Chapter XXXVI: Dengue and Dengue-Like Fevers

DEFINITION AND SYNONYMS

=Definition.=—Dengue is an epidemic disease due to an ultramicroscopic, filterable virus which has been stated to be transmitted by _Culex fatigans_. More recent work points to _Stegomyia_.

It is characterized by an initial three or four-day febrile paroxysm of very sudden onset, a remission, which comes on about the fourth day and a terminal rise of temperature for two or three days—_the saddle-back temperature course_.

Backache and pains about the muscular attachments at the joints and especially a marked postorbital soreness are important features.

An eruption appears about the third or fourth day. Leucopenia and polymorphonuclear reduction are constantly noted. Apathy and a mild neurasthenic state may continue into convalescence.

=Synonyms.=—Dandy Fever (the word dengue is supposed to be derived from the Spanish equivalent of dandy or denguero), Break-bone Fever, Bouquet. German. Dengue-fieber.

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—While Hirsch gives the credit for the first mention
of the disease to the chronicler Gaberti, who described a disease
with certain resemblances to dengue as existing in Cairo in 1779,
yet, for the reason that certain clinical features of this epidemic
would hardly appear to belong to dengue, as we now know it, there
would seem to be good ground upon which to give the credit of
priority to Benjamin Rush, who, under the designation break-bone
fever, gave us a true picture of dengue as it manifested itself in
Philadelphia in 1780.

Gaberti was particularly impressed with the knee involvement so
that from his description the disease was known as the disease of
the knees. He further noted swelling of the fingers and that the
pains continued for more than a month. The sudden onset and the
sweating would seem to belong to relapsing fever as well as to
dengue and in support of the view that the disease described by
Gaberti might have been relapsing fever we have the statement of
Sandwith that bone pain, chiefly of the knee, is the symptom most
complained of by the Egyptian native with relapsing fever.

Boylon, who reported an outbreak of an epidemic disease in Batavia
in 1780 stated that everybody was attacked and that the symptoms
were almost the same as those ushering in plague—headache,
lassitude and pains in the joints. He noted, however, that this
epidemic had no bad consequences, patients getting rid of it in
three days under moderate diet and copious beverages.

Ashburn and Craig, in 1907, proved that the disease could be
transmitted by injections of blood, unfiltered as well as filtered.

=Geographical Distribution.=—The disease may occur in epidemic
form in almost any part of the tropical or subtropical world. It is
very common in the countries about the China Sea and in the West
Indies.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—One can only state that the disease is caused by a filterable virus which is present in the patient’s blood from the second to the fifth day. Graham reported a piroplasm-like organism as the cause but other workers have failed to confirm this. Reports as to bacterial causative organisms have not been verified. Cleland and his colleagues inoculated guinea pigs and rabbits without result and were unable to find spirochaetes. Couvy has reported the presence of short spirochaetes in the blood 2 or 3 hours before the onset of the fever,—never later. They had two or three turns and fine extremities.

=Epidemiology.=—As regards the epidemiology of dengue there seems to be a general acceptance of the idea that dengue is transmitted by the common culicine mosquito of the tropics, _Culex fatigans_. There is not, however, that definiteness which attaches to the transmission of yellow fever by _Stegomyia calopus_ or to pappataci fever by _Phlebotomus papatasii_, in both of which a certain period of development of the unknown filterable virus in the arthropod host is necessary before the insects become capable of transmitting the infections.

It will be remembered that in the nine experiments as to dengue
transmission, conducted by Ashburn and Craig, the authors threw out
five of the cases for such reasons as previous immunity or refusal
of the experimental mosquitoes to bite. Of the four remaining
volunteers only one developed dengue. This man, however, had been
on duty at the Division Hospital in Manila and the statement is
made that he had not been exposed to the disease so far as could
be determined. This of course rather militates against the value
of this isolated experiment and furthermore the mosquitoes which
bit him had fed on the blood of a dengue patient only two nights
previously. If this is to be considered as a valid experiment, we
must believe that only a short sojourn of the virus in the mosquito
is requisite, which is rather at variance with the twelve days for
the yellow fever virus and eight days for that of pappataci fever.

In the recent Australian epidemic (1916) experiments failed to show
_C. fatigans_ capable of transmitting the disease. _Stegomyia_,
however, gave success in 4 out of 7 cases, the volunteers
developing dengue in from six to nine days after being bitten.

_Stegomyia_ mosquitoes are often termed the domesticated ones,
since they are observed to breed and pass their lives in the
immediate environment of man and further to be distinctly urban,
rather than rural, in their distribution. For their breeding places
they choose artificial collections of water, such as cisterns,
barrels, pails, bottles and cans, in or near dwellings.

These mosquitoes are small in size, silver-striped, vicious feeders
and very alert. The female alone bites, blood apparently being
necessary for ovulation. It feeds especially during the morning
and afternoon hours,—much less commonly at night unless there is
a light. The life history of _Stegomyia_ is discussed more fully
under yellow fever.

As regards the transmission of the disease by blood filtered through a diatomaceous filter it will be remembered that Ashburn and Craig, by proving this fact, placed the dengue virus in the same category with the filterable viruses of the two diseases just considered. Cleveland found the virus in the washed cells as well as in the serum. The virus maintains its potency for several days outside the body it being present in the blood at periods of from 18 to 90 hours.

Lavinder injected dengue blood from cases in the second to fifth
day into rhesus monkeys without noting any variation in their
temperature or blood findings.

Graham in Beirut carried out some experiments, one of which would
seem almost positively to demonstrate mosquito transmission. He
took mosquitoes which had fed on dengue patients, to a village in
the mountains where no case of dengue existed. He caused these
mosquitoes to feed on two natives of the village and both men
became sick with dengue four and five days respectively after
being bitten by the mosquitoes. Graham’s claims to have noted
piroplasma-like organisms in dengue blood have not been verified
and do not receive credence.

The most convincing evidence as to mosquito transmission of dengue is that afforded by the absence of dengue in Port Said during the years 1906 and 1907 notwithstanding the prevalence of the disease in adjacent parts of Egypt. This was attributed to the absence of mosquitoes, these having been destroyed in the fight to make Port Said malaria-free. This campaign was commenced in May, 1906.

Other species of culicine mosquitoes, among which may be noted
_Stegomyia_, have been incriminated. In the Philippines I was
convinced that _Culex microannulatus_ might transmit the disease
as well as _C. fatigans_. In one of his experiments Graham claimed
to have produced dengue by injecting an emulsion of the salivary
glands of a mosquito which had fed on a dengue patient one or two
days previously.

PATHOLOGY

As death almost never occurs from the disease there is nothing to note other than the marked leucopenia.

SYMPTOMATOLOGY

After a period of incubation of from four to fifteen days the disease manifests itself with striking suddenness, in fact the patient can generally recall almost the hour of the onset.

The temperature rapidly rises and in a few hours reaches a maximum of from 102° to 105°F. Associated with this primary fever we have frequently a blotchy congestion of the face—the so-called initial rash.

We also have intense headaches, principally supraorbital and
postorbital. The pulse rate is slightly accelerated at first but
soon becomes slow and may fall to 50 from the fourth to fifth day.

There is no involvement of the joints, and the so-called joint pains are really pains of the muscular insertions about the joints.

The backache of dengue is usually a well marked feature. Pain on motion of the eyeballs is a prominent symptom—it is a deep soreness.

Insomnia, characterized by frequent dropping off to sleep to be awakened immediately by disturbing dreams, is often noted.

The depression, mental and physical, is altogether out of
proportion to the lack of seriousness of the disease.

Malaise and anorexia are marked. Constipation is the rule at first.

About the third or fourth day the temperature drops to normal or about that and remains so lowered for from twelve hours to three days. At this time the patient feels much better and views his affection in a less serious light. After this variable intermission the temperature rises to possibly a greater height than primarily, although as a rule it is less marked. This interval, or intermission, separating two periods of fever gives us a chart designated “saddle-back.” There may be only one rise of fever.

This second febrile attack is attended with pains and possibly
greater depression than the first accession. It is usually,
however, of shorter duration and during this period the terminal
rash appears. This is the most characteristic feature of the
disease. It generally manifests itself about the dorsal surface
of hands and feet advancing up forearms and legs. Later on it may
involve all extremities, face and trunk. The eruption is much like
that of measles but lacks the dusky red appearance of the measles
rash. It may however be punctiform and thus resemble the rash of
scarlet fever.

With the appearance of the terminal rash we may have crises such as
profuse sweating or marked diarrhoea or epistaxis.

The desquamation is furfuraceous in character and may be attended by marked itching.

In some patients (European) there is a rosy carmine flush of palms of hands and soles of feet. Some authorities have reported glandular enlargements in dengue.

Convalescence is apt to be protracted, being especially
characterized by malaise and nervous depression, practically
neurasthenia.

Leucopenia and polymorphonuclear percentage reduction appear by the second day.

_Clinical Types._—In different epidemics it is noted that some one clinical feature may seem outstanding. Of these we may note:—

(1) The pulse rate is slow for the temperature rise, thus reproducing a phenomenon common in yellow fever (Faget’s law). It is in recent epidemics particularly that clinical descriptions have recorded the frequency of a very slow pulse, most of the older authorities having noted a pulse rate which corresponded to the elevation of temperature.

(2) In some epidemics the feature of glandular swelling is prominent, while in others the swelling is so slight as to be overlooked.

(3) The characteristic “saddle-back” temperature chart seems lacking in the general run of cases in certain outbreaks. It is possible that such epidemics, showing atypical temperature curves, may have been due to phlebotomus fever, or seven-day fever, instead of dengue.

(4) In some epidemics, the rash is insignificant or very slight in most cases. This observation is possibly dependent on the ephemeral character of the eruption in certain groups of cases.

(5) From the chart Fig. 138, analyzing the symptoms in one epidemic, it will be noted that Lane observed cold, clammy, dusky extremities in 17 per cent of his cases. This is an unusual finding.

Symptoms in Detail

_Onset and the Temperature Chart._—Dengue probably sets in more
abruptly than any other disease. The temperature chart is typically
saddle-back.

_The Pains._—Very marked soreness deeply seated about the place of
origin of the ocular muscles so that every movement of the eyeballs
is at once complained of as giving pain.

General pains all over the body, more especially of the back and
about tendinous insertions of the muscles which cause the pains to
be referred to the joints. The knee-joint pains are probably the
most frequent. The rachialgia may be as great as that in variola or
yellow fever.

_The Eruption._—The characteristic eruption does not appear until
about the time of the intermission or with the accession of the
terminal fever.

The fall of fever about the third or fourth day is often attended
by a critical epistaxis, sweat or diarrhoea, to be succeeded by an
intermission of from one to three days of a feeling of well-being.
About this time or with the secondary rise of fever the true dengue
rash appears. It is at first noted about the bases of the thumbs
and extending over the dorsal surfaces of the wrists. Almost
simultaneously a measles-like rash appears over the dorsal and
internal surfaces of the big toe extending to the ankle, especially
over the internal malleolus. Later on the elbows and knees may be
involved or the rash may cover thickly the entire body. A carmine
flush of the palms of the hands and soles of the feet is not
uncommon. A furfuraceous desquamation with much itching at times
follows the eruption. The so-called primary eruption is nothing
more than an initial flushing of the face, it is ephemeral. The
true dengue rash may also be quite ephemeral but usually it lasts
for two or three days, or possibly four or five days.

_The Nervous System._—Besides the headaches we have insomnia and
depression which extends through convalescence. Apathy is marked.

_The Blood._—This shows a leucopenia of about 4000 from shortly
after the onset together with a reduction of the percentage of
polymorphonuclears to about 45%. During the attack the eosinophiles
are decreased but there is an increase during convalescence.

DIAGNOSIS

The two diseases with which dengue can be most easily confused are influenza and yellow fever. In fact when the great pandemic of influenza (1890) first made its appearance in France, many regarded it as an atypical form of dengue.

FIG. 138.—Dengue. Analysis of Symptoms, from 100 cases occurring in epidemic at St. Thomas, V. I. (After Lane, from U. S. Naval Medical Bulletin.)]

The respiratory involvement of influenza and the eruption and
comparatively slow pulse of dengue are the principal points of
difference. It must be remembered that affections in the tropics,
diagnosed as influenza, have shown but slight respiratory symptoms,
the cases being more of a nervous or intestinal type. The eruption
of dengue may fail to appear or be missed in the study of the case.
The blood findings should aid in differentiation from influenza as
is also true of yellow fever, a disease which likewise has blood
findings of practically a normal character. Other than the blood
picture we have in yellow fever (1) albuminuria, coming on about
the second day, and (2) jaundice appearing about the third day.
In dengue the eruption appears from the third to the fifth day.
Albuminuria is absent in dengue.

Dengue may be mistaken for measles, but the early coryza, Koplik spots and marked rash, first appearing about the face, should differentiate.

In scarlet fever the rapid pulse, angina and leucocytosis should be sufficiently differentiating.

Confusion with articular rheumatism may arise when the pain
about wrists, knees and ankles has been mistaken for true joint
involvement.

The headache and backache of smallpox may be confusing until the
eruption about the forehead appears. The leucopenia of dengue is
the main differential point in these first three days of doubt.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—This would seem to rest entirely upon the question of destruction of mosquitoes and prevention of the mosquito from biting a patient. In dengue the virus is apparently in the blood for four or five days so that screening of patients is necessitated for a longer period than for yellow fever or phlebotomus fever.

=Treatment.=—The malaise and depression are generally so great that the patient keeps his bed voluntarily. A light diet is indicated although the anorexia is so marked that it is difficult to persuade a patient to take food.

Cold spongings, provided the patient is not disturbed by being
moved, are of value for the insomnia. Phenacetine may be given for
the relief of the headache and backache. It is rarely necessary to
give morphine.

During convalescence tonics are indicated and if there is any
condition where a good wine is of value, it is in this, to
counteract the terrible depression. It has been suggested that
adrenal insufficiency may account for the asthenic, protracted
convalescence and from this standpoint adrenalin has been
recommended.

DENGUE-LIKE FEVERS

PHLEBOTOMUS OR PAPPATACI FEVER

=Etiology and Epidemiology.=—This fever, which is often called three-day fever, on account of its running its course in this period, is caused by a filterable virus. This virus only seems to be in the blood of the patient’s peripheral circulation during the first twenty-four hours of the illness, blood abstracted toward the end of the second day and injected into a well person failing to reproduce the disease.

If the blood is filtered through a Pasteur candle F, the filtrate
will set up an attack just as well as the unfiltered blood, in this
respect being like dengue and yellow fever. Couvy reports having
found spirochaetes in the blood 3 hours and 24 hours after the
onset.

The transmitting agent is a moth midge, _Phlebotomus papatassii_. This midge, as is true of the psychodid family, to which it belongs, is very hairy. It has long slender legs and narrow wings. The proboscis is as long as the head and the lancets project beyond the labium.

The female alone bites, which act takes place chiefly at night;
cool, moist, shady places, away from sleeping rooms, being
preferred in the day time. The insect is a persistent, vicious
feeder, difficult to escape from, as mosquito nets offer no
protection. It takes from six to eight days after feeding on a
patient in the first day of the fever before the midge is capable
of transmitting the disease, this being in accordance with the
twelve-day developmental period in the mosquito, that holds
for yellow fever. Doerr thinks that the pappataci virus may be
transmitted hereditarily by the insect to the egg.

At present, of the genera of the three families of midges, only
_Phlebotomus_ is known to transmit disease. _P. papatasii_
transmits phlebotomus fever in the Balkans. _P. minutus_ is the
host at Aden. Another species, _P. perniciosus_, can transmit the
disease. These moth midges are 2 mm. in length and have the body
densely covered with long yellow hairs. The second longitudinal
vein has three distinct branches. The antennae have 16 restricted
joints and the proboscis is as long as the head. The species of
_Phlebotomus_ are separated by slight variations in wing venation,
palpal lengths, etc., thus the second segment of palpi of _P.
papatasii_ is a little longer than the third one, while with _P.
perniciosus_ these segments are of equal lengths. In _P. minutus_
the second segment is only half the length of the third. The insect
lays about 40 eggs in damp dark places. The period of metamorphosis
from egg to insect is about one or two months, according to
temperature.

_Phlebotomus_ larvae die out in dry soil and very wet earth is unfavorable. Moderate moisture and protection from light seem necessary for their development. The remains of dead insects also seem to make good breeding places. It is in cracks of old damp brick or stone walls that the female most often deposits her eggs. Caves are also selected.

Blood seems necessary for the fertilization of the eggs but lizard
blood seems more common in the stomach of _P. minutus_ than human
blood. They have also been observed to feed on other reptilian
bloods. The female insect has been kept alive in captivity up to
forty-six days.

Cases first appear in the late Spring and the disease becomes
epidemic during the Summer.

An attack produces quite an immunity.

The disease has chiefly been studied in the Balkan States but
undoubtedly it is widespread.

The disease is almost never fatal so that we know nothing of its
pathology.

=Symptomatology.=—The symptoms will answer perfectly for cases of dengue one sees in a dengue epidemic in which, instead of the saddle-back course of fever, we have a three-day primary rise and then a fall to normal without any secondary fever rise. Cases of phlebotomus fever are occasionally reported where the fever continues seven or eight days.

The symptoms as usually given are as follows: After a period of
incubation of from three to six days there is an abrupt onset with
congested face and injected conjunctivae. There is pain in head,
eyes and back. There is marked malaise with great depression of
spirits. There is anorexia with coated tongue and rarely vomiting
and diarrhoea. There may be some congestion of the pharynx and
even a slight bronchitis. So much in common with influenza has it
clinically that a synonym is summer influenza. The liver and spleen
are normal. Mental depression is frequently noted. Epistaxis is
rather common.

There is a leucopenia and polymorphonuclear percentage decrease. The two points which are chiefly advanced in its clinical differentiation from dengue are (1) slow pulse, a bradycardia, and (2) only three days of fever and absence of eruption.

SEVEN-DAY FEVER

Rogers first described a dengue-like fever which occurred in India during the summer months as seven-day fever. The fever course was at times typically saddle-back and again would be of continuous type. A pulse relatively slow for the temperature is generally recorded, together with sudden onset and general malaise. The spleen is at times enlarged and there is a definite leucopenia and polynuclear percentage reduction. The eruption is only occasionally present (about 10%) and is an erythema which makes its appearance on the extensor surfaces of the forearm about the fourth day after the onset.

=Etiology.=—In cases similar clinically to the seven-day fever of Rogers, Ido, Ito and Wani have found a spirochaete resembling that of infectious jaundice and designated _Leptospira hebdomadalis_. It can be differentiated from _L. icterohaemorrhagiae_ by immunity reactions. It is found in the blood during the fever period and young guinea pigs can be infected by such blood either subcutaneously or by mouth. The organism can be cultured by Noguchi’s method. The spirochaete is to be found in the urine towards the end of the disease and the urine is probably the source of infection. In Japan field mice seem to be the carriers of this spirochaete. In about 3% of such rodents the spirochaete can be found in the urine and the disease is limited to the sections in which the field mice are found. There is practically no mortality and the treatment is symptomatic.

SAND-FLY FEVER, AND THREE-DAY FEVER

These dengue-like fevers of India are practically identical clinically with phlebotomus fever. The usual idea is that dengue epidemics are far more explosive in character than is true of epidemics transmitted by the sand-fly.

The strongest point in differentiation of sand-fly fever and dengue is that neither confers any immunity for the other disease.

The distinctions of enlarged glands and break-bone pains are often advanced as characteristic of dengue and not of sand-fly fever. I have never observed other than slight glandular enlargement in dengue cases.

SIX-DAY FEVER

Deeks has described a disease from Panama with a dengue-like clinical course.

There were but slight changes from normal in the pulse rate or blood findings. Some of the cases showed a late scarlatiniform eruption.

It was considered that the continuous fever for six days and the enlargement of the spleen, which accompanied the disease, differentiated it from dengue.