Chapter I: Malaria (2)

Anophelines seem to prefer small collections of water or sluggish
clear streams. The pools made by excavations following railway or
other similar construction are favorite breeding places. Proper
cultivation of rural districts makes the country more healthful and
Carter has stated that tile drainage is the key to rural malaria
control.

The most practical method for the identification of anopheline
species is to collect the larvae and later to study the adults
which develop from the pupae. On the whole culicines do not seem to
object to foul collections of water while anophelines avoid such
breeding places.

PATHOLOGY AND MORBID ANATOMY

The pathological lesions are those connected with the destruction of enormous numbers of red cells, not only each infected red cell being destroyed but others not so parasitised. There has been an idea that at the time of sporulation and rupture of the merocyte a pyrogenetic toxin was given off and along and with this there were haemolysins and endotheliolysins. Following Brown we are justified in thinking that the malarial pigment (melanin or haemozoin) can act as a haemolysin and by being taken up by endothelial cells bring about their degeneration with associated capillary haemorrhages. All three factors—red-cell destruction by parasites, haemolytic action on red cells and capillary haemorrhages lead to anaemia.

The brain has a leaden hue caused by the black pigment. As
discussed under pernicious manifestations the blocking of the
capillaries may be explained in several ways. When examining
sections of a malarial brain one often encounters punctiform
haemorrhages.

The spleen is enlarged and the surface dark. In acute cases it may
be diffluent instead of hard, as in ague cake. Microscopic sections
show a striking absence of pigment in the Malpighian corpuscles,
the haemozoin being pushed off into the surrounding spleen pulp.
Bone marrow is dark from deposit of pigment. In the liver the
endothelial and Kupfer cells are packed with black pigment. The
parenchymatous cells do not contain this pigment but may show
grains of a yellow pigment, haemosiderin, which gives the iron
reaction. Haemozoin, although it contains iron, does not give this
reaction. Haemozoin is soluble in alkalis, but not in alcohol while
haemosiderin is soluble in alcohol but not in alkalis.

The splenic blood is more rich in haemozoin than that of the other vessels, this indicating the spleen as the place of destruction of infected red cells or as the nursery for the development of malarial parasites. As a matter of fact splenectomy may cure an old malarial cachectic.

The finding of pigmented mononuclears or pigmented parasites in a
cross section of a blood vessel makes for a diagnosis of a malarial
infection.

Malarial manifestations are common in tropical autopsies and one
must be very chary about reporting malaria as the real rather than
contributing cause of death.

There is usually a marked increase in large mononuclears in malaria
and if this is noted along with a leucopenia it is very suggestive.
Melaniferous leucocytes occur in malaria only.

The kidneys may show degenerative changes and the presence of
urobilin in the urine is an important indication of latent malaria.

SYMPTOMATOLOGY

CLINICALLY, WE HAVE TWO TYPES OF MALARIAL PAROXYSMS, (1) _Those presenting a cold stage, followed by a hot stage, with a terminal sweating stage_. Such attacks are brought about by the benign infections which include the benign tertian and the quartan. Owing to the fact that in such paroxysms the temperature makes a critical fall to normal or subnormal readings such fevers are frequently designated _intermittent fevers_.

While these benign infections rarely or never exhibit pernicious
manifestations, they may, equally with the more dangerous
aestivo-autumnal parasite, lead to the production of malarial
cachexia, in which the clinical manifestations are similar whether
produced by a benign or malignant species.

(2) _Those in which the succession of cold, hot and sweating stages is lacking._ There is not the frank well-defined chill of the former group, so that the term dumb chill is frequently applied. With the possible exception of the first paroxysm the temperature tends to remain well above normal giving a continuous, or at any rate a remittent type of fever, instead of the intermittent temperature curve of the benign infections. The designation _remittent fever_, is often applied to such fevers. Clinically there is a resemblance to typhoid fever.

Such malarial fevers are caused by the small hair-like ring
parasite with its crescent sexual forms. There are many
designations for this type of malarial fever of which the
best recognized are: _malignant tertian_, _subtertian_,
_aestivo-autumnal_ and _tropical_. It is preëminently the malarial
fever of the tropics and, from its appearing in temperate climates
chiefly in the late summer and through the autumn months, received
from the Italians the designation aestivo-autumnal.

Such fevers were called subintrant by Torti because the succeeding paroxysm set in before the completion of the long-continued preceding one. This type of fever was greatly dreaded. The designation _malignant tertian_ is to be preferred as indicating the greater seriousness of this type of malaria.

INCUBATION PERIOD

Depending in great part on the number of sporozoites introduced by
one or more infecting anophelines at the time of biting we have
with quartan fever (8-12 merozoites) a period of incubation of
approximately three weeks, for benign tertian (16-24 merozoites)
two weeks and for malignant tertian (32 merozoites in culture)
eight to twelve days. These periods however may be much longer.

PRODROMATA

There may be prodromata of the nature of malaise, vague muscular pains, headache and anorexia, possibly showing a periodicity in their appearance or intensity.

It is only when a sufficient number of parasites sporulate
simultaneously and pour out into the circulation sufficient toxic
material to cause a well-marked paroxysm that such occurs—with
less poison we may only have vague suggestions of an attack of ague.

In a large proportion of cases there are no prodromata, they begin with a sudden onset.

Malarial paroxysms show a preference for the forenoon or at any rate tend to occur in the early afternoon, rather than in the evening.

MIXED AND MULTIPLE INFECTIONS

When there are two generations of tertian parasites, each maturing
on successive days, we have a paroxysm every day—a quotidian
fever. Such a tertian infection is called a double tertian. In
quartan infections, with the seventy-two-hour cycle of development,
if we have two generations of parasites sporulating on succeeding
days, but with an apyretic day intervening, we have a double
quartan. If three generations of quartan parasites sporulate on
three successive days we have a triple quartan infection. When two
species of parasites are present in the same case we have a mixed
infection. Mixed infections of malignant tertian and benign tertian
are the most common, next, those of quartan and malignant tertian
and very rarely those showing quartan and benign tertian. All three
species have been found in a single individual.

CLINICAL TYPES

_A Typical Benign Tertian or Quartan Paroxysm._—(Other than for the difference in periodicity the paroxysms of these two malarial infections are alike.)

The ague attack generally commences with malaise and slight headache, frequently accompanied by yawning and stretching. Chilly sensations radiating from the spinal column to the extremities and the jaws give way to actual chill with shaking body and chattering teeth, face pinched and bluish and cutis anserina.

The pulse is frequent, small and of rather high tension, there is increased frequency of urination and nausea and vomiting may be present.

Notwithstanding the fact that the rectal temperature is steadily
rising five or six degrees during this cold stage there is a desire
on the part of the patient to cover himself with all the wraps
obtainable.

The cold stage, which usually lasts from twenty to sixty minutes, is succeeded by the hot stage.

At first there is a feeling of slight relief from the misery of the
chill but this is soon lost sight of in the increasing headache and
feeling of intense heat.

The previously welcome blankets are cast aside. The face now becomes flushed, the eyes shining, and the pulse more full. Epigastric discomfort, nausea and vomiting are apt to become more prominent in this stage. The patient often complains of a throbbing headache. It is at this time that he may become slightly delirious. A sense of tension or even pain may be experienced in the region of the spleen, which organ will be found tender even if not already palpable. Herpes about the nose and lips is almost as common as in lobar pneumonia.

An attending bronchitis is not uncommon.

The fever remains high, from 105° to 106°F., and continues so
elevated for from four to six hours to be succeeded by the sweating
stage. In this the dry skin becomes moist and perspiration breaks
out first on the forehead to be followed by a more or less marked
profuse sweating of the entire body. The pulse becomes slower, the
temperature falls rapidly and the patient falls asleep to awake
slightly exhausted but feeling well.

This feeling of well-being continues during the fever-free day which is often referred to by a patient as “my good day.”

The sweating stage lasts usually about four hours so that the
entire paroxysm of cold, hot and sweating stages occupies
approximately eight to twelve hours.

While most cases of the benign infections show the typical stages
yet we meet cases where the cold and sweating ones are absent or
but slightly marked.

Blood examination will show the parasites of the benign infections
to be in the peripheral circulation during the entire apyrexial
period. During the paroxysm we have a moderate leucocytosis
and during the afebrile period a leucopenia with an increased
percentage of large mononuclears.

Billet thinks that quartan paroxysms can be distinguished from
benign tertian ones by their showing a less abrupt fever rise and
a more rapid fall of temperature with a shorter duration of the
paroxysm, four or five hours as against eight to twelve hours for
benign tertian.

_A Typical Malignant Tertian Paroxysm._—The characteristic features of the paroxysm are slight chilliness instead of a frank chill, prolonged and intensified hot stage, lack of marked terminal sweating and a tendency to exhibit a continuous or at least remittent fever curve instead of the distinct intermittence, with an apyrexial period, of the benign infections.

During the period of the remittence the patient fails to experience a sense of well-being. He is sick and does not have a “well day.”

The temperature of a malignant tertian paroxysm may fall to
normal during the first attack but succeeding attacks only show
the tertian periodicity by an exacerbation of the more or less
continuous fever.

In these cases the temperature rise is gradual rather than abrupt and the fall rather by lysis than crisis.

The paroxysm lasts from twenty to thirty-six hours instead of ten hours.

To explain the continuous type of fever it is often stated that
anticipation and retardation are characteristic of malignant
tertian infections. This simply means that the new paroxysm tends
to come on before the tertian periodicity of forty-eight hours
has expired and, having appeared, tends to delay its termination.
At any rate there is an extreme irregularity in the course of the
paroxysm. These attacks are often termed “dumb chills” and are
greatly dreaded.

The onset is insidious, occurring as a rule in the forenoon or early afternoon, with rarely a chill but only chilly sensations. The headache and backache are severe, the face is flushed, the pulse quickened and the thirst urgent.

The patient feels more prostrated and ill than does one in a benign paroxysm and there is a distinct tendency to mental confusion or delirium. Nausea and vomiting may be prominent features of an attack. At times an apathetic state may suggest typhoid fever. In these malignant malarial attacks the spleen is palpable and very tender. There is also a sense of weight in the region of the liver.

In a blood examination one is not apt to find any other parasites
than the young hair-like ring forms which begin to appear a few
hours after the onset of the paroxysm. The rings may be observed
to broaden, but prior to that development in which pigment would
appear in the ring, the parasite-containing red cell is caught in
the capillaries of spleen or other organs. The finding of young
ring forms while fever continues is suggestive of a malignant
tertian infection.

In the absence of quinine administration the finding of parasites is to be expected in benign tertian and quartan infections, but with the tropical parasite a smear may fail to show any organisms where a few hours previously a blood examination would have shown a large percentage of infected red cells in every field of the microscope.

=Pernicious Manifestations of Malaria.=—These grave manifestations arise almost exclusively in the course of malignant tertian infections. In his study of malaria Stott had about 1% of his cases showing well-marked pernicious symptoms.

As explanations of perniciousness are given: (1) the very large
number of red cells infected and destroyed by the malarial
parasites; (2) the throwing off at the time of sporulation of
the merocyte of a large amount of toxic material owing to the
presence of such a large number of disintegrating merocytes, and
(3) from the plugging of the capillaries of important internal
organs by adult parasites. This may arise as the result of (_a_)
the sporulating parasites acting as emboli, being too large to
pass the lumen of the capillary; (_b_) from degenerative changes
or distension with pigment of the endothelial cells lining the
capillaries, or (_c_) as the result of an ovoid shape on the part
of the malignant tertian parasite there is an inability to pass
through capillaries which the flattened benign parasites can do by
infolding (Bass), or (_d_) resulting from the tendency of malignant
tertian parasites to agglutinate.

_Types of Pernicious Malaria._—It is customary to divide pernicious malaria into the following divisions—(1) Cerebral, (2) Algid, (3) Bilious Remittent and, possibly, also (4) Pneumonic and (5) Cardiac types.

Blackwater fever is often included in the grouping but would appear to be best considered as a separate disease although almost surely brought about by malaria.

We do not understand why in one case sporulating parasites
should plug the capillaries of the central nervous system,
with the production of conditions resembling well-recognized
nervous diseases, while in another case the damage is done the
intestinal mucosa, pancreas or lungs. At any rate these pernicious
manifestations of malaria should always be kept in mind when a case
of sudden cerebral involvement or acute abdominal disease shows
itself in a patient in a malarious country and a blood examination
should be promptly made.

_Cerebral Manifestations of Pernicious Malaria._—Various authorities give different clinical pictures but the more commonly accepted types are:

(1) The hyperpyrexial, when the symptoms are those of heat stroke, with a temperature going up as high as 110°F. or even higher. Such patients rapidly become comatose and as a rule die.

(2) The delirious and comatose forms are apt to be associated, the comatose condition following a delirious state. Such manifestations may or may not set in with a chill. Cases belonging to this group may arise from a typical malignant tertian infection in which the headache and restlessness have been unusually marked. The pulse is full and fast with sighing respiration, hot dry skin and flushed face. There may be rigidity of the neck muscles.

(3) Such terms as epileptiform, tetanic, aphasic, cerebellar and bulbar have been applied to malarial manifestations and are self-explanatory.

Cerebral malaria may give rise to a delusional insanity. Various
psychoses or amnesia at times follow cerebral types of pernicious
malaria.

_Algid Manifestation of Pernicious Malaria._—In such cases we have a small thread-like pulse and a cold clammy skin. There are signs of collapse. The respiration is slow and shallow and the voice weak. It is customary to consider some of these cases, when there is vomiting and diarrhoea, with painful cramps of the legs and scanty or suppressed urine, as of choleraic type, while other cases, with blood and mucus in the stools and marked abdominal pain are termed dysenteric. Most dysenteric types only show a diarrhoea with the presence of blood.

The dysenteric type is more common but the question always arises
whether the case may not have been really dysentery lighting up
a latent malaria or the lowering of resistance from the malaria
favoring a dysenteric infection. Stott had five algid cases of
dysenteric type but not one of choleraic. The choleraic types have
often been reported during outbreaks of cholera.

When epistaxis and haemorrhages from the intestines or stomach are
marked features of an attack the cases are termed haemorrhagic and,
if a prostrating, collapse-producing sweat be a characteristic
feature, they are called diaphoretic.

Cases have been observed when the excessive sporulation was apparently taking place in the pancreas, giving the symptomatology of acute haemorrhagic pancreatitis.

_Bilious Remittent Fever._—This is the most common and the least dangerous of the pernicious manifestations but tends rapidly to produce malarial cachexia. Slight jaundice and bilious vomiting may appear in the course of an ordinary malignant tertian paroxysm and only severe types, with fatal tendency, should be classed as pernicious. It sets in with marked nausea followed by bilious vomiting and bile-rich stools. Jaundice shows itself by the second day; earlier than in yellow fever, but much later than the rapidly appearing jaundice of blackwater fever. The urine shows bile pigment and a yellow foam. Epigastric distress and liver tenderness are marked features and there may even be gastric haemorrhage.

_Pneumonic and Cardiac Types._—Other recognized types are when,
with the symptoms of a broncho-pneumonia, we find an element of
periodicity and a response to quinine—the so-called pneumonic
type.

Again, usually in elevated regions, dilatation of the right
heart and death have been noted as occurring in cardiac types of
pernicious malaria.

Another type is one in which the sweating stage is excessive, the
so-called diaphoretic type. These cases may result in collapse and
such a termination may be syncopal in character.

=Relapses.=—Relapses are distinct features of malarial diseases, the tendency being most marked in quartan and least so in malignant tertian. A relapse after an interval of two years is very rare in malignant tertian but periods as long as nine years may intervene between attacks of quartan fever.

Relapses are intimately associated with conditions which tend to
lower the body resistance, so that exposure to cold or wet or
hot sun may bring on an attack. Alcoholic or venereal excesses,
as well as errors of diet, may be provocative. Persons returning
home from the tropics often experience relapses as they approach
the cooler climate of the temperate zone. It has been well stated
that the old resident of the tropics owes his condition of health
rather to education than acclimatization—experience has taught him
discretion.

There are three explanations of relapses of which the one supported by Ross and Bignami seems more reasonable and is that the disappearance of nonsexual parasites is only apparent and that they continue their cycle but in insufficient numbers to excite symptoms.

_Parthenogenesis._—Schaudinn thought that, either spontaneously
or as the result of treatment, there was a disappearance of the
nonsexual forms and the male gametes, the female gametes however
surviving and, eventually, through the process of parthenogenesis,
producing a set of spores or merozoites which set up a nonsexual
cycle. It would seem probable that Schaudinn saw red cells
containing a merozoite along with a female gamete and interpreted
his findings as a sporulating sexual form.

Craig thinks that as the result of the conjugation of two young
schizonts a more resisting parasite is evolved, which under
favorable circumstances for its development may start anew a
nonsexual cycle.

=Latent Malaria.=—The persistence of a malarial infection, in the absence of clinical and to a great extent of laboratory manifestations, is shown by the occurrence of relapses, so that the section treating of malarial relapses applies equally to this paragraph. In addition to the factors influencing relapses, such as exposure to sun, rain and excesses of various kinds, we note a particular tendency for a latent malaria to develop activity following surgical operations and childbirth. In untreated latent cases we may have delayed healing of surgical operations.

In another paragraph there is noted the importance of examining
placental smears for evidence of a latent malarial infection.
Persons returning to a cool climate from the tropics, who may not
have shown evidence of active malaria for months, may come down
with a paroxysm upon encountering cool weather (refrigeration).
Latency may be complete or there may be vague manifestations of ill
health such as anorexia, malaise, irritability, headaches, anaemia
and alimentary tract disturbances. Not infrequently tropical
residents without symptoms may show crescents in their blood and
such cases are of prime importance in connection with infection
of mosquitoes. To a certain extent they are the typical carriers
and should be actively treated from a standpoint of malarial
prophylaxis.

=Masked Malaria.=—While as a rule one should not accept such a diagnosis, unless the possibility of some other explanation than malaria is excluded, yet there are manifestations, chiefly neuralgic, gastro-intestinal or in the form of varied skin eruptions which at times show periodicity and which respond to treatment with quinine.

=Malarial Cachexia.=—As the result of repeated attacks of any type of malaria a condition of anaemia and physical and mental incapacity may be produced. The skin has a dirty earthy hue, particularly of the face, and the sclerae show a yellowish tinging. The patient is sensitive to the slightest cold and is the victim of mental depression with deterioration of memory or at any rate lack of concentration.

There may be long periods in which the temperature is normal or
subnormal but slight febrile accessions may occur from time to time
and at such times the blood may show parasites.

The spleen is enlarged as may also be the liver. Twisting of the pedicle of the spleen or its rupture from even slight blows may necessitate surgical intervention.

There is anorexia and alimentary tract disturbances. A very
important feature of malarial cachexia may be the occurrence of
haemorrhages, particularly serious being those from the retinal
vessels.

It is probable that hookworm infection has frequently been
confused with the anaemia of malarial cachexia as in both of these
conditions we may have a high-grade anaemia with swelling about
the ankles, palpitation of the heart and shortness of breath. Some
authorities have recently called attention to splenic enlargement
in hookworm disease, but this is not generally accepted. There may
be also ascites in malaria. Urobilinuria is an important sign in
malaria where other causes for red cell destruction are excluded.

=The Sequelae of Malaria.=—The anaemia and other manifestations of malarial cachexia have been described above. The enlarged spleen not only is a source of danger from rupture but it may cause sensations of pain or tension. The skin of those with chronic malaria tends to ulcerate from slight wounds and phagedenic lesions may occur. There may be various disorders of the nervous system varying from mental confusion or lack of mental concentration to melancholia. Neuritis and possibly peripheral neuritis may have origin in repeated attacks of malignant tertian malaria. Ulceration of the cornea is the most frequent of the ocular sequelae although even this is rare. It only occurs after many relapses. It is painful, heals slowly and tends to recur with relapses. Iritis may accompany it. Abortions are frequent unless the malaria is adequately treated.

Symptoms in Detail

_General Appearance._—In the cold stage of the benign infections
the face is pinched and blue to become decidedly flushed when the
hot stage sets in. In malarial cachexia there is an earthy color
with the pigmentation more marked about the face and knuckles. In
the algid forms of pernicious malaria the skin is pale, cold and
clammy, in a measure simulating cholera. Herpes labialis is very
common in the benign infections, but less so in the malignant
tertian ones. Jaundice is a feature of bilious remittent fever.

_The Temperature._—Even in the cold stage the temperature is
steadily rising and may have reached 105°F. or higher by the time
of onset of the hot stage. It remains elevated during the four to
six hours of the hot stage and then falls rapidly to normal during
the sweating stage. The paroxysm tends to occur in the forenoon or
early afternoon. In 793 typical paroxysms Stott found only 37% to
occur before noon. Intermittent fever curves are characteristic
of benign infections. In malignant tertian a prolonged hot stage
(fifteen to thirty-six hours) is a marked feature. The onset also
is more gradual and the fever tends only to remit or may remain
continuous over several days, but even with such a chart there are
apt to be indications of slight rises every other day.

In the hyperpyrexial form of cerebral perniciousness the
temperature may rise to 112°F. and the case resemble sun stroke. In
the algid forms the axillary and rectal temperatures are usually
elevated.

_The Circulatory System._—The pulse is small, rapid and of high
tension in the cold stage to become full and bounding in the hot
stage. A cardiac type of perniciousness in which the right heart
dilates has been referred to.

_The Alimentary Tract._—Nausea and vomiting are common
manifestations of malarial paroxysms and in bilious remittent fever
the bilious vomiting is an especially distressing feature.

So-called choleriform and dysenteric manifestations of
perniciousness of the algid type are rarely observed.

Cases with the clinical picture of acute haemorrhagic pancreatitis
have been reported as incident to excessive sporulation of malarial
parasites in the capillaries of the pancreas.

_The Respiratory System._—There may be a slight bronchitis
in ordinary types of malarial fever. In the cerebral types of
perniciousness the breathing may be markedly altered—even of
Cheyne-Stokes character.

A broncho-pneumonia which shows a periodicity and responds to
quinine is often considered as a pernicious type of malaria.

_The Skin._—Herpes labialis is a common manifestation of benign
tertian and not rarely of malignant tertian infection. Urticaria
may also be noted. The skin of malarial cachexia is earthy. Of
course, one must always keep in mind the skin eruptions due to
quinine administered in treatment, and of these urticaria is
probably the most frequent.

_The Nervous System._—In both the benign and malignant infections
headache is a marked feature and is accentuated during the hot
stage. There may be a “flighty” condition in the hot stage of
benign tertian and quartan but in aestivo-autumnal infections there
may be actual delirium.

Delirious and comatose states are prominent features of cerebral
pernicious attacks. At times there may be an apathetic condition
suggesting typhoid fever.

Almost any type of central nervous system disease may be simulated
as the result of focal sporulation so that we have aphasic,
epileptiform, hemiplegic, bulbar and other clinical types.

Some authors have recorded cases of multiple neuritis of malarial
origin. Catto has recently examined the blood of a number of cases
of multiple neuritis in Jamaica and has obtained negative malarial
findings in every case. Neuralgic manifestations are features of
latent malaria. Some loss of memory may be apparent after severe
malaria.

_The Special Senses._—Plugging of the retinal arteries may lead to
blindness which may be either transient or lasting. The discs are
grayish red instead of white as is the case with quinine amblyopia.
The ringing in the ears is connected with the quinine treatment.

_The Genito-urinary System._—In the cold stage there is apt to be
frequent urination with increased secretion. Later on, there is a
scanty febrile urine.

Albuminuria is rather common in aestivo-autumnal attacks and true
nephritis occurs in about 2% of cases.

Plehn attaches great importance to the examination of the urine for
urobilin as showing malarial infection when parasites cannot be
found. The pigment particles in urinary sediment (Uriola) do not
give reliable information. Bile in the urine is an important sign
of bilious remittent fever.

Orchitis has been reported as a malarial complication.

_The Liver and Spleen._—There is very little of importance to note
in connection with the liver except tenderness and jaundice in
bilious remittent fever. The spleen, however, is the organ in which
centers the infection and its tenderness and enlargement are of
special diagnostic value in malaria.

Even in comatose conditions pressure on the spleen may bring about
indications of pain. The liability to rupture of the friable spleen
of aestivo-autumnal infections is a real danger and the patient
should not expose himself to injury.

_The Blood Examination._—This is of prime value in the recognition
of malaria, and one should examine both fresh blood preparations
and stained films as well. More information is gotten from the
stained films but we should also avail ourselves of the different
characteristics of the 3 malarial species, which can be noted in a
preparation made by taking up a small drop of exuding blood on a
cover-glass and allowing it to drop on a slide and run out without
any pressure on the cover-glass.

The crescents, when found, show a malignant tertian infection but
there may also be present one of the benign parasites. A stained
film should be used to identify malignant tertian young ring forms.

Pigmented rings are rarely observed in aestivo-autumnal fever,
such parasites being caught in the capillaries as they enlarge to
the stage where pigment begins to be present. Flagellated forms
only develop in fresh blood preparations, 15 to 20 minutes after
the taking of the blood. Of the greatest differential value is the
swollen pale infected red cell of benign tertian, the normal red
cell of quartan and the distorted shrunken red cell of malignant
tertian.

Quinine administration may cause parasites to disappear from the
peripheral circulation or it may so affect the parasite that the
staining would indicate a degenerated parasite—the so-called
quinine-affected parasite. It is difficult to diagnose the species
of malaria from such a parasite.

Large mononuclears and transitionals containing phagocytized
pigment (melaniferous leucocytes) are characteristic of
malaria—the pigment however must be in the leucocyte and not
free. There is a leucocytosis during the malarial paroxysm with
a leucopenia and increase in the large mononuclears during the
apyrexial period.

Among natives of India the large mononuclears and transitionals
averaged 21% in the apyrexial stage of malaria while healthy
natives rarely showed as much as a 10% count (Stott).

Some authorities have reported positive Wassermann reactions in
serum of malarial patients taken during a paroxysm. All agree,
however, that the serum of malarial patients at other times is
negative.

DIAGNOSIS

In the diagnosis of malaria the special points to consider are: (1) presence of malarial parasites, (2) periodicity, (3) splenic enlargement, (4) response to quinine therapy, (5) the presence of melaniferous leucocytes and (6) a high large mononuclear percentage when leucopenia is present. In the examination for parasites one should not only consider the species of parasite present but, as well, the stage of development and the presence of the sexual forms.

In an intensive investigation Bass has shown that 55.09% of those
showing parasites in the blood give a clinical history of malaria
while 44.91% of those with parasites in the blood fail to be
associated with clinical manifestations.

Blood platelets are the findings most frequently mistaken for
malarial parasites in stained blood, and the vacuoles in fresh
blood. Quartan and tertian periodicity is only found in malaria,
but quotidian periodicity is a feature of a host of diseases.

There are very few tropical diseases which have not been mistaken for malaria and many of these have been considered as of malarial etiology before the discovery of the real cause.

Of the cosmopolitan diseases, typhoid fever, septic conditions,
including malignant endocarditis, tuberculosis, influenza, pyelitis
and even syphilis are to be considered in a diagnosis of malaria.

As regards tropical diseases, kala-azar, Malta fever, liver abscess, filariasis, trypanosomiasis, leprosy, relapsing fever and yellow fever are to be thought of in differential diagnosis.

As was noted under the discussion of the pernicious manifestations
of malaria, scores of diseases may be simulated by the sporulation
of the malarial parasite in certain organs or areas of organs. One
should always keep in mind the possibility of pain in the appendix
region or in the gall bladder area as connected with malaria if in
the tropics. A polynuclear increase negatives malaria and indicates
appendicitis or cholecystitis. Malarial pancreatitis has been
referred to before.

With malarial cachexia we must in particular keep from mistaking it for hookworm disease or other secondary anaemias due to intestinal parasites.

_Provocative Measures._—Kohlbrugge’s recommendation to have
patients suspected of malaria climb mountains and drink copiously
of cold water, in order to bring on a relapse, is of value in the
diagnosis. (Effects of fatigue and refrigeration.) It must always
be borne in mind that quinine causes the parasites to disappear
from the peripheral circulation. It is interesting to note that
small doses of quinine given over ten days or two weeks may make
a latent case active. Other provocative agents are subcutaneous
injections of adrenalin (the best), or anti-typhoid inoculations.
Certain physical methods, as hot and cold douches or alternating
the hot air chamber at 55°C. for 10 minutes, followed by a cold
bath for 3 minutes have been recommended. After injection of
adrenalin the presence of parasites in the blood is at its height
at the end of an hour. Sunlight is a factor in relapse.

_The laboratory diagnosis_ of malaria has already been fully gone into in the section on etiology and that on blood examination under the heading of symptoms in detail.

The evenly spread stained film undoubtedly gives more accurate
information as to species and stage of cycle than any other
method. Still one should always examine a fresh specimen and if
the parasites are very scarce, a thick film preparation. The thick
film methods of Ross, Ruge and James are given under the chapter on
the blood in tropical diseases. During winter parasites tend to
disappear from the circulation regardless of treatment.

PROGNOSIS

The prognosis in benign tertian and quartan is most favorable when proper treatment is instituted, as such infections are never fatal in first attacks. Not only may malignant tertian kill in a first attack but it leads rapidly to a cachexia while the cachexia following upon benign infections is more gradual.

It is the tendency to perniciousness which makes us dread malignant
tertian as we can never be sure that a paroxysm may not develop
cerebral or algid manifestations and these show a very high death
rate, 25 to 50%, even when promptly treated.

As regards relapses quartan is the malarial fever which is most
apt to show this feature and aestivo-autumnal the least. Deaderick
gives the percentage of cases showing relapses in quartan, benign
tertian and aestivo-autumnal as 65, 55 and 45.

The great importance of malaria is rather its invaliding tendency and by thus reducing the powers of resistance it makes the death rate from intercurrent diseases higher. Tropical malaria does not seem to affect the native as it does the European but the high death rate of infants among the natives is undoubtedly largely connected with this disease.

Statistics vary greatly as to the percentage of fatal cases in
malaria. Certain figures from tropical countries give fatal results
as occurring in from 2 to 10% of cases, while statistics from
temperate climates show a death rate below 1%. The mortality from
pernicious types of malaria is about 25%.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—There are three methods in the prevention of malaria, all of which may be combined, as was the case in the Canal Zone region of Panama. These are: (1) Destruction of anopheline mosquitoes; (2) protection of the individual from the bites of mosquitoes, and (3) quinine prophylaxis.

It may be stated that it is frequently advisable to carry on the
mosquito warfare without regard to the question of the kind of
mosquitoes destroyed. In general terms the malarial mosquito breeds
in the suburbs of towns or in districts more distinctly rural,
while the transmitter of the more dreaded yellow fever, prefers
breeding places in the immediate vicinity of city houses.

Bentley has recently noted that, with improvement in agricultural
methods and utilization of marshy lands, malaria tends to disappear
as much from the physical improvement and thereby greater
resistance of the people as from the destruction of mosquitoes by
the draining of the swamps. The resulting greater prosperity makes
better food and shelter obtainable.

1. _Destruction of Mosquitoes._

Such measures may be directed either toward the larva or fully developed insect.

(_a_) Measures against larvae. When practicable permanent measures should be preferred to temporary ones and when agricultural development goes along with drainage of swamps the cost is repaid.

The doing away with mosquito breeding places may be accomplished
by filling in pools or by making ditches with smooth sloping sides
to carry away the water. These ditches require a great deal of
attention to prevent their filling up with tropical vegetation and
thereby adding to breeding places. Subsoil drainage with tiled
drains is better. Care should be exercised that public works
operations do not raise the level of the subsoil water.

Anophelines tend to breed in sluggishly moving streams or in
stagnant pools especially where there is a luxuriant growth of
weeds or grass, and are not apt to be found in rapidly flowing
streams, hence the necessity for constant care of ditches and the
like to prevent their becoming obstructed by vegetation or silt.
When filling in or drainage is not practicable the method of oiling
the surface of the pool with crude petroleum is to be recommended.
One uses about ½ pint for every 100 square feet of surface and the
process should be repeated every two weeks.

In places where oil is not effective, Barber recommends Paris
green mixed with dust and so used as to form a scant surface
deposit. Anopheline larvae, being surface feeders, ingest it and
are killed. It does not affect Culex larvae. On account of its ease
of transportation, and adaptability to weedy places where oil does
not penetrate, Paris green dust will doubtless prove a valuable
selective larvicide. Mayne and Jackson recommend cresol as the best
larvicide. In 1 to 1,000,000 parts it is an effective larvicide,
and even in 1 to 1,000,000,000 it is destructive to young larvae.

Mixtures of soft soap and petroleum are better than petroleum alone.

Winds are apt to blow away the surface coating of oil and it is
difficult to oil the surface of a pool filled with grass. Wise
recommends crude carbolic acid, using 1 ounce to 16 cubic feet of
water.

In using any larvicide it is well to introduce it along the banks
of water collections with a long-spout can and mix it thoroughly
with a stiff reed broom.

There are many enemies of mosquito larvae, such as tadpoles,
water-beetle larvae and various small fish such as “millions.”

Terni suggests the using of such fish as carp and tench which have
a food value as well as a larvicidal one.

(_b_) Measures against the mosquito. The clearing away of grass and brush from around houses exposes the mosquitoes to the sun in which they cannot live long.

When inside the house they may be destroyed by sulphur fumigation, 1 or 2 pounds of sulphur for each 1000 cubic feet and with an exposure of two hours.

It is usually stated that mosquitoes may hibernate during winter
following infection in the autumn and that cases of malaria in
early Spring may be explained by their bites. Examination of
hibernating mosquitoes for zygotes does not give strong proof to
this view but such mosquitoes, becoming active with a rise in
temperature, may bite gamete carriers in the house and thus spread
malaria.

Pyrethrum powder, which is set on fire with a little alcohol, may
be burned, using 2 pounds per 1000 cubic feet, and an exposure
of four hours. This does not certainly kill the insect and the
stupified mosquitoes should be swept up and burned.

Giemsa’s spray is now considered an excellent measure for killing
mosquitoes in rooms. The composition is as follows: Pyrethrum
tincture (20 parts powdered pyrethrum blossoms to 100 parts
alcohol), 480 grams; odorless potash soap, 180 grams; glycerine,
240 grams. Before using it dilute with 20 times its own weight of
water, and spray the walls of the room with a spray pump.

The use of a small square of wire gauze on a handle (fly swatter)
to kill mosquitoes as they rest on a wall is of great value in
keeping them down in a screened house.

2. _Protection of the Individual._

The house should be thoroughly screened with copper-wire screens which should have 18 meshes to the inch. Mosquitoes can pass through a 15 mesh screen. Screen doors should always open outward and close automatically with spring hinges.

It is almost impossible to screen a ship’s hatches effectually.
Then too the screening of fan intakes and ports interferes with
free circulation of air, thus adding to the discomfort of the heat
of the tropics.

As malarial mosquitoes bite chiefly toward evening one should not
expose himself after sunset.

Houses should be far removed from native habitations.

Mosquitoes prefer the lower floors of a house so that the upper
stories are preferable for sleeping.

Mosquito nets at night, with protection by veils for the face or
coverings for the hands and ankles, when going out of the house,
are well-known measures.

It is stated that Emin Pascha always carried a mosquito net and
never suffered from malaria. He thought that the cause of malaria
was too large to go through the net.

Even when mosquito nets are intact and well tucked in there is the
weak point that a person sleeping on a narrow cot is apt to put his
arm or leg against the net, in which case the mosquitoes readily
bite the skin presenting at the open spaces.

Oil of citronella is often used to keep away mosquitoes.

Brooks recommends Neal’s method. In this daub a solution of 1 ounce
Epsom salts in 10 ounces of water on the exposed parts and allow to
dry.

Application of certain pine products used as mange cures will keep away mosquitoes.

3. _Quinine Prophylaxis._

The ease of application of quinine prophylaxis, as compared with the more permanent methods of mosquito destruction and screening, appeals to the sanitarian, especially in the tropics.

It is just as easy to give quinine to a man in the tropics as it is
in temperate climates, but when one considers the propositions of
draining tropical swamps and shutting off circulation of air on a
torrid night with fine wire gauze in the windows and closely woven
mosquito nets around the bed, the question is decidedly different.
In consequence, the tendency is for the average man to despair
of accomplishing anything in the way of mosquito destruction and
screening and to seize eagerly on the inferior alternative, that of
quinine prophylaxis.

Ronald Ross presents this matter concisely and to the point when
he states that it is not a good policy to substitute a measure
which does not exclude infection, but is merely extirpative in
some cases, for positive prevention. From this it will be seen
that unless it is clearly recognized that quinine prophylaxis may
in some cases extirpate, but does not prevent, there might be a
tendency to adopt this measure and neglect the two proper ones.

As regards the relative merits of quinine prophylaxis and
protection from mosquitoes Celli gives the following figures:

Treatment Infected
Mosquito protection plus quinine prophylaxis 1.76 %
Mosquito protection alone 2.5 %
Quinine prophylaxis alone 20.0 %
No protection at all 33.0 %

With quinine prophylaxis, there is the possibility of producing an immunity to quinine on the part of the parasites which have been introduced by infected mosquitoes and held in check by the prophylactic but not curative dose of quinine. Later on when the quinine prophylaxis is discontinued the parasites begin to multiply vigorously and seem to possess an immunity to quinine.

As an instance of this, 398 marines served in 1906 for about one
month on the Isthmus of Panama during which time they were given 9
grains of quinine daily as a prophylactic.

During this month there was only an occasional case of malaria
among the men. At the end of the month 298 of the original 398
returned aboard ship and sailed for the North. Two days later
20 cases of malaria developed, followed the next day by 53 and
the day following that by 45. The medical officer then resumed
10-grain prophylactic doses for those not down with malaria but
notwithstanding this there were 215 acute malarial paroxysms, some
of them of pernicious type, among the 298 men.

It was noted that these men did not respond satisfactorily
to quinine treatment even when the drug was administered
intramuscularly.

Of the greatest value have been the observations of Stott. Using native Indian troops he gave one group (3931) prophylactic quinine while the other (3906) did not take quinine prophylactically. He continued this experiment one year giving 15 grains 3 times weekly for five months, and 10 grains 3 times weekly for the remaining seven months. Those taking quinine gave 170 primary admissions while those not taking it gave 179 (43.2 per thousand strength for the former as against 45.8 per thousand for those not taking quinine prophylaxis). Further observations were that those taking quinine prophylaxis showed a greater tendency to relapse, had somewhat longer fever, and required more quinine for treatment.

Linnell states that he used quinine prophylaxis among 2000 coolies
for a year, giving 5 grains or more daily with most discouraging
results. It seemed to act as a slow poison and did not protect.

_Quinine Immunity._—Bignami thinks that malarial relapses may be connected with insufficient initial treatment so that quinine-resisting forms survive and later, when some factor lowers the patient’s resistance, active multiplication of parasites, which are not readily destroyed by quinine, follows.

While quinine prophylaxis may not be desirable on board ship, where
one is in a position to readily recognize and treat the onset
of malaria and to more or less efficiently carry out mosquito
protection methods, or in a wealthy seaport, where sufficient
interest in and funds for draining and screening exist, yet on
military expeditions or exploring trips in tropical or subtropical
countries it is the only practical method of keeping a force
efficient.

Of course, one should also utilize mosquito nets as assisting in
protection from malaria, and as effective for yellow fever, dengue
and filariasis.

_Methods of Prophylaxis._—There are innumerable methods of carrying out quinine prophylaxis among which may be noted.

(_a_) Celli’s method. In this there is given 3 grains of quinine
each morning and 3 grains each night. Taken in this way Celli
thinks that harmful effects from quinine are avoided, that quinine
immunity does not occur and that there is no danger from quinine
haemoglobinuria. For children he recommends the tannate in
chocolate tablets.

(_b_) In 1909 Bertrand and other members of a French Commission
recommended two consecutive doses of 5 to 10 grains every
seventh and eighth day for benign infections and two consecutive
prophylactic doses of 10 to 15 grains every third and fourth days
where malignant tertian was prevalent.

(_c_) Ziemann gives 15 grains every fourth day with the idea that
the quinine is entirely eliminated in four days. Nocht gives about
12 grains on two succeeding days of each week in divided doses of
2 or 3 grains instead of the entire amount in one dose.

Koch gave 15 grains on tenth and eleventh days.

(_d_) Castellani’s method of 5 grains daily and a double dose once
a week is the one I recommend.

_Sterilization of Carriers._—In addition to quinine prophylaxis for those not infected we also have quinine disinfection for native or other carriers of malaria. For these infected persons Koch recommends 15 grains on two to three successive days of each week, the course to be continued for three months. This plan of extirpation of the parasites of _malarial carriers_ is of great practical application. Gill uses 10 grains of quinine daily for six months after discharge from hospital. The effect of tartar emetic on malarial gametes may prove of value.

=Treatment.=—Cinchona bark was first introduced into Europe in 1640 and has its name from Countess Chinchon, wife of the Peruvian Viceroy, who was cured of a fever by this bark in 1638.

Much of our knowledge of the therapeutics of cinchona bark is due
to Torti. In giving the drug he used a large dose the first day and
the same for the subsequent two days. After that he administered
smaller doses for a week and then still smaller doses for two or
three weeks. Quinine was not introduced until 1820.

At present quinine or some salt of the alkaloid is used in malaria instead of preparations of cinchona bark.

_Toxic Effects of Quinine._—The most important untoward
manifestations of cinchonism are the very common scarlatiniform,
eczematous or urticarial rashes, gastric disturbances and vertigo.
Impairment of vision may be brought about by quinine and quinine
haemoglobinuria is a recognized possibility. In quinine amblyopia
the pupils do not react to light and the optic disc is very pale,
thus distinguishing the impairment of vision due to the plugging of
the retinal vessels by the malarial parasite, in which condition
the pupils do react to light and the disc is a grayish red.

_Quinine Idiosyncrasy._—Fortunately the taking of quinine is well
borne by the great majority of persons but in exceptional cases
we may have developing, even after doses as small as one grain,
of (_a_) severe nausea vomiting or diarrhoea, (_b_) various skin
eruptions, usually of a scarlatiniform or urticarial type, (_c_)
marked ringing in the ears, dizziness or deafness, (_d_) impairment
of vision, (_e_) dyspnoea and (_f_) malarial haemoglobinuria. To
determine an idiosyncrasy make a scratch on the flexor surface of
the forearm and apply a drop of a 1 to 10 solution of quinine.
Oedema with a wide zone of erythema in about 5 minutes shows
idiosyncrasy. A control with normal saline should be made. It is
well to make this skin test before giving quinine intravenously.
For desensitization we give 1/10 grain of quinine combined with 5
grains of bicarbonate of soda and in about 1½ hours we give 1 grain
with 5 grains of bicarbonate of soda.

The cheapest and most generally obtainable salt is the sulphate. It is soluble in 720 parts of water and contains 74% of alkaloid. The opinion now prevails that this is one of the less desirable of forms for the administration of quinine. It is frequently obtained in pill or tablet form and it must not be forgotten that such preparations may be almost stone-like and pass through the alimentary tract without absorption. If used it is best to give it in acid solution made by dissolving 5 grains of quinine sulphate in one teaspoonful (1 dram) of water with one drop of concentrated hydrochloric acid.

_Dosage of Quinine._—The ordinary full dose of quinine for an
adult is 10 grains repeated three times in a day or 30 grains
daily. Some authorities recommend 15 grains three times daily (45
grains) at the commencement of treatment and such dosage seems to
be just as efficient as the larger dose of 60 grains in a day.
In cinchonism we have ringing in the ears, fullness in the head,
deafness and dizziness. For children Bass recommends 1/20 of the
adult dose for each year of age so that a child of 5 years age
would receive ¼ of the adult dose. Beyond 15 years of age the dose
is that of an adult.

There now seems to be a tendency to use the alkaloid itself instead
of its salts, it having been found that the alkaloid and its very
insoluble tannate are absorbed from the digestive tract equally as
well as the soluble salts. Quinine is almost insoluble in water
(1-1560) and hence has less bitter taste than the soluble salts. It
is also less haemolytic so that it may be used with greater safety
where blackwater fever is feared.

Euquinine or ethylcarbonate of quinine contains 81% quinine, and
is only soluble in 1-12,000 parts of water, hence its comparative
tastelessness. It is expensive.

Quinine tannate contains only about 30% of quinine and is
practically insoluble in water. It is often given to children in
chocolate tablet form. It can often be taken by those who suffer
disagreeable effects from other salts. The dose should be 2½ times
that of quinine sulphate.

Until recently the bimuriate (72% of alkaloid and soluble in 1 part
of water) or the chlorhydrosulphate (74% of alkaloid and soluble
in 2 parts of water) have been considered the most desirable salts
for hypodermic injections or oral administration. At present,
owing to its extensive use in local anaesthesia and incident
availability, bimuriate of quinine and urea is to be recommended
for intramuscular use. It contains 60% of quinine and is soluble in
an equal amount of water.

It has been found to have a slightly greater tendency to produce
amblyopia than other quinine salts and should not be used
intravenously.

In a very important series of experiments on prisoners,
MacGilchrist found that hydroquinine (a synthetic product of
quinine) was about 20% more efficient than quinine. Cinchonine was
about the same as quinine while quinidine was about one-half as
potent as quinine.

Acton has praised the value of cinchona febrifuge (the combined
alkaloids of cinchona) given in daily doses of 21 grains for ten
days.

Methods of Administration

_By Mouth._—This is the usual method and is the one to be preferred in all cases where other methods of administration are not necessitated.