Dengue fever is an acute, febrile, infectious disease, Aedes mosquito-borne, and breakbone fever.It is caused by a dengue virus. Typically it has an abrupt onset associated with malaise and severe prostration, pain of muscles and joints, one or two episodes of exanthems, lymphadenopathy, leukopenia, and duration of about a week followed by severe depression and weakness. It is observed most frequently in epidemic form.
Four distinct immunologic subtypes of dengue virus have been isolated from patients during epidemics. These viruses produce only partial cross-immunity. A primary infection with one will protect against another subtype only for a few months, although homologous immunity lasts many years. There is accumulating evidence, however, to indicate that sequential infection with any two subtypes produces long-lasting protection against subsequent infection with disease by any of the remaining two subtypes.
Incidence and Prevalence.
The distribution of the viruses is only partially known, but it appears that all continents and many islands are or have been involved. The size of human populations and the ecologic factors affecting the mosquito vector and virus multiplication in that host seem to be of principal importance. Thus, dengue fever occurs only in “summer-like” temperatures, and only where there are large numbers of Aedes aegypti, Aedes albopictus, or some of the Aedes scutellaris complex mosquitoes, the only recognized natural vectors.
Most primary infections produce clinically apparent disease. Thus, there is a strong correlation between morbidity and infection rates, the latter measured during epidemics by serologic methods. In contrast, conditions favorable to endemic transmission of the virus, e.g., large human populations, perpetual “summer” with continuous mosquito breeding, lead to a smoldering situation in which age-specific acquisition of dengue virus immunity is high in the absence of clinically apparent clustering of dengue fever disease. In specific circumstances, often associated with insular ecology, introduction of dengue virus at intervals measured in decades may produce morbidity rates as high as 50 to 80 per cent within a few months.
Man and certain Aedes mosquitoes are both essential links in the recognized natural epidemiologic cycle. Viremia adequate for mosquito infection is present for the first three to five days of illness. A mosquito of a suitable species feeding on a patient during this period requires about eight to twelve days at summer temperatures to become infective. It is then capable of initiating infection in one or a series of susceptible persons it may feed on or probe. The mosquito remains infectious as long as it lives. Transovarial infection has not been demonstrated. The incubation period and interval until viremia occurs in man is about five to six days.
Aedes aegypti, the common urban vector, usually breeds only in and near human habitations, rests and feeds ordinarily only in the house, and is primarily attracted to man. It is a daylight and twilight feeder. These qualities make it an ideal epidemic vector. Multiple cases occur within a house, and daytime visitors carry the infection to other domiciles, where another group of mosquitoes acquires infection.
No jungle reservoir has been discovered, but monkeys and forest mosquitoes are suspected of playing such a role, as in jungle yellow fever.The virus is frequently transported over great distances when infected human travelers carry it during the incubation period or when infected mosquitoes are carried by land, sea, or air vehicles.
In rural areas, Aedes albopictus or other Aedes species may serve as vectors, but their habits and the more sparsely distributed human hosts render severe, explosive epidemics less likely.
Because dengue fever is rarely, if ever, fatal, the pathologic processes are unknown except as revealed by biopsy of the skin rash. In this regard Sabin states that “the chief abnormality occurred in and about small blood vessels and consisted of endothelial swelling, perivascular edema and infiltration with mononuclear cells. In the petechial lesions extensive extravasation of blood, without appreciable inflammatory reaction, was observed.” Pathologic findings have been reported in fatal cases, but as none was of confirmed origin, the diagnosis is very much open to question. The various stages in the pathogenesis of the disease are unknown.
Clinical Manifestations of Dengue Fever.
As described by Ham- mon in previous editions of this text, the “classic” case of dengue from etiologically identified epidemics and inoculation of volunteers has a sudden onset marked by rapidly rising temperature, usually without a shaking chill, but almost always associated with some chilliness. Headache and fatigue are severe. By the second day the temperature is 103 to 105° F., the headache is still very severe, and the patient complains of severe ocular or retrobulbar pain, particularly on moving the eyes. There are excruciating back pain and generalized aching of various muscles, frequently involving joints.
In walking this results in a stiffness of the joints and the mincing gait of a “dandy,” from which the disease is said by some to have deceived its name. A fleeting erythematous macular or pinpoint rash may be noted during the first or second day, particularly on the limbs, but more frequently the only skin manifestation is a diffuse blushing, particularly of the face, neck, and chest. Anorexia is severe. Pulse and temperature at this stage are roughly proportionate. General lymphadenopathy is usually apparent, but hepatomegaly and splenomegaly are seldom present. The leukocyte count at this early stage is likely to be essentially normal.
Beginning about the third or fourth day, a rather conspicuous maculopapular or scarlatiniform rash appears. It usually starts on the trunk and spreads to the face and extremities. This generally lasts three or more days and may be conspicuous even after the temperature is normal. The fever generally lasts for five to seven days frequently with a fall on about the fourth day, giving a saddle-back type of curve. The final bout of fever may be the most severe. Occasionally on about the last day of illness, a few petechiae appear, usually about the ankles.
The total leukocyte count falls considerably as the disease progresses and by the fourth or fifth day may be extremely low. The number of segmented leukocytes is greatly reduced, but the more immature or non segmented polymorphonuclear cells typically show an absolute increase in number. Monocytes and lymphocytes decrease in absolute numbers.
A relative or even absolute bradycardia may exist during the last phase of the illness and during early convalescence. The fading rash is frequently itchy but rarely desquamates. During convalescence extreme weakness, anorexia, and mental depression form an important part of the disease pattern. The patient may not feel able or may not desire to resume normal activity for two weeks or more following return of the temperature to normal.
As children have not been reported in volunteer studies with known viruses and have not been referred to in detail in authenticated outbreaks, the widely varying clinical responses attributed to them in epidemics of undetermined cause lead to uncertain interpretation. The disease is generally described as much milder and frequently unrecognized in the very young, and it is probable that many infections in children go undiagnosed because of their mildness. This appears to account for the absence of recognized dengue among natives in endemic areas, where only children are susceptible to primary infection.
Diagnosis of Dengue Fever.
In the presence of a sharp epidemic with many “classic” cases, compatible environmental temperatures, and heavy exposure to bites of recognized vector species of mosquitoes, the diagnosis of many cases with average severity will usually be correct. However, it must be recalled that chikungunya, also known to be transmitted by Aedes aegypti, and probably other viruses may also be the cause. Thus, laboratory confirmation of a few cases during every epidemic becomes important. When cases occur sporadically, the cause of each one must be determined in the laboratory.
During the period of viremia, virus may be isolated from blood or serum by intracerebral inoculation of suckling mice or by certain types of tissue culture. Isolation of virus provides the most convincing proof of the cause. Serologic diagnosis is less satisfactory. In areas where several group B arthropod-borne viruses are present, if the patient has been infected previously with one or more of these (the usual finding in tropical and subtropical areas), it is not usually possible by presently available serologic methods to distinguish the particular group B virus responsible for the current infection.
It may not be possible even to determine whether the infecting virus is in the dengue subgroup. Serologic tests performed on an acute and a convalescent phase serum sample from a patient not previously infected with a related group B agent, using any dengue virus as an antigen, will usually demonstrate a titer rise; but the titer will be highest when the infecting type of dengue virus is used. Complement-fixation, neutralization and hemagglutination-inhibition tests are all of use. THeir relative ability to differentiate specifically between dengue types is approximately in the order listed.
In differential diagnosis, without the assistance of a virus laboratory, careful attention must be paid to clinical symptoms, the presence or absence of other similar cases in the area, the ambient climatic temperature, and exposure to and bites from known vector species. Travel in a known endemic or epidemic area five to eight days prior to onset may be an important part of the history of a sporadic case encountered in a region where the disease is not ordinarily seen.
There is no specific therapy. The nonspecific therapy should include bed rest, if possible, maintenance of fluid and electrolyte balance, and alleviation of discomfort. Aspirin, 0.3 to 0.6 gram, alone or in suitable combination with phenacetin and caffeine, should be given every three to four hours. (Salicylates may produce aberrations from the typical fever chart.) Severe pains may necessitate oral or subcutaneous administration of codeine sulfate, 30 to 60 mg. Other therapeutic measures should be designed to keep the patient as comfortable as possible. Complications should be anticipated, recognized, and treated as indicated. Resumption of normal activities should not be rushed; a two-week period of convalescence is desirable and often needed.
Except in severely debilitated persons the prognosis is excellent. The case fatality rate in etiologically proved cases is zero except for patients concurrently suffering from another relatively severe disease. Final recovery is usually complete, although temporary emotional disturbances, usually depression, are not uncommon during convalescence.
No vaccine is available from commercial sources, but experimental attenuated mouse-brain (live) vaccine for both types 1 and 2 has been produced and tested in volunteers. This gives rise to a relatively mild febrile disease with rash, and apparently affords solid immunity to experimental inoculation with virulent virus.Community protection is possible only through eradication or effective control of the appropriate Aedes vector. Bed nets are essentially useless for individual protection of older children and adults, because biting by the specific vectors does not occur at night. Mosquito repellents have limited usefulness.
Patients during the febrile stage ‘first four or five days) must be kept in mosquito-free quarters or under a bed net to prevent infection of more mosquitoes. All mosquitoes in the home or building in which a patient has resided or visited during the onset or early phase of disease should be killed by space spraying, as viremia has usually been present before the diagnosis can be made.