally occur in the European Union and in continental Europe because these areas do not have an appropriate vector population to allow further spread of dengue from viremic patients returning from other countries. As such, the disease is not statutorily notifiable in most member states. However, dengue does occur in several overseas territories of European Union members. In recent decades, reports of dengue infections in long-term expatriates, aid workers, military personnel, immigrants, and travelers returning from the tropics and subtropics have been increasing.
Factors believed to be responsible for dengue's spread include explosive population growth, unplanned urban overpopulation with inadequate public health systems, poor standing water and vector control, climate change (increased virus transmission has been associated with El Niño conditions), and increased international recreational, business, and military travel to endemic areas. All of these factors must be addressed to control the spread of dengue and other mosquito-borne infections.
Pathophysiology
Dengue infection is caused by 1 of 4 related, but antigenically distinct, viral serotypes: dengue virus (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3), and dengue virus 4 (DENV-4). Albert Sabin speciated these in 1944. Each serotype is known to have several different genotypes. Dengue viruses are small, spherical, single-stranded enveloped RNA viruses of the family Flaviviridae, genus Flavivirus.
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 all 4 serotypes. Several serotypes can be in circulation during an epidemic.
Dengue viruses are transmitted by the bite of an infected Aedes mosquito. Globally, A aegypti is the predominant highly efficient mosquito vector for dengue infection, but A albopictus and other Aedes species can also transmit dengue with varying degrees of efficiency.
Aedes mosquito species have adapted well to human habitation, often breeding around dwellings in small amounts of stagnant water found in old tires or other small containers discarded by humans. Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite and are easily disturbed during a blood meal, causing them to move on to finish a meal on another individual, making them efficient vectors. Entire families who develop infection within a 24- to 36-hour period, presumably from the bites of a single infected vector, are not unusual.
Humans serve as the primary reservoir for dengue; however, certain nonhuman primates in Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes acquire the virus when they feed on a carrier of the virus. The mosquito can transmit dengue if it immediately bites another host. In addition, transmission occurs after 8-12 days of viral replication in the mosquito's salivary glands (extrinsic incubation period). The mosquito remains infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of dengue virus in mosquitoes has been documented.1 The eggs of Aedes mosquitoes withstand long periods of desiccation, reportedly as long as 1 year, but are killed by temperatures of less than 10°C.
Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 d) while viral replication takes place in target dendritic cells. Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells, result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections. Following incubation, a 5- to 7-day acute febrile illness ensues. Recovery is usually complete by 7-10 days.
Dengue hemorrhagic fever or dengue shock syndrome usually develops around the third to seventh day of illness, approximately at the time of defervescence. The major pathophysiological abnormalities caused by dengue hemorrhagic fever and dengue shock syndrome include plasma leakage and bleeding. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.
In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–alpha, interleukin [IL]–2), similar to that seen with fatal yellow fever and Ebola infections.2
Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior infection with one or more dengue serotypes. In individuals with low levels of neutralizing antibodies, nonneutralizing antibodies to one dengue serotype, when bound by macrophage and monocyte Fc receptors, have been proposed to result in increased viral entry and replication, and increased cytokine production and complement activation. This phenomenon is called antibody-dependent enhancement. In addition, certain dengue strains, particularly those of DEN-2, have been proposed to be more virulent, in part because more epidemics of dengue hemorrhagic fever have been associated with DEN-2 than with the other serotypes.
Frequency
United States
In 1998, 90 confirmed or probable cases of dengue fever were imported into the United States, resulting in one fatality. The current estimate is 100 cases per year; however, the true number of dengue fever cases is believed to be higher because reporting is voluntary, many US physicians are not aware of dengue or its manifestations, and the manifestations are often nonspecific.
In 1999, more than 300 cases of dengue fever were reported from Nuevo Laredo, Tamaulipas, Mexico.3 Nuevo Laredo lies directly across the Rio Grande River from Laredo, Texas. At that time, no dengue cases had been reported in Laredo in more than 12 years. Aedes mosquitoes are present in both cities. The Texas Department of Health reviewed 494 patient records from 5 outpatient sites and was able to confirm 11 cases of dengue fever. Mosquito abatement measures were instituted in Laredo, and health care providers were notified of the dengue fever cases. In the latter half of 1999, Laredo-area health care providers identified 161 suspected dengue fever cases and serologically confirmed 18 cases. This report underscores the need for health care providers to be aware of dengue fever and its manifestations and to test for it in appropriate cases.
International
An estimated 2.5-3 billion people in approximately 110 countries worldwide are at risk for dengue infection. Yearly, approximately 100 million people are infected with dengue, and 250,000 individuals develop dengue hemorrhagic fever. Annually, approximately 24,000 deaths are attributed to dengue worldwide. The Pan American Health Organization (PAHO) member states reported twice as many cases of dengue fever and dengue hemorrhagic fever in 1998 as they did in 1997.
A recent 5-year prospective study in Thai children examined the relative economic burden of dengue infection in children on the local population.4 Most disability-adjusted life years (DALYs) lost to dengue resulted from long-duration illness in children who had not been hospitalized. The infecting serotype appeared to be a determining factor of DALYs lost, with DENV-2 and DENV-3 responsible for 30% and 29%, respectively. The mean cost of illness from dengue was significantly higher than that from other febrile illnesses.
Mortality/Morbidity
Recovery from dengue infection is usually complete. Even patients who meet strict criteria for dengue hemorrhagic fever or dengue shock syndrome usually recover without sequelae.
The fatality rate associated with dengue shock syndrome varies by country from 12-44%. In a 1997 Cuban epidemic, the fatality rate in patients who met criteria for dengue hemorrhagic fever or dengue shock syndrome was approximately 6%. The mortality rate associated with dengue fever is less than 1%.
Data from the 1997 Cuban epidemic suggests that, for every clinically apparent case of dengue fever, 13.9 cases of dengue infection went unrecognized because of absent or minimal symptoms.
Factors that affect disease severity include patient age, nutritional status, ethnicity, the sequence of infection with different dengue serotypes, virus genotype, and the quality and extent of available medical care.
Race
Dengue affects all races. Some African and Haitian data demonstrate a relative dearth of dengue hemorrhagic fever and dengue shock syndrome during dengue fever epidemics, suggesting that these populations may share a genetic advantage to the virus. This merits further study.
Sex
Dengue viruses affect both sexes.
Age
Dengue affects people of all ages. In Southeast Asia, where dengue is hyperendemic, dengue hemorrhagic fever usually affects children younger than 15 years. However, in the Americas, where dengue is becoming progressively hyperendemic, dengue hemorrhagic fever shows no age predilection.
History
Fever in persons with symptomatic dengue fever may be as high as 41°C. The fever typically begins on the third day and lasts 5-7 days, abating with the cessation of viremia. Fever is often preceded by chills, erythematous mottling of the skin, and facial flushing (a sensitive and specific indicator of dengue fever). Occasionally, and more commonly in children, the fever abates for a day and then returns, a pattern that has been called saddleback fever. Patients are at risk for development of dengue hemorrhagic fever or dengue shock syndrome at approximately the time of defervescence. In travelers, symptoms that begin more than 2 weeks after they depart from an endemic area and fever that lasts longer than 10 days are probably not due to dengue.
Headache is usually generalized. Retroorbital pain is common and is often described as severe.
Patients may report nausea and vomiting.
Patients typically describe a maculopapular or macular confluent rash over the face, thorax, and flexor surfaces, with islands of skin sparing. The rash typically begins on day 3 and persists 2-3 days.
Patients may have severe myalgias, particularly of the lower back, arms, and legs, and arthralgias, especially of the knees and shoulders.
Hemorrhagic manifestations may range from small amounts of bleeding from the nose or gums to melena, menorrhagia, or hematemesis.
Abdominal pain is reported; often, abdominal pain in conjunction with restlessness, change in mental status, hypothermia, and a drop in the platelet count presages the development of dengue hemorrhagic fever.
Patients report fatigue and malaise.
Patients may report conjunctival injection, sore throat, and cough.
Cardiomyopathy is reported, with tachycardia during the febrile period and bradycardia and conduction defect. Myocarditis and congestive heart failure are rare.
Physical
Fever is present.
Rash is described as follows:
Up to half of patients with dengue fever develop a characteristic rash.
The rash is variable and may be maculopapular or macular.
Petechiae and purpura may develop as hemorrhagic manifestations.
Conjunctival injection develops in approximately one third of patients with dengue hemorrhagic fever.
Pharyngeal injection develops in almost 97% of patients with dengue hemorrhagic fever.
Generalized lymphadenopathy is observed.
Hepatomegaly is present more often in dengue shock syndrome than in milder cases. Hepatic transaminase levels may be mildly elevated.
Hemorrhagic manifestations include the following
Petechiae and bleeding at venipuncture sites are most common.
Results from a tourniquet test are often positive. This test is performed by inflating a blood pressure cuff on the upper arm to midway between diastolic and systolic blood pressures for 5 minutes. The results are considered positive if more than 20 petechiae per square inch are observed on the skin of the arm.
Other hemorrhagic manifestations include nasal or gingival bleeding, melena, hematemesis, and menorrhagia.
Dengue fever presents in a nonspecific manner and may not be distinguishable from other viral or bacterial illness. The PAHO has developed the following case definitions for the diagnosis of dengue fever and dengue hemorrhagic fever or dengue shock syndrome:
The clinical description of dengue fever is an acute febrile illness of 2-7 days duration associated with 2 or more of the following:
Severe headache
Retroorbital pain
Severe myalgias
Arthralgia
Characteristic rash
Hemorrhagic manifestations
Leukopenia
Laboratory criteria for diagnosis include one or more of the following:
Isolation of the dengue virus from serum, plasma, leukocytes, or autopsy samples
Demonstration of a 4-fold or greater change in reciprocal immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody titers to one or more dengue virus antigens in paired serum samples
Demonstration of dengue virus antigen in autopsy tissue via immunohistochemistry or immunofluorescence or in serum samples via enzyme immunoassay (EIA)
Detection of viral genomic sequences in autopsy tissue, serum, or cerebral spinal fluid (CSF) samples via polymerase chain reaction (PCR)
Cases are classified as suspected if they are compatible with the clinical description.
Cases are classified as probable if they are compatible with the clinical definition and satisfy one or more of the following criteria:
Supportive serology (reciprocal hemagglutination-inhibition antibody titer greater than 1280, comparable IgG EIA titers, or positive IgM antibody test in late acute or convalescent-phase serum specimen)
Occurrence at the same location and time as other confirmed cases of dengue fever
A confirmed case is one that is compatible with the clinical definition and is confirmed by the laboratory.
Criteria for the diagnosis of dengue hemorrhagic fever include a probable or confirmed case of dengue infection and hemorrhagic tendencies as evidenced by one or more of the following:
A positive result from the tourniquet test
Petechiae, ecchymoses, or purpura
Bleeding from the mucosa, gastrointestinal tract, injection sites, or other sites
Hematemesis or melena and thrombocytopenia (<100,000 cells/μL) and evidence of plasma leakage due to increased vascular permeability that manifests as one or more of the following: greater than 20% rise in average hematocrit level for age and sex, greater than 20% drop in hematocrit level following volume replacement compared to baseline, or signs of plasma leakage (eg, pleural effusion, ascites, hypoproteinemia)
Dengue shock syndrome is diagnosed in cases meeting all of the above criteria plus evidence of circulatory failure, such as the following:
Rapid, weak pulse
Narrow pulse pressure (<20 mm Hg)
Hypotension
Cool, clammy skin
Altered mental status
The WHO classification system was recently studied in Indonesian children and was found to have a sensitivity of 86% (95% CI, 76-94) for the detection of dengue shock syndrome.5 The clinical reliability of the WHO criteria was compared with those of several modified systems, which added the above early predictors of compensated shock and considered models using varying combinations of evidence of hemorrhagic tendencies, thrombocytopenia, and hemoconcentration. These modified systems were found to yield higher sensitivities (88-99%) for dengue diagnosis than the WHO classification system and were more in line with clinical determinations made by local expert physicians.
A recent Belgian study examined predictors of diagnosis in 1962 febrile travelers and expatriates returning from the tropics. After malaria was ruled out, the main predictors of dengue infection included skin rash, thrombocytopenia, and leukopenia.
Causes
Dengue infection is caused by 1 of the 4 dengue viruses (ie, DENV-1, DENV-2, DENV-3, DENV-4) and is transmitted to humans by the bite of an infected mosquito.
Lab Studies
Complete blood cell count findings include the following:
Leukopenia, often with lymphopenia, is observed near the end of the febrile phase of illness. Lymphocytosis, with atypical lymphocytes, commonly develops before defervescence or shock.
A hematocrit level rise of greater than 20% is a sign of hemoconcentration and precedes shock. The hematocrit level should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever and every 3-4 hours in severe cases of dengue hemorrhagic fever or dengue shock syndrome.
Thrombocytopenia has been demonstrated in up to 50% of dengue fever cases. Platelet counts of less than 100,000 cells/μL are seen in dengue hemorrhagic fever or dengue shock syndrome and occur before defervescence and the onset of shock. The platelet count should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever.
Basic metabolic panel findings include the following:
Hyponatremia is the most common electrolyte abnormality in patients with dengue hemorrhagic fever or dengue shock syndrome.
Metabolic acidosis is observed in those with shock and must be corrected rapidly.
Elevated BUN levels are observed in those with shock.
Liver function test findings include the following:
Transaminase levels may be mildly elevated.
Low albumin levels are a sign of hemoconcentration.
Coagulation studies may help to guide therapy in patients with severe hemorrhagic manifestations. Findings are as follows:
Prothrombin time is prolonged.
Activated partial thromboplastin time is prolonged.
Low fibrinogen and elevated fibrin degradation product levels are signs of disseminated intravascular coagulation.
Typing and crossmatching of blood should be performed in cases of severe dengue hemorrhagic fever or dengue shock syndrome because blood products may be required.
Serum specimens should be sent to the laboratory for serodiagnosis, PCR, and viral isolation. Because the signs and symptoms of dengue fever are nonspecific, attempting laboratory confirmation of dengue infection is important. Serodiagnosis is made based on a rise in antibody titer in paired IgG or IgM specimens. Results vary depending on whether the infection is primary or subsequent. The IgM capture enzyme-linked immunosorbent assay (MAC-ELISA) has become the most widely used assay, although other tests, including complement fixation (CF), neutralization test (NT), hemagglutination inhibition (HI), and IgG ELISA are also used. A recent European study found that, if only a single serum sample is available, a single positive result on ELISA (PanBio IgM or IgG) was found to have a high rate of false positivity and should be confirmed using a second more specific diagnostic technique.7
Cultures of blood, urine, CSF, and other body fluids should be performed as necessary to exclude or confirm other potential causes of the patients' condition.
Imaging Studies
Chest radiography: Right-sided pleural effusion is typical. Bilateral pleural effusions are common in patients with dengue shock syndrome.
Serial ultrasonography
Ultrasonography has often been suggested as a potentially timely, cost-effective, and easily used modality in the evaluation of potential dengue hemorrhagic fever. Positive sonogram findings include fluid in the chest and abdominal cavities, pericardial effusion, and a thickened gallbladder wall.
The utility of previous studies was limited because of the use of single studies for evaluation. However, a recent study involving 158 patients examined the role of daily serial ultrasonographic examinations of the thorax and abdomen in the evaluation of patients with suspected dengue hemorrhagic fever.8 Plasma leakage was detected in some patients within 3 days of fever onset. Pleural effusion was the most common sign. Based on ultrasonographic findings, dengue hemorrhagic fever was predicted in 12 patients before hemoconcentration criteria had been met.
Other Tests
Arterial blood gas should be assessed in patients with severe cases to assess pH, oxygenation, and ventilation.
Procedures
Large-bore intravenous catheter - For fluid administration
Central venous catheter
For fluid administration
For central venous pressure measurement
Arterial catheter
For continuous blood pressure measurement
For serial arterial blood gas measurement
Urethral catheterization - May be useful to strictly monitor urine output
Medical Care
Dengue fever is usually a self-limited illness, and only supportive care is required. Acetaminophen may be used to treat patients with symptomatic fever. Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids should be avoided.
Patients with known or suspected dengue fever should have their platelet count and hematocrit measured daily from the third day of illness until 1-2 days after defervescence. Patients with a rising hematocrit level or falling platelet count should have intravascular volume deficits replaced. Patients who improve can continue to be monitored in an outpatient setting. Patients who do not improve should be admitted to the hospital for continued hydration.
Patients who develop signs of dengue hemorrhagic fever warrant closer observation. Patients who develop signs of dehydration, such as tachycardia, prolonged capillary refill time, cool or mottled skin, diminished pulse amplitude, altered mental status, decreased urine output, rise in hematocrit levels, narrowed pulse pressure, or hypotension, require admission for intravenous fluid administration.
Intravascular volume deficits should be corrected with isotonic fluids such as Ringer lactate solution. Boluses of 10-20 mL/kg should be given over 20 minutes and may be repeated. If this fails to correct the deficit, the hematocrit value should be determined, and, if it is rising, limited clinical information suggests that a plasma expander may be administered. Starch, dextran 40, or albumin 5% at a dose of 10-20 mL/kg may be used. One recent study has suggested that starch may be preferable because of hypersensitivity reactions to dextran.9 If the patient does not improve after this, blood loss should be considered. Patients with internal or gastrointestinal bleeding may require transfusion. Patients with coagulopathy may require fresh frozen plasma.
After patients with dehydration are stabilized, they usually require intravenous fluids for no more than 24-48 hours. Intravenous fluids should be stopped when the hematocrit level falls below 40% and adequate intravascular volume is present. At this time, patients reabsorb extravasated fluid and are at risk for volume overload if intravenous fluids are continued. Do not interpret a falling hematocrit value in a clinically improving patient as a sign of internal bleeding.
Patients who are resuscitated from shock rapidly recover. Patients with dengue hemorrhagic fever or dengue shock syndrome may be discharged from the hospital when they meet the following criteria:
Afebrile for 24 hours without antipyretics
Good appetite, clinically improved condition
Adequate urine output
Stable hematocrit level
At least 48 hours since recovery from shock
Absence of respiratory distress
Platelet count greater than 50,000 cells/μL
Surgical Care
No specific surgical intervention is necessary in patients with dengue fever, dengue hemorrhagic fever, or dengue shock syndrome.
Consultations
Consultation with an infectious diseases specialist may be helpful in guiding decisions regarding diagnosis and treatment.
Consultation with a critical care medicine specialist may be helpful when treating patients with dengue hemorrhagic fever or dengue shock syndrome and severe hemorrhagic manifestations or shock.
Diet
No specific diet is necessary for patients with dengue fever.
Patients may become dehydrated from fever, lack of oral intake, or vomiting. Patients who are able to tolerate oral fluids should be encouraged to drink oral rehydration solution, fruit juice, or water to prevent dehydration.
Return of appetite after dengue hemorrhagic fever or dengue shock syndrome is a sign of recovery.
Activity
Bedrest is recommended for patients with symptomatic dengue fever, dengue hemorrhagic fever, or dengue shock syndrome.
MEDICATION
No specific antiviral medication currently is available to treat dengue infections. Single-dose methylprednisolone showed no mortality benefit in the treatment of dengue shock syndrome (dengue shock syndrome) in a prospective, randomized, double-blind, placebo-controlled trial.10
Acetaminophen (paracetamol) is recommended for treatment of pain and fever. Aspirin, other salicylates, and NSAIDs should be avoided.
Drug Category: Analgesics/antipyretics
The treatment of dengue fever is symptomatic and supportive in nature. Bedrest and mild analgesic-antipyretic therapy are often helpful in relieving lethargy, malaise, and fever associated with the disease.
Drug Name Acetaminophen (Tylenol, Feverall)
Description Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating. Used in dengue infections to relieve pain and lower temperature when fever is thought to contribute to patient discomfort.
Adult Dose 325-650 mg PO/PR q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric Dose 15 mg/kg PO/PR q4h prn; not to exceed 2.6 g/d
Contraindications Documented hypersensitivity
Interactions Rifampin can reduce analgesic effects; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity; chronic use may potentiate effects of warfarin
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Hepatotoxicity possible in those with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; APAP is contained in many OTC products, and combined use with these products may result in cumulative APAP doses that exceed recommended maximum dose
Drug Category: Volume expanders
Plasma volume expanders are used in the treatment of intravascular volume deficits or shock to restore intravascular volume, blood pressure, and tissue perfusion.
Drug Name Lactated ringers with isotonic sodium chloride solution
Description Used to expand intravascular volume. Both fluids are essentially isotonic and have equivalent volume restorative properties. Although administration of large quantities of either fluid may lead to some differences in metabolic changes, for practical purposes and in most situations, these differences are clinically irrelevant. Importantly, no demonstrable difference in hemodynamic effect, morbidity, or mortality exists between resuscitation using either product.
Adult Dose 10-20 mL/kg IV initially administered rapidly, over 20 min; followed by reassessment of hemodynamic response; repeat prn
Pediatric Dose Administer as in adults
Contraindications Pulmonary edema (may lead to the development of ARDS)
Interactions None reported
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in CHF; caution admixing other agents (monitor for incompatibilities)
Drug Name Dextran 40 (Macrodex, LMD)
Description Polymer of glucose. When infused, it increases intravascular volume, blood pressure, and capillary perfusion. Used to restore intravascular volume when isotonic crystalloid use fails.
Adult Dose Variable; not to exceed 20 mL/kg IV on d 1 or 10 mL/kg thereafter
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; pulmonary edema
Interactions Caution when administering parenteral fluids to patients receiving corticosteroids or corticotropin, especially if the solution contains sodium ions; can interfere with blood cross-matching and measuring serum glucose and bilirubin levels (draw blood for laboratory testing prior to administration)
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions May cause nausea, which also may occur with hypoglycemia; IV dextrose solutions may result in dilution of serum electrolyte concentrations or overhydration in the setting of fluid overload; caution in patients experiencing congested states or pulmonary edema; hypertonic dextrose given peripherally may cause thrombosis (administer instead through central venous catheter); caution in subclinical diabetes mellitus or carbohydrate intolerance
Increased risk of inducing significant hyperglycemia or hyperosmolar syndrome if solution is administered rapidly, especially in patients with chronic uremia or carbohydrate intolerance; concentrated solutions should not be administered SC or IM; rates of dextrose infusion faster than 0.5 g/kg/h may produce glycosuria; at infusion rates of 0.8 g/kg/h, the incidence of glycosuria is 5%; closely monitor fluid balance, electrolyte concentrations, and acid-base balance; dextrose administration may produce vitamin B complex deficiency
Drug Name Albumin (Albuminar-5, Buminate)
Description Human albumin is a sterile solution of albumin (major plasma protein responsible for colloid oncotic pressure of blood). Pooled from blood, serum, plasma, or placenta from healthy donors. Infusion of albumin results in a shift of fluid from extracellular space into circulation, thereby decreasing hemoconcentration and blood viscosity.
May be administered wide open when treating shock. Patient response must be assessed before repeating dose.
Adult Dose 25 g IV; not to exceed 250 g/48 h
Pediatric Dose <37 weeks' gestation: 1 g/kg IV
Infants and children: 25-50% of adult dose IV
Contraindications Documented hypersensitivity; pulmonary edema; protein load of 5% albumin
Interactions None reported
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in poor left ventricular systolic function (monitor central venous pressure during infusion)
Drug Name Starch (hetastarch, 6% hydroxyethyl starch)
Description Hydroxyethyl starch is a sterile solution of starch responsible for colloid oncotic pressure of blood.
Infusion of albumin results in a shift of fluid from extracellular space into circulation, thereby decreasing hemoconcentration and blood viscosity.
Adult Dose May be administered in 6% solution, 15 mL/kg IV over 1 h; patient response must be assessed and then an additional dose of 10 mL/kg IV over 1 h may be administered
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in poor left ventricular systolic function (monitor central venous pressure during infusion)
Further Inpatient Care
Report known or suspected cases of dengue fever, dengue hemorrhagic fever, or dengue shock syndrome to public-health authorities. Such reports should include patient demographics, case classification, date of onset of illness, whether or not hospitalization was necessary, outcome, and recent travel history. When multiple patients are involved, reports should include the number of cases of dengue fever and dengue hemorrhagic fever/dengue shock syndrome stratified by age, number of confirmed cases and serotypes, and number of hospitalizations and deaths.
Draw serum specimens for diagnosis as soon as possible after the onset of illness or hospitalization and at the time of death or discharge from the hospital. Immediately place specimens on wet ice and send to the laboratory.
Evaluate and treat patients appropriately for other possible conditions until the diagnosis of dengue fever or dengue hemorrhagic fever/dengue shock syndrome is established.
Further Outpatient Care
Draw a serum specimen 7-21 days after the acute-phase serum specimen was drawn. Ideally, draw the convalescent-phase serum specimen 10 days after the acute-phase specimen. Immediately place the specimen on wet ice and send it to the laboratory.
In/Out Patient Meds
No specific medications are needed for patients with dengue fever or dengue hemorrhagic fever/dengue shock syndrome. In general, patients should continue to take any medications necessary for the treatment of other medical conditions. However, use diuretics, aspirin, NSAIDs, and antihypertensives with caution in patients with dengue hemorrhagic fever because these medications may exacerbate the pathophysiologic derangement associated with dengue hemorrhagic fever. Review the risks and benefits of each medication and decide on an individuals basis whether the medication should be continued.
The differential diagnoses of dengue fever and dengue hemorrhagic fever/dengue shock syndrome include many conditions that are treatable with specific medications, such as antibiotics. Until such conditions are excluded, they should be treated.
Transfer
Transfer patients with dengue fever or dengue hemorrhagic fever/dengue shock syndrome when necessary monitoring and treatment cannot be provided in the current unit or facility. Treat patients with dengue shock syndrome in intensive/critical care units.
Deterrence/Prevention
No vaccine is available for the prevention of dengue infection. Immunogenic, safe tetravalent vaccines have been developed and are undergoing clinical trials. Because immunity to a single dengue strain is the major risk factor for dengue hemorrhagic fever and dengue shock syndrome, a vaccine must provide high levels of immunity to all 4 dengue strains to be clinically useful.
The only way to prevent dengue virus acquisition is to avoid being bitten by a vector mosquito. This can be accomplished in several ways, as follows:
Avoid travel to areas where dengue is endemic. This is not an ideal strategy because it would require a person to avoid most tropical and subtropical regions of the world, and many of these regions are popular travel and work destinations.
Wear N,N-diethyl-3-methylbenzamide (DEET)–containing mosquito repellant.
Wear protective clothing, preferably impregnated with permethrin insecticide.
Remain in well-screened or air-conditioned places.
The use of mosquito netting is of limited benefit, as Aedes are day-biting mosquitoes.
Eliminate the mosquito vector using indoor sprays.
Eliminate the breeding ground of the mosquitoes by not allowing them access to small accumulations of stagnant water around human habitats. Such accumulations can be found in pots, old tires, or any vessel capable of holding water.
Support community-based vector control programs.
Complications
Neurologic manifestations such as seizures and encephalitis/encephalopathy have been reported in rare cases of dengue infection. Some of these cases did not manifest other typical features of dengue infection. Other neurological complications associated with dengue infection include neuropathies, Guillain-Barré syndrome, and transverse myelitis.
Liver failure has been associated with dengue hemorrhagic fever/dengue shock syndrome epidemics. Whether this is a viral effect or a product of prolonged liver hypoperfusion remains unclear.
Overhydration is a well-recognized complication of dengue fever and dengue hemorrhagic fever/dengue shock syndrome.
Dengue must be carefully differentiated from pre-eclampsia during pregnancy. An overlap of symptoms and signs, including thrombocytopenia, impaired liver function, capillary leak, ascites, and decreased urine output may make this clinically challenging. Definitive diagnosis is confirmed via serology. Pregnant women with dengue fever respond well to the usual therapy of fluids, rest, and antipyretics. If the mother acquires infection in the peripartum period, newborns should be evaluated for dengue with platelet counts and serologic studies.
Prognosis
The prognosis of patients with dengue fever is excellent, with complete recovery being the norm. Patients with dengue hemorrhagic fever or dengue shock syndrome who do not die usually recover without sequelae.
Patient Education
Educate patients, especially those who have experienced prior dengue fever, to avoid mosquito bites when traveling to dengue-endemic areas. Current evidence suggests that those with a history of dengue fever are at highest risk for dengue hemorrhagic fever or dengue shock syndrome if they are infected with a different dengue strain.
Medical/Legal Pitfalls
Failure to suspect dengue infection in febrile patients with a history of travel to dengue endemic areas within 2 weeks of the onset of illness
Failure to suspect, identify, and treat other possible diseases such as meningitis or malaria
Failure to admit patients with signs and symptoms of intravascular volume loss for intravenous hydration
Failure to administer appropriate fluids to patients with dengue hemorrhagic fever or dengue shock syndrome
Failure to notify public health authorities about suspected cases of dengue infection
Special Concerns
Older patients, particularly those with congestive heart failure, must not be given excessive amounts of intravenous fluids.
Rare cases of vertical dengue transmission have been reported. Dengue should be suspected in pregnant patients with compatible clinical features. The potential for a neonate to be born with signs and symptoms of dengue fever should be anticipated.
Dengue, the most common arboviral illness transmitted worldwide, is caused by infection with 1 of the 4 serotypes of dengue virus. Dengue is transmitted by mosquitoes of the genus Aedes, which are widely distributed in subtropical and tropical areas of the world, and is classified as a major global health threat by the World Health Organization (WHO).
Initial dengue infection may be asymptomatic, may result in a nonspecific febrile illness, or may produce the symptom complex of classic dengue fever (DF). A small percentage of persons who have previously been infected by one dengue serotype develop bleeding and endothelial leak upon infection with another dengue serotype. This syndrome is termed dengue hemorrhagic fever (DHF). Some patients with dengue hemorrhagic fever develop shock (dengue shock syndrome [DSS]), which may cause death.
Dengue virus transmission follows two general patterns—epidemic dengue and hyperendemic dengue. Epidemic dengue transmission occurs when dengue virus is introduced into a region as an isolated event that involves a single viral strain. If the number of vectors and susceptible pediatric and adult hosts is sufficient, explosive transmission can occur, with an infection incidence of 25-50%. Mosquito-control efforts, changes in weather, and herd immunity contribute to the control of these epidemics. This is the current pattern of transmission in parts of Africa and South America, areas of Asia where the virus has reemerged, and small island nations. Travelers to these areas are at increased risk of acquiring dengue during these periods of epidemic transmission.
Hyperendemic dengue transmission is characterized by the continuous circulation of multiple viral serotypes in an area where a large pool of susceptible hosts and a competent vector (with or without seasonal variation) are constantly present. This is the predominant pattern of global transmission. In these populations, antibody prevalence increases with age and most adults are immune. Hyperendemic transmission appears to be a major risk for dengue hemorrhagic fever. Travelers to these areas are more likely to be infected than are travelers to areas that experience only epidemic transmission.
Dengue fever–like illnesses were described in Chinese medical writings dating back to 265 AD. Outbreaks of febrile illnesses compatible with dengue fever have been recorded throughout history. In 1789, Benjamin Rush, MD, published an account of a probable dengue fever epidemic that had occurred in Philadelphia in 1780. Rush coined the term breakbone fever to describe the intense symptoms reported by one of his patients. Probable outbreaks of dengue fever occurred sporadically every 10-30 years until after World War II. The socioeconomic disruptions caused by World War II resulted in increased worldwide spread of dengue viruses.
The first epidemic of dengue hemorrhagic fever was described in Manila in 1953. After that, outbreaks of dengue fever became more common. A pattern developed in which dengue fever epidemics occurred with increasing frequency and were associated with occasional dengue hemorrhagic fever cases. Subsequently, dengue hemorrhagic fever epidemics occurred every few years. Eventually, dengue hemorrhagic fever epidemics occurred yearly, with major outbreaks occurring approximately every 3 years. This pattern has repeated itself as dengue fever has spread to new regions.
Although initial epidemics were located in urban areas, increased dengue spread has involved suburban and rural locales in Asia and Latin America. The only continents that do not experience dengue transmission include Europe and Antarctica. In the 1950s, 9 countries reported dengue outbreaks; today, the geographic distribution includes more than 100 countries worldwide. Several of these countries had not previously reported dengue, and many had not reported dengue in 20 years.
Dengue transmission spread from Southeast Asia into surrounding subtropical and tropical Asian countries, southern China and southern Taiwan, the Indian subcontinent and Sri Lanka, and down the island nations of Malaysia, the Philippines, New Guinea, northeastern Australia, and several Pacific islands, including Tahiti, Palau, Tonga, and the Cook Islands. Nepal has not reported dengue transmission. Hyperendemic transmission is reported in Vietnam, Thailand, Indonesia, Pakistan, India, Malaysia, and the Philippines.
Currently, dengue hemorrhagic fever is one of the leading causes of hospitalization and death in children in many Southeast Asian countries, with Indonesia reporting the majority of dengue hemorrhagic fever cases. Of interest and significance in prevention and control, 3 surveillance studies in Asia report an increasing age among infected patients and increasing mortality rate. Since 1982 in Singapore, more than 50% of deaths have occurred in individuals older than 15 years. In Indonesia, young adults in Jakarta and provincial areas make up a larger percentage of infected patients. During the 2000 epidemic in Bangladesh, up to 82% of hospitalized patients were adults, and all deaths occurred in patients older than 5 years.
The epidemiology of dengue fever in Africa is more poorly characterized. Aedes aegypti is present in a large portion of the Middle East and sub-Saharan Africa. Dengue fever is present in 19 countries on the African continent. In a 1993 epidemic in the Comoros, an estimated 60,000 persons were infected with dengue. Of note, no major dengue hemorrhagic fever epidemics have occurred in Africa, despite the fact that all 4 dengue serotypes circulate in the continent. This may be explained by a genetic factor in these populations.
In the Americas, dengue epidemics were rare postwar because Aedes mosquitoes had been eradicated from most of the region through coordinated vector-control efforts. Systematic spraying was halted in the early 1970s because of environmental concerns. By the 1990s, A aegypti mosquitoes repopulated most of the countries in which they had been eliminated.
The first dengue hemorrhagic fever epidemic in the Americas occurred in Cuba in 1981, with 24,000 cases of dengue hemorrhagic fever, 10,000 cases of dengue shock syndrome, and 158 reported deaths. Since then, dengue fever and dengue hemorrhagic fever cases have progressively increased. A aegypti is abundant year-round in most countries in the Caribbean basin. Significant outbreaks of dengue have been reported in 2005 and 2006 in Puerto Rico, the US Virgin Islands, the Dominican Republic, Barbados, Curacao, Cuba, Guadeloupe, and Martinique.
Aedes albopictus, originally from Asia, is now found in limited areas of Brazil, Bolivia, Colombia, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Cuba, and the Cayman Islands. A aegypti is present in all countries in South America except Chile. Hyperendemic circulation of all 4 dengue serotypes is present in the northern countries of South America. Brazil (700,000 cases in 2002), Colombia, and Venezuela report the most cases of dengue and dengue hemorrhagic fever, with low-level transmission occurring year-round but with most occurring during periods of epidemic transmission.
In 1986, the first clearly identified local transmission of dengue in the United States occurred in Texas. Carriers of the virus were believed to have crossed the border from Mexico; the local vector population was then infected. Since then, seasonal autochthonous infection has been reported in both Texas and Hawaii.
Two competent vectors, A aegypti and A albopictus, are currently seasonally abundant in some areas of the southwestern and southeastern United States, including Texas, Arizona, New Mexico, Louisiana, Mississippi, Alabama, Georgia, and mid to south Florida. A aegypti has also been reported sporadically in portions of North Carolina, South Carolina, Tennessee, Arkansas, Maryland, and New Jersey. The range of A albopictus extends almost as far north as the Great Lakes. Since many cases of dengue in US citizens occur as a result of endemic transmission in some US territories, the Centers for Disease Control and Prevention (CDC) currently conducts laboratory-based surveillance in Puerto Rico.
Dengue fever does not naturally occur in the European Union and in continental Europe because these areas do not have an appropriate vector population to allow further spread of dengue from viremic patients returning from other countries. As such, the disease is not statutorily notifiable in most member states. However, dengue does occur in several overseas territories of European Union members. In recent decades, reports of dengue infections in long-term expatriates, aid workers, military personnel, immigrants, and travelers returning from the tropics and subtropics have been increasing.
Factors believed to be responsible for dengue's spread include explosive population growth, unplanned urban overpopulation with inadequate public health systems, poor standing water and vector control, climate change (increased virus transmission has been associated with El Niño conditions), and increased international recreational, business, and military travel to endemic areas. All of these factors must be addressed to control the spread of dengue and other mosquito-borne infections.
Pathophysiology
Dengue infection is caused by 1 of 4 related, but antigenically distinct, viral serotypes: dengue virus (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3), and dengue virus 4 (DENV-4). Albert Sabin speciated these in 1944. Each serotype is known to have several different genotypes. Dengue viruses are small, spherical, single-stranded enveloped RNA viruses of the family Flaviviridae, genus Flavivirus.
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 all 4 serotypes. Several serotypes can be in circulation during an epidemic.
Dengue viruses are transmitted by the bite of an infected Aedes mosquito. Globally, A aegypti is the predominant highly efficient mosquito vector for dengue infection, but A albopictus and other Aedes species can also transmit dengue with varying degrees of efficiency.
Aedes mosquito species have adapted well to human habitation, often breeding around dwellings in small amounts of stagnant water found in old tires or other small containers discarded by humans. Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite and are easily disturbed during a blood meal, causing them to move on to finish a meal on another individual, making them efficient vectors. Entire families who develop infection within a 24- to 36-hour period, presumably from the bites of a single infected vector, are not unusual.
Humans serve as the primary reservoir for dengue; however, certain nonhuman primates in Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes acquire the virus when they feed on a carrier of the virus. The mosquito can transmit dengue if it immediately bites another host. In addition, transmission occurs after 8-12 days of viral replication in the mosquito's salivary glands (extrinsic incubation period). The mosquito remains infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of dengue virus in mosquitoes has been documented.1 The eggs of Aedes mosquitoes withstand long periods of desiccation, reportedly as long as 1 year, but are killed by temperatures of less than 10°C.
Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 d) while viral replication takes place in target dendritic cells. Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells, result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections. Following incubation, a 5- to 7-day acute febrile illness ensues. Recovery is usually complete by 7-10 days.
Dengue hemorrhagic fever or dengue shock syndrome usually develops around the third to seventh day of illness, approximately at the time of defervescence. The major pathophysiological abnormalities caused by dengue hemorrhagic fever and dengue shock syndrome include plasma leakage and bleeding. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.
In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–alpha, interleukin [IL]–2), similar to that seen with fatal yellow fever and Ebola infections.2
Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior infection with one or more dengue serotypes. In individuals with low levels of neutralizing antibodies, nonneutralizing antibodies to one dengue serotype, when bound by macrophage and monocyte Fc receptors, have been proposed to result in increased viral entry and replication, and increased cytokine production and complement activation. This phenomenon is called antibody-dependent enhancement. In addition, certain dengue strains, particularly those of DEN-2, have been proposed to be more virulent, in part because more epidemics of dengue hemorrhagic fever have been associated with DEN-2 than with the other serotypes.
Frequency
United States
In 1998, 90 confirmed or probable cases of dengue fever were imported into the United States, resulting in one fatality. The current estimate is 100 cases per year; however, the true number of dengue fever cases is believed to be higher because reporting is voluntary, many US physicians are not aware of dengue or its manifestations, and the manifestations are often nonspecific.
In 1999, more than 300 cases of dengue fever were reported from Nuevo Laredo, Tamaulipas, Mexico.3 Nuevo Laredo lies directly across the Rio Grande River from Laredo, Texas. At that time, no dengue cases had been reported in Laredo in more than 12 years. Aedes mosquitoes are present in both cities. The Texas Department of Health reviewed 494 patient records from 5 outpatient sites and was able to confirm 11 cases of dengue fever. Mosquito abatement measures were instituted in Laredo, and health care providers were notified of the dengue fever cases. In the latter half of 1999, Laredo-area health care providers identified 161 suspected dengue fever cases and serologically confirmed 18 cases. This report underscores the need for health care providers to be aware of dengue fever and its manifestations and to test for it in appropriate cases.
International
An estimated 2.5-3 billion people in approximately 110 countries worldwide are at risk for dengue infection. Yearly, approximately 100 million people are infected with dengue, and 250,000 individuals develop dengue hemorrhagic fever. Annually, approximately 24,000 deaths are attributed to dengue worldwide. The Pan American Health Organization (PAHO) member states reported twice as many cases of dengue fever and dengue hemorrhagic fever in 1998 as they did in 1997.
A recent 5-year prospective study in Thai children examined the relative economic burden of dengue infection in children on the local population.4 Most disability-adjusted life years (DALYs) lost to dengue resulted from long-duration illness in children who had not been hospitalized. The infecting serotype appeared to be a determining factor of DALYs lost, with DENV-2 and DENV-3 responsible for 30% and 29%, respectively. The mean cost of illness from dengue was significantly higher than that from other febrile illnesses.
Mortality/Morbidity
Recovery from dengue infection is usually complete. Even patients who meet strict criteria for dengue hemorrhagic fever or dengue shock syndrome usually recover without sequelae.
The fatality rate associated with dengue shock syndrome varies by country from 12-44%. In a 1997 Cuban epidemic, the fatality rate in patients who met criteria for dengue hemorrhagic fever or dengue shock syndrome was approximately 6%. The mortality rate associated with dengue fever is less than 1%.
Data from the 1997 Cuban epidemic suggests that, for every clinically apparent case of dengue fever, 13.9 cases of dengue infection went unrecognized because of absent or minimal symptoms.
Factors that affect disease severity include patient age, nutritional status, ethnicity, the sequence of infection with different dengue serotypes, virus genotype, and the quality and extent of available medical care.
Race
Dengue affects all races. Some African and Haitian data demonstrate a relative dearth of dengue hemorrhagic fever and dengue shock syndrome during dengue fever epidemics, suggesting that these populations may share a genetic advantage to the virus. This merits further study.
Sex
Dengue viruses affect both sexes.
Age
Dengue affects people of all ages. In Southeast Asia, where dengue is hyperendemic, dengue hemorrhagic fever usually affects children younger than 15 years. However, in the Americas, where dengue is becoming progressively hyperendemic, dengue hemorrhagic fever shows no age predilection.
History
Fever in persons with symptomatic dengue fever may be as high as 41°C. The fever typically begins on the third day and lasts 5-7 days, abating with the cessation of viremia. Fever is often preceded by chills, erythematous mottling of the skin, and facial flushing (a sensitive and specific indicator of dengue fever). Occasionally, and more commonly in children, the fever abates for a day and then returns, a pattern that has been called saddleback fever. Patients are at risk for development of dengue hemorrhagic fever or dengue shock syndrome at approximately the time of defervescence. In travelers, symptoms that begin more than 2 weeks after they depart from an endemic area and fever that lasts longer than 10 days are probably not due to dengue.
Headache is usually generalized. Retroorbital pain is common and is often described as severe.
Patients may report nausea and vomiting.
Patients typically describe a maculopapular or macular confluent rash over the face, thorax, and flexor surfaces, with islands of skin sparing. The rash typically begins on day 3 and persists 2-3 days.
Patients may have severe myalgias, particularly of the lower back, arms, and legs, and arthralgias, especially of the knees and shoulders.
Hemorrhagic manifestations may range from small amounts of bleeding from the nose or gums to melena, menorrhagia, or hematemesis.
Abdominal pain is reported; often, abdominal pain in conjunction with restlessness, change in mental status, hypothermia, and a drop in the platelet count presages the development of dengue hemorrhagic fever.
Patients report fatigue and malaise.
Patients may report conjunctival injection, sore throat, and cough.
Cardiomyopathy is reported, with tachycardia during the febrile period and bradycardia and conduction defect. Myocarditis and congestive heart failure are rare.
Physical
Fever is present.
Rash is described as follows:
Up to half of patients with dengue fever develop a characteristic rash.
The rash is variable and may be maculopapular or macular.
Petechiae and purpura may develop as hemorrhagic manifestations.
Conjunctival injection develops in approximately one third of patients with dengue hemorrhagic fever.
Pharyngeal injection develops in almost 97% of patients with dengue hemorrhagic fever.
Generalized lymphadenopathy is observed.
Hepatomegaly is present more often in dengue shock syndrome than in milder cases. Hepatic transaminase levels may be mildly elevated.
Hemorrhagic manifestations include the following
Petechiae and bleeding at venipuncture sites are most common.
Results from a tourniquet test are often positive. This test is performed by inflating a blood pressure cuff on the upper arm to midway between diastolic and systolic blood pressures for 5 minutes. The results are considered positive if more than 20 petechiae per square inch are observed on the skin of the arm.
Other hemorrhagic manifestations include nasal or gingival bleeding, melena, hematemesis, and menorrhagia.
Dengue fever presents in a nonspecific manner and may not be distinguishable from other viral or bacterial illness. The PAHO has developed the following case definitions for the diagnosis of dengue fever and dengue hemorrhagic fever or dengue shock syndrome:
The clinical description of dengue fever is an acute febrile illness of 2-7 days duration associated with 2 or more of the following:
Severe headache
Retroorbital pain
Severe myalgias
Arthralgia
Characteristic rash
Hemorrhagic manifestations
Leukopenia
Laboratory criteria for diagnosis include one or more of the following:
Isolation of the dengue virus from serum, plasma, leukocytes, or autopsy samples
Demonstration of a 4-fold or greater change in reciprocal immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody titers to one or more dengue virus antigens in paired serum samples
Demonstration of dengue virus antigen in autopsy tissue via immunohistochemistry or immunofluorescence or in serum samples via enzyme immunoassay (EIA)
Detection of viral genomic sequences in autopsy tissue, serum, or cerebral spinal fluid (CSF) samples via polymerase chain reaction (PCR)
Cases are classified as suspected if they are compatible with the clinical description.
Cases are classified as probable if they are compatible with the clinical definition and satisfy one or more of the following criteria:
Supportive serology (reciprocal hemagglutination-inhibition antibody titer greater than 1280, comparable IgG EIA titers, or positive IgM antibody test in late acute or convalescent-phase serum specimen)
Occurrence at the same location and time as other confirmed cases of dengue fever
A confirmed case is one that is compatible with the clinical definition and is confirmed by the laboratory.
Criteria for the diagnosis of dengue hemorrhagic fever include a probable or confirmed case of dengue infection and hemorrhagic tendencies as evidenced by one or more of the following:
A positive result from the tourniquet test
Petechiae, ecchymoses, or purpura
Bleeding from the mucosa, gastrointestinal tract, injection sites, or other sites
Hematemesis or melena and thrombocytopenia (<100,000 cells/μL) and evidence of plasma leakage due to increased vascular permeability that manifests as one or more of the following: greater than 20% rise in average hematocrit level for age and sex, greater than 20% drop in hematocrit level following volume replacement compared to baseline, or signs of plasma leakage (eg, pleural effusion, ascites, hypoproteinemia)
Dengue shock syndrome is diagnosed in cases meeting all of the above criteria plus evidence of circulatory failure, such as the following:
Rapid, weak pulse
Narrow pulse pressure (<20 mm Hg)
Hypotension
Cool, clammy skin
Altered mental status
The WHO classification system was recently studied in Indonesian children and was found to have a sensitivity of 86% (95% CI, 76-94) for the detection of dengue shock syndrome.5 The clinical reliability of the WHO criteria was compared with those of several modified systems, which added the above early predictors of compensated shock and considered models using varying combinations of evidence of hemorrhagic tendencies, thrombocytopenia, and hemoconcentration. These modified systems were found to yield higher sensitivities (88-99%) for dengue diagnosis than the WHO classification system and were more in line with clinical determinations made by local expert physicians.
A recent Belgian study examined predictors of diagnosis in 1962 febrile travelers and expatriates returning from the tropics. After malaria was ruled out, the main predictors of dengue infection included skin rash, thrombocytopenia, and leukopenia.
Causes
Dengue infection is caused by 1 of the 4 dengue viruses (ie, DENV-1, DENV-2, DENV-3, DENV-4) and is transmitted to humans by the bite of an infected mosquito.
Lab Studies
Complete blood cell count findings include the following:
Leukopenia, often with lymphopenia, is observed near the end of the febrile phase of illness. Lymphocytosis, with atypical lymphocytes, commonly develops before defervescence or shock.
A hematocrit level rise of greater than 20% is a sign of hemoconcentration and precedes shock. The hematocrit level should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever and every 3-4 hours in severe cases of dengue hemorrhagic fever or dengue shock syndrome.
Thrombocytopenia has been demonstrated in up to 50% of dengue fever cases. Platelet counts of less than 100,000 cells/μL are seen in dengue hemorrhagic fever or dengue shock syndrome and occur before defervescence and the onset of shock. The platelet count should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever.
Basic metabolic panel findings include the following:
Hyponatremia is the most common electrolyte abnormality in patients with dengue hemorrhagic fever or dengue shock syndrome.
Metabolic acidosis is observed in those with shock and must be corrected rapidly.
Elevated BUN levels are observed in those with shock.
Liver function test findings include the following:
Transaminase levels may be mildly elevated.
Low albumin levels are a sign of hemoconcentration.
Coagulation studies may help to guide therapy in patients with severe hemorrhagic manifestations. Findings are as follows:
Prothrombin time is prolonged.
Activated partial thromboplastin time is prolonged.
Low fibrinogen and elevated fibrin degradation product levels are signs of disseminated intravascular coagulation.
Typing and crossmatching of blood should be performed in cases of severe dengue hemorrhagic fever or dengue shock syndrome because blood products may be required.
Serum specimens should be sent to the laboratory for serodiagnosis, PCR, and viral isolation. Because the signs and symptoms of dengue fever are nonspecific, attempting laboratory confirmation of dengue infection is important. Serodiagnosis is made based on a rise in antibody titer in paired IgG or IgM specimens. Results vary depending on whether the infection is primary or subsequent. The IgM capture enzyme-linked immunosorbent assay (MAC-ELISA) has become the most widely used assay, although other tests, including complement fixation (CF), neutralization test (NT), hemagglutination inhibition (HI), and IgG ELISA are also used. A recent European study found that, if only a single serum sample is available, a single positive result on ELISA (PanBio IgM or IgG) was found to have a high rate of false positivity and should be confirmed using a second more specific diagnostic technique.7
Cultures of blood, urine, CSF, and other body fluids should be performed as necessary to exclude or confirm other potential causes of the patients' condition.
Imaging Studies
Chest radiography: Right-sided pleural effusion is typical. Bilateral pleural effusions are common in patients with dengue shock syndrome.
Serial ultrasonography
Ultrasonography has often been suggested as a potentially timely, cost-effective, and easily used modality in the evaluation of potential dengue hemorrhagic fever. Positive sonogram findings include fluid in the chest and abdominal cavities, pericardial effusion, and a thickened gallbladder wall.
The utility of previous studies was limited because of the use of single studies for evaluation. However, a recent study involving 158 patients examined the role of daily serial ultrasonographic examinations of the thorax and abdomen in the evaluation of patients with suspected dengue hemorrhagic fever.8 Plasma leakage was detected in some patients within 3 days of fever onset. Pleural effusion was the most common sign. Based on ultrasonographic findings, dengue hemorrhagic fever was predicted in 12 patients before hemoconcentration criteria had been met.
Other Tests
Arterial blood gas should be assessed in patients with severe cases to assess pH, oxygenation, and ventilation.
Procedures
Large-bore intravenous catheter - For fluid administration
Central venous catheter
For fluid administration
For central venous pressure measurement
Arterial catheter
For continuous blood pressure measurement
For serial arterial blood gas measurement
Urethral catheterization - May be useful to strictly monitor urine output
Medical Care
Dengue fever is usually a self-limited illness, and only supportive care is required. Acetaminophen may be used to treat patients with symptomatic fever. Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids should be avoided.
Patients with known or suspected dengue fever should have their platelet count and hematocrit measured daily from the third day of illness until 1-2 days after defervescence. Patients with a rising hematocrit level or falling platelet count should have intravascular volume deficits replaced. Patients who improve can continue to be monitored in an outpatient setting. Patients who do not improve should be admitted to the hospital for continued hydration.
Patients who develop signs of dengue hemorrhagic fever warrant closer observation. Patients who develop signs of dehydration, such as tachycardia, prolonged capillary refill time, cool or mottled skin, diminished pulse amplitude, altered mental status, decreased urine output, rise in hematocrit levels, narrowed pulse pressure, or hypotension, require admission for intravenous fluid administration.
Intravascular volume deficits should be corrected with isotonic fluids such as Ringer lactate solution. Boluses of 10-20 mL/kg should be given over 20 minutes and may be repeated. If this fails to correct the deficit, the hematocrit value should be determined, and, if it is rising, limited clinical information suggests that a plasma expander may be administered. Starch, dextran 40, or albumin 5% at a dose of 10-20 mL/kg may be used. One recent study has suggested that starch may be preferable because of hypersensitivity reactions to dextran.9 If the patient does not improve after this, blood loss should be considered. Patients with internal or gastrointestinal bleeding may require transfusion. Patients with coagulopathy may require fresh frozen plasma.
After patients with dehydration are stabilized, they usually require intravenous fluids for no more than 24-48 hours. Intravenous fluids should be stopped when the hematocrit level falls below 40% and adequate intravascular volume is present. At this time, patients reabsorb extravasated fluid and are at risk for volume overload if intravenous fluids are continued. Do not interpret a falling hematocrit value in a clinically improving patient as a sign of internal bleeding.
Patients who are resuscitated from shock rapidly recover. Patients with dengue hemorrhagic fever or dengue shock syndrome may be discharged from the hospital when they meet the following criteria:
Afebrile for 24 hours without antipyretics
Good appetite, clinically improved condition
Adequate urine output
Stable hematocrit level
At least 48 hours since recovery from shock
Absence of respiratory distress
Platelet count greater than 50,000 cells/μL
Surgical Care
No specific surgical intervention is necessary in patients with dengue fever, dengue hemorrhagic fever, or dengue shock syndrome.
Consultations
Consultation with an infectious diseases specialist may be helpful in guiding decisions regarding diagnosis and treatment.
Consultation with a critical care medicine specialist may be helpful when treating patients with dengue hemorrhagic fever or dengue shock syndrome and severe hemorrhagic manifestations or shock.
Diet
No specific diet is necessary for patients with dengue fever.
Patients may become dehydrated from fever, lack of oral intake, or vomiting. Patients who are able to tolerate oral fluids should be encouraged to drink oral rehydration solution, fruit juice, or water to prevent dehydration.
Return of appetite after dengue hemorrhagic fever or dengue shock syndrome is a sign of recovery.
Activity
Bedrest is recommended for patients with symptomatic dengue fever, dengue hemorrhagic fever, or dengue shock syndrome.
MEDICATION
No specific antiviral medication currently is available to treat dengue infections. Single-dose methylprednisolone showed no mortality benefit in the treatment of dengue shock syndrome (dengue shock syndrome) in a prospective, randomized, double-blind, placebo-controlled trial.10
Acetaminophen (paracetamol) is recommended for treatment of pain and fever. Aspirin, other salicylates, and NSAIDs should be avoided.
Drug Category: Analgesics/antipyretics
The treatment of dengue fever is symptomatic and supportive in nature. Bedrest and mild analgesic-antipyretic therapy are often helpful in relieving lethargy, malaise, and fever associated with the disease.
Drug Name Acetaminophen (Tylenol, Feverall)
Description Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating. Used in dengue infections to relieve pain and lower temperature when fever is thought to contribute to patient discomfort.
Adult Dose 325-650 mg PO/PR q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric Dose 15 mg/kg PO/PR q4h prn; not to exceed 2.6 g/d
Contraindications Documented hypersensitivity
Interactions Rifampin can reduce analgesic effects; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity; chronic use may potentiate effects of warfarin
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Hepatotoxicity possible in those with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; APAP is contained in many OTC products, and combined use with these products may result in cumulative APAP doses that exceed recommended maximum dose
Drug Category: Volume expanders
Plasma volume expanders are used in the treatment of intravascular volume deficits or shock to restore intravascular volume, blood pressure, and tissue perfusion.
Drug Name Lactated ringers with isotonic sodium chloride solution
Description Used to expand intravascular volume. Both fluids are essentially isotonic and have equivalent volume restorative properties. Although administration of large quantities of either fluid may lead to some differences in metabolic changes, for practical purposes and in most situations, these differences are clinically irrelevant. Importantly, no demonstrable difference in hemodynamic effect, morbidity, or mortality exists between resuscitation using either product.
Adult Dose 10-20 mL/kg IV initially administered rapidly, over 20 min; followed by reassessment of hemodynamic response; repeat prn
Pediatric Dose Administer as in adults
Contraindications Pulmonary edema (may lead to the development of ARDS)
Interactions None reported
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in CHF; caution admixing other agents (monitor for incompatibilities)
Drug Name Dextran 40 (Macrodex, LMD)
Description Polymer of glucose. When infused, it increases intravascular volume, blood pressure, and capillary perfusion. Used to restore intravascular volume when isotonic crystalloid use fails.
Adult Dose Variable; not to exceed 20 mL/kg IV on d 1 or 10 mL/kg thereafter
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; pulmonary edema
Interactions Caution when administering parenteral fluids to patients receiving corticosteroids or corticotropin, especially if the solution contains sodium ions; can interfere with blood cross-matching and measuring serum glucose and bilirubin levels (draw blood for laboratory testing prior to administration)
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions May cause nausea, which also may occur with hypoglycemia; IV dextrose solutions may result in dilution of serum electrolyte concentrations or overhydration in the setting of fluid overload; caution in patients experiencing congested states or pulmonary edema; hypertonic dextrose given peripherally may cause thrombosis (administer instead through central venous catheter); caution in subclinical diabetes mellitus or carbohydrate intolerance
Increased risk of inducing significant hyperglycemia or hyperosmolar syndrome if solution is administered rapidly, especially in patients with chronic uremia or carbohydrate intolerance; concentrated solutions should not be administered SC or IM; rates of dextrose infusion faster than 0.5 g/kg/h may produce glycosuria; at infusion rates of 0.8 g/kg/h, the incidence of glycosuria is 5%; closely monitor fluid balance, electrolyte concentrations, and acid-base balance; dextrose administration may produce vitamin B complex deficiency
Drug Name Albumin (Albuminar-5, Buminate)
Description Human albumin is a sterile solution of albumin (major plasma protein responsible for colloid oncotic pressure of blood). Pooled from blood, serum, plasma, or placenta from healthy donors. Infusion of albumin results in a shift of fluid from extracellular space into circulation, thereby decreasing hemoconcentration and blood viscosity.
May be administered wide open when treating shock. Patient response must be assessed before repeating dose.
Adult Dose 25 g IV; not to exceed 250 g/48 h
Pediatric Dose <37 weeks' gestation: 1 g/kg IV
Infants and children: 25-50% of adult dose IV
Contraindications Documented hypersensitivity; pulmonary edema; protein load of 5% albumin
Interactions None reported
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in poor left ventricular systolic function (monitor central venous pressure during infusion)
Drug Name Starch (hetastarch, 6% hydroxyethyl starch)
Description Hydroxyethyl starch is a sterile solution of starch responsible for colloid oncotic pressure of blood.
Infusion of albumin results in a shift of fluid from extracellular space into circulation, thereby decreasing hemoconcentration and blood viscosity.
Adult Dose May be administered in 6% solution, 15 mL/kg IV over 1 h; patient response must be assessed and then an additional dose of 10 mL/kg IV over 1 h may be administered
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Caution in poor left ventricular systolic function (monitor central venous pressure during infusion)
Further Inpatient Care
Report known or suspected cases of dengue fever, dengue hemorrhagic fever, or dengue shock syndrome to public-health authorities. Such reports should include patient demographics, case classification, date of onset of illness, whether or not hospitalization was necessary, outcome, and recent travel history. When multiple patients are involved, reports should include the number of cases of dengue fever and dengue hemorrhagic fever/dengue shock syndrome stratified by age, number of confirmed cases and serotypes, and number of hospitalizations and deaths.
Draw serum specimens for diagnosis as soon as possible after the onset of illness or hospitalization and at the time of death or discharge from the hospital. Immediately place specimens on wet ice and send to the laboratory.
Evaluate and treat patients appropriately for other possible conditions until the diagnosis of dengue fever or dengue hemorrhagic fever/dengue shock syndrome is established.
Further Outpatient Care
Draw a serum specimen 7-21 days after the acute-phase serum specimen was drawn. Ideally, draw the convalescent-phase serum specimen 10 days after the acute-phase specimen. Immediately place the specimen on wet ice and send it to the laboratory.
In/Out Patient Meds
No specific medications are needed for patients with dengue fever or dengue hemorrhagic fever/dengue shock syndrome. In general, patients should continue to take any medications necessary for the treatment of other medical conditions. However, use diuretics, aspirin, NSAIDs, and antihypertensives with caution in patients with dengue hemorrhagic fever because these medications may exacerbate the pathophysiologic derangement associated with dengue hemorrhagic fever. Review the risks and benefits of each medication and decide on an individuals basis whether the medication should be continued.
The differential diagnoses of dengue fever and dengue hemorrhagic fever/dengue shock syndrome include many conditions that are treatable with specific medications, such as antibiotics. Until such conditions are excluded, they should be treated.
Transfer
Transfer patients with dengue fever or dengue hemorrhagic fever/dengue shock syndrome when necessary monitoring and treatment cannot be provided in the current unit or facility. Treat patients with dengue shock syndrome in intensive/critical care units.
Deterrence/Prevention
No vaccine is available for the prevention of dengue infection. Immunogenic, safe tetravalent vaccines have been developed and are undergoing clinical trials. Because immunity to a single dengue strain is the major risk factor for dengue hemorrhagic fever and dengue shock syndrome, a vaccine must provide high levels of immunity to all 4 dengue strains to be clinically useful.
The only way to prevent dengue virus acquisition is to avoid being bitten by a vector mosquito. This can be accomplished in several ways, as follows:
Avoid travel to areas where dengue is endemic. This is not an ideal strategy because it would require a person to avoid most tropical and subtropical regions of the world, and many of these regions are popular travel and work destinations.
Wear N,N-diethyl-3-methylbenzamide (DEET)–containing mosquito repellant.
Wear protective clothing, preferably impregnated with permethrin insecticide.
Remain in well-screened or air-conditioned places.
The use of mosquito netting is of limited benefit, as Aedes are day-biting mosquitoes.
Eliminate the mosquito vector using indoor sprays.
Eliminate the breeding ground of the mosquitoes by not allowing them access to small accumulations of stagnant water around human habitats. Such accumulations can be found in pots, old tires, or any vessel capable of holding water.
Support community-based vector control programs.
Complications
Neurologic manifestations such as seizures and encephalitis/encephalopathy have been reported in rare cases of dengue infection. Some of these cases did not manifest other typical features of dengue infection. Other neurological complications associated with dengue infection include neuropathies, Guillain-Barré syndrome, and transverse myelitis.
Liver failure has been associated with dengue hemorrhagic fever/dengue shock syndrome epidemics. Whether this is a viral effect or a product of prolonged liver hypoperfusion remains unclear.
Overhydration is a well-recognized complication of dengue fever and dengue hemorrhagic fever/dengue shock syndrome.
Dengue must be carefully differentiated from pre-eclampsia during pregnancy. An overlap of symptoms and signs, including thrombocytopenia, impaired liver function, capillary leak, ascites, and decreased urine output may make this clinically challenging. Definitive diagnosis is confirmed via serology. Pregnant women with dengue fever respond well to the usual therapy of fluids, rest, and antipyretics. If the mother acquires infection in the peripartum period, newborns should be evaluated for dengue with platelet counts and serologic studies.
Prognosis
The prognosis of patients with dengue fever is excellent, with complete recovery being the norm. Patients with dengue hemorrhagic fever or dengue shock syndrome who do not die usually recover without sequelae.
Patient Education
Educate patients, especially those who have experienced prior dengue fever, to avoid mosquito bites when traveling to dengue-endemic areas. Current evidence suggests that those with a history of dengue fever are at highest risk for dengue hemorrhagic fever or dengue shock syndrome if they are infected with a different dengue strain.
Medical/Legal Pitfalls
Failure to suspect dengue infection in febrile patients with a history of travel to dengue endemic areas within 2 weeks of the onset of illness
Failure to suspect, identify, and treat other possible diseases such as meningitis or malaria
Failure to admit patients with signs and symptoms of intravascular volume loss for intravenous hydration
Failure to administer appropriate fluids to patients with dengue hemorrhagic fever or dengue shock syndrome
Failure to notify public health authorities about suspected cases of dengue infection
Special Concerns
Older patients, particularly those with congestive heart failure, must not be given excessive amounts of intravenous fluids.
Rare cases of vertical dengue transmission have been reported. Dengue should be suspected in pregnant patients with compatible clinical features. The potential for a neonate to be born with signs and symptoms of dengue fever should be anticipated.
Acute bronchitis
DESCRIPTION
Inflammation of the air passages (trachea; bronchi; bronchioles) of the lungs. Acute bronchitis is of sudden onset and short duration (chronic bronchitis is persistent over a long period and recurring over several years).
FREQUENT SIGNS AND SYMPTOMS
• Cough that produces little or no sputum initially, but does later on.
• Low fever (usually less than 101°F or 38.3° C).
• Burning chest discomfort or feeling of pressure behind the breastbone.
• Wheezing or uncomfortable breathing (sometimes).
CAUSES
• Infection from one of many respiratory viruses. Most cases of acute bronchitis begin with a cold
virus in the nose and throat that spreads to the airways. A secondary bacterial infection is common.
• Lung inflammation from breathing air that contains irritants, such as chemical fumes (ammonia), acid fumes, dust or smoke.
RISK INCREASES WITH
• Chronic obstructive pulmonary disease (COPD).
• Smoking.
• Cold, humid weather.
• Poor nutrition.
• Recent illness that has lowered resistance.
• Areas with high atmospheric pollution.
• Elderly and very young age groups.
PREVENTIVE MEASURES
• Avoid close contact with persons who have bronchitis.
• Don't smoke.
• If you work with chemicals, dust or other lung irritants, wear an appropriate face mask.
EXPECTED OUTCOMES
Usually curable with treatment in 1 week. Cases with complications are usually curable in 2 weeks with medication.
POSSIBLE COMPLICATIONS
• Bacterial lung infection (various kinds of pneumonia).
• Chronic bronchitis from recurrent episodes of acute bronchitis.
• Cough may persist for several weeks after initial improvement.
• Pleurisy (inflammation of the lining of the lungs) (rare).
TREATMENT
GENERAL MEASURES
• Diagnosis is usually based on the symptoms displayed, but a sputum culture may be done to check for bacterial infection.
• Treatment is directed toward relieving the symptoms, unless there are signs of secondary bacterial infection: green sputum, fever over 101° F or worsening symptoms.
• If you are a smoker, don't smoke during your illness. This delays recovery and makes complications more likely.
• Increase air moisture. Take frequent hot showers. Use a cool-mist, ultrasonic humidifier by your bed. Clean humidifier daily.
• Additional information available from the American Lung Association, 1740 Broadway, New York, NY 10019, (800) 586-4872.
MEDICATIONS
• For minor discomfort, you may use:
o Acetaminophen to reduce fever.
o Non-prescription cough suppressants. Use only if your cough is non-productive (without sputum). It may be dangerous to stop a cough entirely as this traps excess mucus and irritants in bronchial tubes, leading to pneumonia and poor oxygen exchange in the lungs.
• Other drugs that may be prescribed:
o Antibiotics to fight bacterial infections.
o Expectorants to thin mucus so it can be coughed up more easily.
o Cough suppressants.
ACTIVITY
Rest in bed until temperature returns to normal. Then resume normal activity gradually as symptoms improve.
DIET
No special diet. Drink at least 8 to 10 glasses of fluid each day to help thin mucus secretions so they can be coughed up more easily.
NOTIFY YOUR PHYSICIAN IF
• You or a family member has symptoms of bronchitis.
• The following occur during the illness:
o High fever and chills.
o Chest pain.
o Thickened, discolored or blood-streaked sputum.
o Shortness of breath, even when the body is at rest.
o Vomiting.
Inflammation of the air passages (trachea; bronchi; bronchioles) of the lungs. Acute bronchitis is of sudden onset and short duration (chronic bronchitis is persistent over a long period and recurring over several years).
FREQUENT SIGNS AND SYMPTOMS
• Cough that produces little or no sputum initially, but does later on.
• Low fever (usually less than 101°F or 38.3° C).
• Burning chest discomfort or feeling of pressure behind the breastbone.
• Wheezing or uncomfortable breathing (sometimes).
CAUSES
• Infection from one of many respiratory viruses. Most cases of acute bronchitis begin with a cold
virus in the nose and throat that spreads to the airways. A secondary bacterial infection is common.
• Lung inflammation from breathing air that contains irritants, such as chemical fumes (ammonia), acid fumes, dust or smoke.
RISK INCREASES WITH
• Chronic obstructive pulmonary disease (COPD).
• Smoking.
• Cold, humid weather.
• Poor nutrition.
• Recent illness that has lowered resistance.
• Areas with high atmospheric pollution.
• Elderly and very young age groups.
PREVENTIVE MEASURES
• Avoid close contact with persons who have bronchitis.
• Don't smoke.
• If you work with chemicals, dust or other lung irritants, wear an appropriate face mask.
EXPECTED OUTCOMES
Usually curable with treatment in 1 week. Cases with complications are usually curable in 2 weeks with medication.
POSSIBLE COMPLICATIONS
• Bacterial lung infection (various kinds of pneumonia).
• Chronic bronchitis from recurrent episodes of acute bronchitis.
• Cough may persist for several weeks after initial improvement.
• Pleurisy (inflammation of the lining of the lungs) (rare).
TREATMENT
GENERAL MEASURES
• Diagnosis is usually based on the symptoms displayed, but a sputum culture may be done to check for bacterial infection.
• Treatment is directed toward relieving the symptoms, unless there are signs of secondary bacterial infection: green sputum, fever over 101° F or worsening symptoms.
• If you are a smoker, don't smoke during your illness. This delays recovery and makes complications more likely.
• Increase air moisture. Take frequent hot showers. Use a cool-mist, ultrasonic humidifier by your bed. Clean humidifier daily.
• Additional information available from the American Lung Association, 1740 Broadway, New York, NY 10019, (800) 586-4872.
MEDICATIONS
• For minor discomfort, you may use:
o Acetaminophen to reduce fever.
o Non-prescription cough suppressants. Use only if your cough is non-productive (without sputum). It may be dangerous to stop a cough entirely as this traps excess mucus and irritants in bronchial tubes, leading to pneumonia and poor oxygen exchange in the lungs.
• Other drugs that may be prescribed:
o Antibiotics to fight bacterial infections.
o Expectorants to thin mucus so it can be coughed up more easily.
o Cough suppressants.
ACTIVITY
Rest in bed until temperature returns to normal. Then resume normal activity gradually as symptoms improve.
DIET
No special diet. Drink at least 8 to 10 glasses of fluid each day to help thin mucus secretions so they can be coughed up more easily.
NOTIFY YOUR PHYSICIAN IF
• You or a family member has symptoms of bronchitis.
• The following occur during the illness:
o High fever and chills.
o Chest pain.
o Thickened, discolored or blood-streaked sputum.
o Shortness of breath, even when the body is at rest.
o Vomiting.
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