EPIDEMIC TYPHUS FEVER

MALARIA

HEMORRHAGIC FEVERS

 

Synonyms - jail fever; ship fever; putrid fever; petechial fever; typhus exanthematicus.

Definition

Epidemic typhus fever is an acute infections disease caused by Rickettsia Prowazeki. Epidemic typhus fever is characterized by development of generalized thrombovasculitis, meningoencephalitis, severe common intoxication, by appearance of rash, increased lever and spleen. It is transmitted by the louse, Pediculus humanus.

History and geographical distribution

Epidemic typhus fever has been one of the great epidemic diseases of the world. Its history belongs to the dark pages of the world's story, at times when war, famine and misery of every kind are present.

The disease was first described with sufficient accuracy by Frascastoro, in the 16th century, to enable us distinctly to differentiate it from plaque; the stuporous states of the two disease having previously caused them to be confounded.

Epidemics of typhus have very frequently been associated with war. In fact, severe epidemics have occurred during practically every great war in Europe with the exception of the Franco-Prussion war in 1870. In the World War, the epidemic which raged in Serbia in 1915 was one of the most severe which has occurred in modern times. It was characterized not only by its high virulence and high mortality. During the epidemia the number of new fever cases entering the military hospitals alone, reached as high as 2500 per day, and the number of reported cases among the civilian population was approximately three times was this number. The mortality during the epidemic varied during the epidemic at different periods in different localities between 30 and 60 %. Over 150.000 deaths occurred within 6 months, before the epidemic could be suppressed. An astonishing 30 million cases occurred in Russia and Eastern Europe during 1918 - 1922, with an estimated 3 million deaths. During World War II, typhus struck heavily in concentration camps in Eastern Europe and in North Africa.

In the present time this disease may be occurs in Africa (Burundi, Ethiopia), in the Central America (Mexico, Peru).

Etiology

The etiologic agent is Rickettsia Prowazekii(Fig. 1), an obligate intracellular bacterium that is closely related antigenically to the agent that causes murine typhus (Rickettsia typhi). The organism is cocobacillary but has inconstant morphologic characteristics. Reproduction is by binary fission and diplobacilli are produced that are frequently seen in tissue sections. Special staining (Giemsa) provides good visualization of the organisms in the cytoplasm of cells.

Fig. 1. Rickettsia Prowazekii

 

Epidemiology

The source of infection is a sick man. Epidemic typhus (or louse-borne typhus) is transmitted from person to person by the body louse (Pediculus humanus corporis) (Fig. 2). The louse feeds on an infected, rickettsemic person. The organism in the louse infects its alimentary tract and results in large numbers of organisms in its feces within about 4-5 days. Close personal or clothing contact is usually required to transmit lice to others. When the louse takes a blood meal, it defecates. The irritation causes the host to scratch the site, thereby contaminating the bite wound with louse feces. Human infection might also occur by mucous membrane inoculation with contaminated louse feces.

 

 

Fig. 2. Pediculus humanus corporis

Human conditions that foster the proliferation of lice are especially common during winter and during war or natural disasters where in clothing is not changed, crowding occurs, and bathing is very infrequent.

In epidemic the susuptibility is high for all age groups.

Pathogenesis and Morbid Anatomy

After local proliferation at the site of the louse bite, the organism spreads hematogenously. Rickettsia Prowazekii, as with most rickettsia, produces a vasculitis by infecting the endothelial cells of capillaries, small arteries, and veins. The process results in fibrin and platelet deposition and then occlusion of the vessel. Perivascular infiltration with lymphocytes, plasma cells, histiocytes, and polymorphonuclear leukocytes occurs with or without frank necrosis of the vessel. The angiitis is most marked in the skin, heart, central nervous system, skeletal muscle, and kidneys.

The mechanism of the development of epidemic typhus may be represented by the next phases:

1.     Penetration of Rickettsia Prowazekii into organism and reproduction in the endothelial cells of the vessels.

2.     Destruction of endothelial cells and penetration of rickettsia into the blood rickettsiemia, toxinemia.

3.     Functional violations of the vessels in all organs and tissues - vasodilatation, slowdoun of the stream of the blood.

4.     Destructive and proliferative alterations of the capillaries with formation specific granulemas (nodules).

5.     Formation of immunity.

Small hemorrhages in the conjunctivae are frequent. The heart usually shows slight gross changes. Microscopically the blood vessels show similar lesions to those observed in the skin, and sometimes there is considerable infiltration with mononuclear and polymorphonuclear cells. Thrombi are rarely found in the larger blood vessels.

The blood is usually duck colored and liver and kidneys show cloudy swelling. The spleen is somewhat enlarged during the early stages of the disease but tends to be normal in size later on. It is often very soft and then may rupture from being handled at autopsy. Microscopically, engorgement with blood, with extensive phagocytosis of red blood corpuscles and diminution of lymphoid elements, is commonly present.

The lesion in the brain, particularly in the basal ganglia, medulla and cortex of the cerebrum, and more rarely in the white matter and cerebellum, correspond in size to miliary tubercles and are secondary to lesions of the small blood vessels and capillaries, as in the skin. They first consist of a collection of large cells of vascular and perivascular origin, endothelium, and monosytes, with necrosis resulting from occlusion of the vessel.

Clinical manifestations.

Epidemic typhus is cyclic infectious disease. There are the next periods in the course of the disease: incubation period (its duration is from 6 till 25 days). Initial period till appearance of the rash (its duration is 4-5 days), period of climax from appearance of rash till normalization of the temperature (its duration is from 4-5 days till 8-10 days) and period of reconvalescence (its duration is 2-3 weeks).

After an incubation period an abrupt onset with intense headache chills, fever and myalgia is characteristic. There is no eschar. The fever worsens quickly and becomes unremitting and the patient is soon prostrated by the illness. Giddiness, backache, anorexia, nausea are observed in the patients. The appearance of the patient is typical. The face is edemaous, flushed (Fig. 3). Eyes are brilliant with injected sclera (rabbits eyes)(Fig. 4). Enanthema (small hemorrhages) on the basis of uvula is marked on the second or third day of the disease (symptom of Rosenberg). The petechial rash may be revealed on transitive folds of conjunctiva from the third-forth day (symptom of Kjary-Aucyne). the early sign is tremor of the tongue, its declining to the side (symptom Govorov-Godeljae) due to bulbaric disorders. Splenomegaly is marked on the 3-4 day of the disease in the majority of the patients.

 

 

 

 

Fig. 3. Patient with epidemic typhus

 

Fig. 4. Injected sclera (rabbits eyes)

 

Climax period is characterized by development of all clinical manifestations of the disease. The temperature is definite high level (febris remittans). Temperature decreases frequently on the 3-4, 8-9 and 12-13 day of the disease and than the temperature increases again. Climax period is accompanied by intoxication and damage of central nervous system.

The appearance of the rash is an important sign of climax period. A rash begins in the axillary folds and upper part of the trunk on about the fifth day of illness and spread centrifugally. Initially, the rash consists of nonconfluent, pink macules that fade on pressure, may be rose- and petechial like (Fig. 5). Within several days, the rash becomes maculopapular, darker, petechial and confluent and involves the entire body, palms and solls but never the face (Fig. 6). Disappear with decreasing of temperature.

 

Fig. 5. Petechial like rash

 

The Circulatory System. Very outspoken is cardiac weakness due to myocardial degeneration. The heart sounds are very weak and the pulse feeble, rapid and irregular. The blood pressure often is very low, especially the diastolic, and may remain so throughout the disease. Bradycardia may be marked during convalescence.

The Respiratory System. Cough may appear in the first days, but usually is first troublesome about the time of the eruption. By the end of a week, the cough becomes loose and rales of various types may be noted.

The Alimentary Tract. Constipation is usually noted. Very marked is the tendency of the mouth and tongue to become dry and sordes to collect on the teeth. It is often difficult to get the patient to protrude his tongue when told to do so. In the patients with epidemic typhus splenomegaly and hepatomegaly (from one second week) are marked.

 

Fig. 6. Maculopapular rash

 

The Nervous System. Clouding of the consciousness may be as marked in this disease. Dull aching frontal headache is common and is an early predominating symptom. It frequently diminishes before the eruption appears. A dull stuporous state soon comes on. Delirium is marked in some cases. There are often the faces and mental state of alcoholic intoxication. There may be meningitis, meningoencephalitis.

In epidemic typhus fever it may be leucocytosis, neutrophylosis, monocytosis in the blood. ESR is accelerated.

The variants of the course of the disease

There are mild, moderate and serious course of the epidemic typhus fever. During the light course of the disease the occurrences of intoxication are expressed insignificantly. The temperature increases till 38 C. The consciousness is no changed. The rash predominates as roseoles. The liver and spleen increases in the third patients. The duration of fever is till 9 days. The mild course is observed in 10-20 % patients.

The medium serious course of the disease occurs more frequently (60-65 % patients). The temperature increases till 38-39 C. The duration of the fever is 12-14 days. The signs of the intoxication are expressed temperate.

During the serious course of the epidemic typhus fever expressive intoxication, hypotonia, tachycardia ( till 140 in minute) are observed. The tones of the heart are deaf. There is acrocyanosis. The dyspnea occurs, it may be violation of the rhythm of the breathing. The cramps of the muscles, the violation of the swallowing are marked. The temperature increases till 40-41 C. The rash is petechial, it may be hemorrhage. The serious course occurs in 10-15 % patients. The serious and very serious course of the disease takes place in elderly people.

Complications

Bronchitis, pneumonia otitis media, parotitis, nephritis, tromboses of various vessels, both abdominal and peripheral may be present.

Diagnosis

The methods of the laboratory diagnostic are serological: indirect hemagglutination, indirect immunofluorescens, complement fixation. During the period of onset of the diseasethe differential diagnosis is performed with grippe, pneumonia, meningitis, hemorrhagic fevers. During the period of the climax the differential diagnosis is performed with typhoid fever, ornithosis, drug disease, leptospirosis, infectious mononucleosis, trichinellosis.

 

Treatment

The treatment of the patient is complex: etiotropic, pathogenetic and symptomatic.

Etiotropic therapy. Chloramphenicol and tetracycline are more effective in epidemic typhus. The recommended dose for tetracycline is 0.3-0.4g, chloramphenicol 0.5g four times per day. Usually antibiotics are abolished from the third day of the normal temperature.

Pathogenetic therapy includes heart (corglycon, strophantin) and vascular (cordiamin, ephedrine, mezaton) remedies. During the serious course the disintoxicative and dehydrative therapy is performed. Sometime during the case of expressive exciting bromides, aminaszin, barbiturates, seduxen are prescribe. The patients may walk from 7-8 day of the normal temperature. The discharge of the patients from the hospital may be realized at 12 day of the normal temperature.

Prophylaxis

Control of the human body louse and the conditions that foster its proliferation is the mainstay in preveting louse-borne typhus.

Typhus vaccine is prepared from formaldehyde-inactivated Rickettsia Prowazekii grown in embryonated eggs. Typhus vaccination is suggested for special risk group.

 

BRILL-ZINSSER DISEASE.

Brill-Zinsser disease occurs as a recrudescence of previous infection with Rickettsia Prowazekii. It occurs in the United States primarily in immigrants from Eastern Europe whose initial infection was early.

Brill-Zinsser disease is acute cyclic disease. It is endogenic relapse of epidemic typhus. Brill-Zinsser disease is characterized by sporadic morbidity in absence of louse.

In Brill-Zinsser disease the pathogenesis and morbid anatomy are similar epidemic typhus, however the process is less expressive, because the concentration of rickettsia Prowazekii is similar in the blood. The course of Brill-Zinsser disease is more light than epidemic typhus, but the patients have all typical symptoms of the disease.

Initial period (its duration is 3-4 days) is accompanied by temperate intoxication. Headache, disorder of sleep, increase of the temperature till 38-39 are marked. Enanthema is observed rarely (in 20% of the cases). The duration period is usually 5-7 days. It is characterised by temperate hyperthermia (38-39) of remittent or rarely constant type.

The sighs of the damage of the central nervous system are expressed temperately. Meningeal sighs are revealed rarely.

A rash is observed in 60-80%of the patients. The sighs of the damage of the cardiovascular system are marked frequently. Enlarged liver and spleen are revealed inconstantly.

In Brill-Zinsser disease the complications develop rarely. It may be pneumonia, thrombosis, thrombophlebitis.

The treatment is such as in epidemic typhus.

The differentiation of primary louse-borne typhus is made by showing that the antibody produced is IgM (primary louse-borne) or IgG (Brill-Zinsser disease).

 

MALARIA

Definition

Malaria (from the colloquial Italian mala - bad, and aria - air) is an infection characterized by certain febrile disturbances caused by protozoan parasites of the class Sporozoa and of the family Plasmodiidae. Man is the intermediate host of these parasites, which undergo an asexual stage of development in the red corpuscles. The Parasite undergoes a sexual phase of development in the Anopheles mosquito, which is hence the definitive host. Man acquires infection from the bite of such an infected mosquito. Clinically, malaria is characterized by periodic attacks of fever, associated with anemia and enlargement of the spleen, and if untreated, with cachexia and a deposit of black pigment in the various organs. The malady is amenable to treatment with quinine and several other synthetic compounds inimical to the life of the parasite.

 

 

History

Malaria was formerly supposed to be due to poisonous emanations from damp ground, hence the term "malaria," introduced into English literature about 1829. Hippocrates, 460-370 B.C., in his book on epidemics, noted the existence of periodic fevers, divided them into quotidian, tertian, quartan, and subtertian, and referred to the enlarged spleen. Celsus recognized 2 types of tertian fever, one benign and similar to quartan fever, the other in which the attack is of longer duration and far more severe in character, the fever occupying 36 of the 48 hours and not entirely subsiding in the remissions, but being only mitigated.

Columella, about 116 B.C., suggested that the virus of malaria emanated from marshes and associated the disease with insects originating in them which attacked man in swarms. Also in the time of Caesar, views were expressed by Varro that swamp air might be the cause of malaria and furthermore that animals, so small that the eye could not follow them, might transmit diseases by way of the mouth or nose. In view of our present knowledge, it is remarkable that Lancisi. in 1718, should have associated marshes with the development of gnats, which insects he thought could not only introduce with their proboscides the putrefying organic matter of such swamps, but animalcules as well.

In 1638, Countess del Chinchon, wife of the Viceroy of Peru, was cured of an intermittent fever by treatment with the bark of a certain tree, which bark was introduced into Europe in 1640. Linne, who named the genus of quinine-producing about 100 years later, left out the first h in the name, hence the mistaken spelling Cinchona.

Discovery of the Parasite

The year 1880 was a most important one in the history of malaria, for on November 6, 1880, Laveran, at Constantine, first recognized the parasites of malaria while carrying on investigations as to the origin of the "pigmented bodies" and pigmented leukocytes. He observed not only spherical pigmented bodies, but also crescents, and in particular the flagellation of the male gamete, which demonstrated to him that these were living organisms. He proposed the name Oscillaria malarias on account of the movements of the flagellate body, but this had to be dropped as not valid, the generic name Oscillaria having been previously applied to another organism.

Mosquito Transmission. In 1894 Manson formulated the hypothesis of the mosquito transmission of malaria. He based this upon facts he observed in tracing the life-history of filaria and upon the fact that in malaria the flagellation of the male gametocyte does not take place for several minutes after the removal of the blood from the peripheral circulation. He also suggested that larvae might feed upon infected mosquitoes dying upon the water and thus acquire the disease.

Ross for 2 years caused mosquitoes to feed upon the blood of malarial patients which contained crescents, but as he used insects of the genera Culex and Aedes no development of the parasites in the tissues of the mosquitoes occurred, m 1897 he used eight dappled-wing mosquitoes (Anopheles Stephens) and in 2 of these, upon dissection, he noted the development of the pigmentary bodies to be different from anything he had observed in hundreds of dissections of other mosquitoes.

In 1886 Metschnikoff, from observation of sporulating parasites in the brain capillaries at the autopsy of a malarial case, considered them to be coccidial in nature.

Four parasites, all of this genus, may give rise to malaria in man; the names of the species are Plasmodium vivax which produces benign tertian malaria, Plasmodium malarias of quartan malaria, Plasmodium ovate another tertian parasite, and Plasmodium falciparum, which causes malignant tertian malaria. Each of these species shows the following characters which are possessed by the genus, as it affects man.

Before proceeding to study the parasites there are certain terms which require definition.

Life history

This comprises two cycles or phases of development (Fig. 7):

a)                schizogony in the tissues of man, which is succeeded by schizogony occurring in the blood stream of man ; these form the asexual cycle of the parasite ;

b)               sporogony, the sexual cycle, which occurs in the body of an anopheline mosquito.

 

Fig. 7. Cycles of Plasmodium development

 

Schizogony. When the sporozoite is introduced into man's skin by the bite of an anopheline mosquito it passes into the blood stream from which it rapidly disappears to enter a parenchyma cell of the liver. Here a process of growth and multiplication occurs, known as preerythrocytic schizogony, which results in the development of a large schizont, measuring up to 60m in diameter and containing thousands of tiny merozoites less than 1m in size. The mature schizont ruptures about the seventh to the ninth day liberating the merozoites which enter the circulation and invade red blood corpuscles. This starts the phase of erythrocytic schizogony which, however, may not become demonstrable by the examination of blood films until one or two days later.

Erythrocytic schizogony occurs in the circulation and extends from the newly liberated merozoite which is ready to infect a fresh cell, to the rupture of the mature schizont with its contained daughter merozoites. This cycle occupies a period of forty-eight hours in P. vivax, ovale, falciparum and seventy-two in P.malaria, for its completion. The merozoites attack fresh cells, and in them develop into rings, after which the parasites grow through the large trophozoite stage, attain full size, and then proceed to reproduce by division. As soon as this has commenced, when there is evidence that the nucleus has divided and the cytoplasm begun to segment, the term "immature schizont" is applied. Later, when the parasite has reached the stage at which it is fully segmented, and when the merozoites are just about to be liberated by the disruption of the red cells, it is called a "mature schizont." The distended cell ruptures, and the merozoites are thus liberated into the plasma. The residual material is at the same time set free, and, with its contained pigment, is quickly ingested by fixed endothelial cells of the blood vessels, or by wandering phagocytes, usually large mononuclears. Such pigmented leukocytes may be found in stained films if the blood is examined soon after the schizonts have ruptured. The liberated merozoite contains no pigment, immediately enters a fresh red cell and starts the cycle again. As a result of repetition of the erythrocytic cycle and progressive invasion of fresh cells, the infected person in the course of ten days or so develops fever; the period of incubation may, however, be shorter or much longer than this.

There is strong indirect evidence to suggest that in the case of P. vivax, P. ovale and P. malarias the tissue phase of the parasite does not end with the rupture of the pre-erythrocytic schizont and the invasion of the circulation by its merozoites. It is believed that a cycle, known as exoerythrocytic schizogony, continues in the tissues, some of the liberated merozoites invading fresh liver cells and again proceeding to schizogony. According to this hypothesis, even when parasites are absent from the blood, schizogony is continuing repeatedly in the tissues, persisting often for years. On occasions merozoites are discharged into the circulation where they infect red blood corpuscles and thus recommence erythrocytic schizogony, causing parasitaemia. No such evidence exists in the case of P. falciparum, and it is thought that when the preerythrocytic schizonts of this species have discharged their merozoites into the blood stream the cycle of the parasite in the tissues ends.

Sporogony.

The sexual or sporogony cycle occurs almost entirely in the anopheline mosquito. In this method of reproduction there are, however, as we saw, preliminary, and also terminal, stages in the blood. Certain merozoites, instead of repeating the asexual cycle, become gametocytes, of which some are male and some are female. These are found in the peripheral blood. If they are taken up by the mosquito in biting, further development very quickly occurs, the remains of the infected red cell being discarded during the process. The asexual parasites ingested with the blood by the mosquito are destroyed in the gut; it is only the gametocytes which survive, and are able to infect the insect. In the case of P. falciparum, as we saw, the gametocytes are crescent-shaped, and the first step in the development is that they assume a rounded form like those of P. vivax and P. malarias. The next step is, that in the male, or microgametocyte, the pigment is suddenly observed to be in violent commotion and soon several filaments are extruded each of which contains a granule of the nuclear chromatin. These are extremely active, and it is they which caused the rapid movements of the pigment granules. They detach themselves and swim away; these are the male gametes or the microgametes, which correspond to spermatozoa. The female or macrogametocyte has meanwhile undergone a nuclear reduction process by which it is transformed into the female gamete or macrogamete. This is an unfertilized ovum, and it attracts the active microgametes, one of which penetrates and fertilizes it. After this, the ovum or zygote, as it is now called, is capable of slow movements and hence is known as an "ookinete." This passes between the cells lining the insect's gut, till it reaches the outer limiting membrane. It then ceases to move, becomes round and proceeds to grow, the membrane acting as a cyst wall. This stationary growing ookinete with its covering is called the oocyst, and it grows from about 6 to 60 m in size. Since the zygote is simply the female malaria parasite after fertilization by the filamentous male gamete, there is still some pigment in it, and this can be detected inside the oocyst. The nucleus of the zygote divides repeatedly, and finally there are produced, inside the oocyst, thousands of minute thread-like structures called sporozoites. When the oocyst becomes mature it ruptures, and the contained sporozoites are set free in the insect's haemocoele, the circulation of which carries them to all parts of the mosquito's body.

Some of them invade the cells of the salivary glands, pass through them and reach the lumen, which communicates with the salivary ducts. The mosquito is now infective. When next it bites man, the salivary fluid containing the sporozoites passes into the skin wound. A mosquito may acquire and be able to transmit a double infection. It is possible for a single infective mosquito to transmit malaria to several people in succession, and at considerable intervals. The supply of sporozoites in the salivary ducts is replenished by a further passage of those in the hemocoele, through the gland cells, into the lumen.

The sporozoite is a narrow, slightly curved organism, measuring about 12 m in length; it tapers at both ends, has an elongated central nucleus and is devoid of pigment. It is capable of slight undulatory movement As already noted, when it is inoculated into man it is carried in the blood stream to the cells of the liver, which it enters; there it rounds up, starts to grow, and so commences the asexual cycle in man.

The sexual cycle in the mosquito requires about eight to eighteen days for completion, depending on conditions such as moisture and temperature. In the case of P. malarias the sexual cycle in the mosquito is commonly as long as four weeks.

The asexual cycle can be started in a person otherwise than by the bite of an infective mosquito, for example, by inoculating blood which contains asexual forms, into a fresh subject. If it happens that the only forms present in the infected person's blood are gametocytes, such as the crescents of malignant tertian malaria, no infection will result, as these can only infect the mosquito, and do not infect man.

 

 

Epidemiology and endemiology

Conditions which favour the presence and breeding of anopheles mosquitoes tend to the increase of malaria, and vice versa, and, whatever favors access of those insects and the parasites they contain, also favours the acquisition of malaria.

In subtropical regions subtertian malaria is a primary infection in summer and early autumn, hence the popular term - cestio-autumnal fever. This peculiarity can be explained to some extent by the higher atmospheric temperature required for its development in the mosquito. Hence, though benign and subtertian forms are frequently associated, and the latter can be acquired at any time in the tropics, it is only in the summer and early autumn that subtertian can be acquired in more temperate zones. When the temperature falls below 15 C. development of the oocyst in the mosquito is arrested, but when once the sporozoites have entered the salivary glands, they are capable of infecting man, even during the winter season.

Malaria incidence is usually endemic, but hyperendemicity is a distinct form, demanding for its production such an intensity of transmission that a high degree of tolerance to the effects of reinfection is induced in those who experience its effects over a number of years, especially as a result of repeated infections in early childhood.

The World Health Organization has proposed the following classification:

I Hypoendemic Malaria with spleen rate in children 2-10 years of age 0-10 per cent.

II Mesoendemic Malaria with spleen rate in children 2-10 years of age 11-50 per cent.

III Hyperendemic Malaria with spleen rate in children 2-10 years of age constantly over 75 per cent. Spleen rate in adults is also high.

IV Holoendemic Malaria with spleen rate in children 2-10 years of age constantly over 75 per cent. Spleen rate in adults low; it is in this type of endemicity that the strongest adult tolerance is found.

Morbid anatomy and pathology of malaria

The pathology of malaria is based really upon subtertian infections (P. falciparum). Most of the lesions in the internal organs are due to infection of red blood corpuscles with consequent disturbance of the oxygen supply to the tissues. The vascular flow within the organs is disturbed by vascular collapse, obstruction of the smaller vessels by auto-agglutination, thrombosis, infarctions and similar effects brought about by the clumping together of parasitised cells. All these factors slow down the circulation and cause "ludging" (Knisely) which is thought to be mainly due to the production of a fibrin-like substance. Cardiac and vascular failure may ensue. In addition there are explosive discharges of protein from the liberated merozoites and the disintegration of disrupted red cells, defunct parasites and extrusion of pigment. The spleen, when grossly enlarged, used to be popularly known as the "ague cake". Although it is apt to fluctuate in size it is most certainly always swollen during an acute attack. On section the surface is dark, at times almost black, dark-red, purple or chocolate color from congestion and melanin pigmentation. In severe subtertian infections, the parenchyma may be so softened as to be almost diffluent and so swollen that the capsule is tightly stretched. When the pulp is washed, the malpighian bodies stand out as gray particles.

In chronic cases perisplenitis develops from stretching or tearing of the capsule, so that rupture may occur spontaneously or as the result of violence. On microscopic examination the organ contains a large number of macrophage cells, the special cells of Billroth, fibrinous cords, and sinus-lining littoral cells. In the chronic stage there is replacement by fibrous tissue. The malpighian bodies shrink while the pigment becomes scattered. All erythrocytic stages of the parasites can be detected in the red cells (P. vivax or P. falciparum) as well as the merozoites set free in the pulp. Numerically they are more numerous than in any other organ.

Malaria pigment is readily recognized free within the tissue spaces and enclosed within the reticulo-endothelium, and especially in the mononuclear cells. In acute cases the reticulo-endothelial system becomes blocked with pigment and in the later stages this is also replaced by fibrous tissue. Areas of thrombosis and hemorrhagic necrosis also occur.

The liver is usually congested, enlarged, pigmented, and olive-brown in color, especially in the left lobe which receives the splenic blood. Glisson's capsule which surrounds the portal system is thickened and stretched. In chronic malaria there is fibrosis and round-cell infiltration which originates, it is thought, from the cryptozoic or tissue stages of the parasites. In infancy and early childhood, the enlargement, is mainly due to sinusoidal dilatation; in later years, the congestion is

mainly confined to the center of the lobule, and so the appearance resembles that, of the "nutmeg" liver of heart failure. The slaty gray color frequently encountered is due to deposits of pigment. Parasitized erythrocytes and melanin (hemozoin) pigment are found within Kupffer cells.

It is probable that the slight periportal fibrosis which is commonly encountered in African livers has a dual pathology because, in addition to malaria, there is malnutrition which is responsible for diffuse, piecemeal necrosis of the hepatic cells. Parasites, in all erythrocytic stages, are found in the sinusoids and in the parasitized erythrocytes. The parenchyma, cells do not usually take up malaria pigment, but contain granules of hemosiderin. Lysis of the red cells leads to obstruction and over-distension of the bile canaliculi which become obstructed by bile pigment. The parenchyma cells show all stage of degeneration, and in severe P. falciparum infections there is widespread focal necrosis surrounding the central vein. Small hemorrhagic areas may also be present.

Malaria pigment is now termed hemozoin, and is a compound of hematin which contains non-ionizable iron; hemosiderin also does so but it does not give the Prussian blue reaction with potassium ferrocyanide, unless first acted upon by nitric acid and hydrogen peroxide. In the kidneys, it is to be noted that albuminuria is common in malaria and may adumbrate serious renal damage, and this is specially true in subtertian and quartan infections. Sometimes there is azotemia with hyperpiesia and cardiac hypertrophy. In severe cases the lumen of the tubules becomes filled with granular casts and the cells show fatty changes resembling parenchymatous degeneration. Signs of glomerulonephritis are also sometimes present. In quartan nephrosis Surbek (1931) occasionally found the enlarged, pale, white kidneys typical of degenerative parenchymatous nephrosis.

The changes in the heart in subtertian malaria are edema due to cardiovascular failure. In the bone marrow the yellow and adipose tissues are very vascular. The red marrow is of a chocolate brown, especially at the periphery and this is due to deposits of pigment. Phagocytosis is evident with hemozoin, macrophages and parasitized cells in large numbers. In chronic cases the reticulo-endothelium is hypertrophied. In the marrow itself there is a normoblastic response. Occasionally megaloblasts may be seen and reticulocytes are increased in the peripheral blood.

In the pancreas there is often focal necrosis, affecting the nutrient vessels of the Islets of Langerhans. Rarely the pancreas is hemorrhagic. The suprarenals are attacked in subtertian malaria, resulting in partial or complete loss of lipoids in the cortex, with congestion and blockage of vessels with malaria parasites; this is probably responsible for algid symptoms in subterian malaria. In the placenta the . maternal sinuses are packed with parasites interfering with the nutrition of the fetus, which may become infected at birth, possibly through the umbilical cord, or through a tear in the placenta. In the intestinal tract achlorhydria is common in the I acute stages. The blood capillaries are loaded with parasites and degeneration of the mucosa is encountered which may give rise to dysenteric symptoms in life.

The brain usually bears a leaden hue due to deposition of hemozoin and the presence of parasitized cells in the capillaries. The gray matter is smoky gray while the white matter is speckled with punctiform hemorrhages (cerebral purpura). The smaller capillaries become completely blocked with parasitized cells and the plugging is most common at the bifurcation of the blood vessels (Ariete).

Malarial granulomata are focal degenerations in the brain substance, the result of former hemorrhages. Granuloma is sometimes an inappropriate term, for these lesions somewhat resemble tubercles and are formed by an agglomeration of glial cells around a focus of degeneration.

In massive infection the capillaries are blocked and thrombosed. As Maegraith has pointed out, thrombosis takes place. There are numerous small hemorrhages with "granulomata" in the subcortical zones. Clinically this is associated with malarial coma. Generalized toxemia is characterized by fits and convulsions. There are small and scattered hemorrhages. Embolism produces punctiform hemorrhages, especially in the corpus callosum.

Clinical manifestations

An attack of malaria may either be a primary attack or a relapse. A primary attack normally develops after an incubation period of 10-14 days; by direct blood inoculation it is about 11 days. In insect transmitted subtertian malaria, where the number of infecting bites is high, the incubation period tends to be shorter and may only be five days. In naturally transmitted benign tertian malaria, especially in Europe, there may be latent period of several months before symptoms appear; the latent period usually covers the winter months. P. ovale may also show very long latent periods (Trager and Most, 1963). This is known as latent malaria. The latent period preceding the primary attack is known as incubation latency; a period or periods following upon the primary attack are know as infection latency. In subtertian malaria there is no latency in the same sense as in benign tertian. The type of temperature curve, whether intermittent or remittent, is less significant than formerly considered to be the case. Thus primary benign tertian infections may produce a remittent temperature curve before assuming the classical intermittent character. Two or more generations of tertian parasites, maturing in the blood at different times, will produce quotidian fever and two or more generations of quartan will give a fever on two successive daysquartana duplexor conversely on three successive days, a quotidian feverquartana triplex.

Relapses are defined as recurrences of malarious symptoms and the reappearance of malaria parasites in the peripheral blood, following recovery from the initial attack. Therefore relapses must be distinguished from reinfections.

Recrudescences of malaria are defined as relapses of the patient at the time he is removed from the endemic area. Relapses often follow the cessation of suppressive treatment, exposure to cold, exertion, parturition, or surgical operations.

The characteristic ague is divided into three stages : (1) cold stage, (2) hot stage and (3) sweating stage. One or even all these stages may be absent on occasions, especially when the infection is of long standing, whilst in subtertian fever many symptoms are so bizarre that they may be most misleading, so as to enforce the conviction that in many respects it is quite a different disease.

Herpes on lips and nose (fever sores), often extensive, frequently follow the rigors and are an accompaniment of all forms of malaria. Similar eruptions have been noted on the ears.

Premonitory stage.For several days before the actual attack the patient may be conscious of headache, lassitude, a desire to stretch or yawn, aching in the bones, anorexia, sometimes vomiting.

Cold stage.This usually lasts one to two hours, and is the rigor, or "ague." The feeling of cold is intense and universal. The teeth chatter; - the patient shivers from head to foot and wraps himself up in any garment he can lay his hands upon. Vomiting may be most distressing. The features are pinched, the fingers shrivelled and the skin blue like "goose-skin" (cutis anserina). The feeling of cold is purely subjective, because the temperature is rapidly rising. Children usually have convulsive fits.

Hot stage.The hot stage may last from three to four hours. The shivering abates and gives place to, or alternates with, sensations of great heat. The clothes are thrown off. The face is flushed ; pulse full, bounding and usually dicrotic; headache intense ; vomiting usual; respiration hurried ; skin dry and burning; the temperature rising to 40 C, sometimes 41,1 C, rarely higher.

Sweating stage.This usually lasts from two to four hours. The patient breaks out into profuse perspiration with sweat literally running off him in streams, saturating clothes and bedding. With sweating the fever rapidly declines. Headache, thirst and distress give place to a feeling of relief and tranquillity. When it has ceased the patient may feel exhausted, but quite well and able to go about. The body temperature is now subnormal and remains so until the approach of the next paroxysm, one or two days later. The total duration of the fever cycle may be from six to ten hours.

Urine and feces in ague.During the cold stage the urine is abundant and limpid, and micturition frequent; during the hot sweating stages it is scanty, cloudy, sometimes albuminous. Urea excretion is increased during the rigor and hot stages, and so is that of the chlorides and sulphates. Phosphates, on the contrary, diminished during the rigor and hot stages, are increased during defervescence. Augmentation in urea excretion commences several hours before the attack, attains its maximum towards the end of the rigor, and decreases during the terminal stages, though still above the normal figure.

A fleeting glycosuria has also been observed from time to time. The urine usually contains urobilinogen and urobilin in excess during the attack, but they decline with the temperature and form a valuable diagnostic sign, especially in subtertian malaria. The corresponding pigment in the feces (hydrobilirubin) is increased twenty times the normal amount whilst parasites persist in the blood.

The spleen during ague.The spleen is enlarged and painful during the rigor, but in early infections is not always palpable, a feature which became specially noticeable in the second World War in India, Burma, and New Guinea, in benign as well as in subtertian infections. At first, the enlargement recedes during remission, but later, when relapses and reinfections occur, it becomes permanent as in the "ague cake." In primary infections the spleen is soft and spongy and therefore difficult to palpate, but in subsequent relapses it becomes harder and more fibrous. Spontaneous rupture of the spleen has been reported more frequently in P. vivax infections them with other species. Usually it is the result of violence, but Bearn (1961) has shown that in an adherent spleen it may be due to extensive subcapsular hematoma. Successful splenectomy does not necessarily extirpate the malarial infection.

Period of the day at which ague commences.Quite a large proportion of agues " come off" between midnight and noon or in the early afternoon. This time factor may constitute an important point in diagnosis, especially as pyrexial attacks somewhat simulating malarial agues may be caused by liver abscess, tuberculosis, Escherichia coli infections of the urinary tract and septic conditions, in all of which febrile recurrences are apt to take place during the afternoons or evenings.

Course of benign tertian and quartan fevers.Benign tertian ague usually lasts ten hours or less and may be taken as the type of a malarial attack. In some cases the rise of fever is rapid and high, and the temperature may reach 40,6 to 41,1 C within an hour or so; on the other hand, in some cases none of the clinical phenomena are present and the temperature does not rise above 37,2-37,8 C. Benign tertian, unless complicated, is not usually fatal; but the persistent and relapsing character makes it a tiresome disease and, if prolonged, it may produce severe anemia and debility. It may also produce thrombocytopenia.

In Central Russia, a fulminating type of benign tertian malaria, with hyperplasia of the spleen and cerebral edema, especially in children, has been described. Also two types (Nikolaev, 1935) are recognized: the Northern with an incubation period of 8-14 months; the Southern with an incubation period of 9-21 days. The length of this period does not depend upon the number of sporozoites introduced. Different incubation periods are actually produced by mosquito bites of the same batch after feeding on the same donor (Tiburskaya, 1961).

Certainly many strains of P. vivax seem to exist which differ in their virulence ; some are mild, as in Holland ; sometimes the fever is trivial and isolated attacks, without recurrence, are common enough. Various strains of P. vivax have been found to possess distinctive characters and vary in the number and frequency of the relapses they produce.

The presence of a rigor appears to be an index of severity. The mean maximum temperature for the paroxysms is 40,1 C. As a general rule, the duration of a simple benign tertian infection before the parasites die out from the peripheral blood is nine months to one year after leaving the endemic area, but exceptions to this rule occur, as clinical relapses, with parasites in the blood, have been recorded as long as three years after the original infection. As it is seldom fatal, the pathology is not so well known as that of subtertian malaria, but it resembles it in a minor degree.

The fever in quartan malaria is generally smart while it lasts, and is well defined in its various stages, but it does not produce much systemic disturbance or cachexia or rigors. It has often been remarked that, whilst individual attacks of this infection are amenable to quinine and atebrin, the disease is more persistent than tertian or subtertian, so that attacks are apt to occur from time to time over a period of many years and may persist as long as 12-21 (Duggan and Shute, 1961). It is becoming increasingly realized that sometimes quartan parasites may be present in the blood without evoking any special symptoms. Parasites are usually scarce in the peripheral blood. They are more resistant to antimalarial drugs in the sense that they persist in the bloodstream for a week or more while the patient is taking the drug.

Quartan periodicity is the hall-mark of quartan malaria and is hardly ever found in any other disease. Double quartan and triple quartan fevers may be observed. In the latter the temperature course becomes quotidian. Occasionally, quartan fevers are encountered without splenomegaly and apparently when parasites can be found in the blood only after prolonged search: sometimes not at all, so that their true nature can be ascertained solely by the action of chloroquine by injection.

Relapses in quartan malaria may be of two forms: those occurring after a short interval are due to exacerbation of a low-grade parasitemia, but those in the longer interval of several months to release of exoerythrocyte parasites from the liver into the bloodstream.

Coma.Sometimes the patient, without hyperpyrexia (the temperature perhaps not rising above, or even up to, 40), may lapse into coma. The coma may pass away with a crisis of sweating ; on the other hand, an asthenic condition may set in and death supervene. There is often a paralytic squint, extensor plantar response and Cheyne-Stokes respiration. When subcortical hemorrhages are present, death usually ensues. There is a marked increase of pressure in the cerebrospinal fluid, with increase of lymphocytes up to 400 per c.mm., as well as of albumin and globulin. Occasionally, granules of malarial pigment may be found. It is important to note that parasites may be very scanty in the peripheral blood and not infrequently they may be absent altogether. The coma may persist for as long as 46 hours and then recovery ensue with quinine injections, (or chloroquine) as in the case reported by A. Cr. Tresidder in 1914.

Other cerebral manifestations are cerebral depression, excitation, cerebellar ataxia (Sawyer-Brown variety), behavior changes and character alterations, meningismus closely simulating meningitis. Rarely a focal spine lesion may cause paraplegia.

Algid forms.

The algid forms of pernicious attack, as indicated by the name, are characterized by collapse, extreme coldness of the surface of the body or, in other words, by peripheral vascular failure. These symptoms usually co-exist with elevated axillary and rectal temperature. Flooding of the peripheral blood with vast numbers of parasites in all stages of developmentgametocytes as well as schizontsis sometimes found. The prognosis is usually bad, but rarely this may be seen in an attack of average severity. It indicates a continuous fever of at least two weeks, or a relapse of short duration.

There are some misleading clinical forms of subtertian malaria which are important, for instance the gastric, choleraic, dysenteric, hemorrhagic, and edematous forms. The last with generalized anasarca were prevalent in war refugees from Givece (1945) and in the great Ceylon epidemic of 1934. Acute hemolitic anaemia, resembling pernicious anemia, may be a prominent of subtertian malarial cachexia. More rarely seen are the edematous forms with anasarca and ascites and also with nephritic signs with blood cells and albumin in the urine.

Diagnosis from clinical signs.The most important clinical sign is periodicity of the fever, which occurs in its most typical form in the tertian and quartan infections ; in the subtertian, however, fever may be most irregular, or there may be no pyrexia at all.

Enlargement of the spleen is a common clinical sign in all forms of malaria. In old-standing infections it may be very large indeed, and occupy the greater part of the abdominal cavity, but in early, and it may be very severe, cases it may not be sensibly enlarged at all, and therefore fails entirely as a clinical guide ; usually, however, in the absence of splenic enlargement, splenic pain is present during the attack. Moreover, the patient may be suffering from some totally different disease, and the palpable spleen may be the result of a long-standing malaria infection, quite unconnected with the attack in question.

To the clinician accustomed to many cases, the general appearance of malaria patients, the bright glistening eye, set in rather a dusky orbit, contrasted with the pale and ochreous complexion, combine to create an almost diagnostic appearance. Amber colored urine due to excessive urobilinuria. especially in subtertian malaria, and even in the absence of parasites in the peripheral blood, may be suggestive.

Sudden fever in a previously healthy person who has recently arrived from a malarious country usually turns out to be malaria. The patient will generally give a history of similar attacks while resident abroad, but there are exceptions to this rule, for, occasionally, residents of tropical countries may develop their first attack of malaria shortly after arriving in a cold climate, and this attack, aggravated by the conditions, may run a very severe course; this is especially the case with recent arrivals from the west coast of Africa, and it is true for both benign tertian and subtertian infections, the parasite lying dormant in the blood-stream perhaps as long as eight months; in the benign form a year or more. It should be borne in mind that, in the case of P. vivax, P. malarias and P. ovale all "prophylactic" drugs are in reality only suppressive. A possible diagnosis of malaria should therefore not be discounted on the grounds that drugs were continued for the advised 14 days after return to a non-malarious country.

An actual description of the febrile attack itself may be suggestive. The rapid rise of temperature, the history of the cold, the hot, and the sweating stages, the rapid defervescence of the fever, and the subsequent sense of well-being, are more characteristic of a malarial attack than of any other febrile disease. At times periodicity is a trustworthy enough clinical test. Tertian and quartan periodicity usually occur only in malarial disease, but have been seen in meningococcal septicaemia.

 

 

 

 

 

Differential diagnosis of malaria

The differential diagnosis of malaria entails a knowledge of all fevers, both tropical and non-tropical.

The following are often mistaken for malarial fever cerebro-spinal meningitis; fever of urinary origin (sometimes renal calculus); the fever attending the passage of gall-stones, or inflammation of the gall-bladder; that associated with pyelitis and surgical kidney; perirenal abscess; amoebic hepatitis and amoebic abscess of liver; lymphangitis, particularly that form associated with elephantiasis and other filarial diseases; undulant fever, relapsing fever; trypanosomiasis; kala-azar; "short-term fevers" of which dengue and sandfly fever are the most typical; the fever associated with tuberculous disease, with ulcerative endocarditis, with some types of pernicious anemia, with splenic leucocythemia, with visceral syphilis, with pulmonary carcinoma, with rapidly growing sarcoma, with forms of hysteria, and with many obscure and ill-defined conditions.

Treatment

At cupping of fever attacks at any kind of a malaria use preparations with shizotropic action: Chingamin (or.: Delagil, Hlorohin, Nivachin, Resochin, Trochin), and also quinine sulfas, quinine Dichlorid, Hydroxyhlorin (Plaquenil), Chloridin (Pyrimethamin, Tindurin), Sulfanilamid preparations, Meflohin, Tetracyclin, Doxycyclin. These preparations are active against bloody shizontes. The greatest action has Chingamin. Concerning tissue forms of plasmodiums the most active is Primachin.

At acute disorders of disease use Chingamin diphosfat during 3 days more often: in 1 day 1,5 gr. (at once 1 gr. and in 6 hours the others 0,5 gr.), in 2 nd and 3-rd day - unitary 0,5gr. The serious form of a tropical malaria demands prolongation of treatment course by Chingamin 2 days 0,5 gr. 1 time in days If plasmodiums are refractory to Chingamin, indicate quinine Dichlorid 2 ml 50 % of solution 2 times in 6 - 8 hours or in a vein very slowly 1 ml in 20 ml. 40 % solution of glucose, and then two injections under skin 1 ml. 50 % of solution. Chloridin in combination with Sulfanilamides preparations of prolonged action or the combined preparation Fansidar, which contains 0,5 gr. of Sulfadoxin and 0,025 gr. of Chloridin: 3 tablets unitary. Fansidar may be given also for prophylaxis of relapse of tropical malaria.

The mentioned preparations provide complete convalescence at tropical malaria. In case of tetrian fever and oval malaria indicate Primachin which have action upon tissue shizontes and prevent appearance of recedives. Similar activity have also Tetracyclin. Primachin is indicated simultaneously with Chingamin or right after terminations of treatment by it.

Treatment of specific complications is carried out in the urgent order. At development of malarial coma use a solution of quinine Dihydrochlorid. The next days indicate the preparations per os. Simultaneously carry out desintoxication therapy with Reopolyglycin, Polyglucin, Albumin, Rheogluman, Polyionic solutions. The total quantity of infused liquid should not exceed 1500 ml. Infuse up to 150 mg of Prednisolon in vein. Among other agents Diprazin, Suprastin, Furosemid are indicated.

At hemohlobinurine fever treatment starts with an immediate cancellation of Quinine, Primachin, Sulfanilamide preparations which might cause this complication. Infuse Cordiamin, Corglykon or Strophanthin, Phenylephin hydrochlorid, Prednisolon, and also Reopolyglycin, Quartasol or another polyionic solutions. In case of development of serious anemia transfuse the blood of the same group, blood plasma.

Individual chemioprofilaxis is carried out for the persons leaving in the endemic regions. For this purpose use Chingamin 0,5 gr. once a week, and in hyperendemic regions - 2 times per one week. Preparation is indicated during 5 days before arrival, all period of stay and during 8 weeks after departure. Among local population chemioprofilaxis begin 1 - 2 weeks before occurrence of mosquitoes. Occurrence of the tropical malaria is caused by drug resistant plasmodiums, prevent by reception of Fansidar once a week. To the persons who have arrived from endemic center of a tetrian fever, seasonal prophylaxis of relapses by Primachin in tablets 0,027 gr. per day during 2 weeks is carried out.