MALARIA 2 page

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

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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.

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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 days - quartana duplex - or conversely on three successive days,a quotidian fever - quartana 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.

Malaria

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 °Ñ, sometimes 41.1 °Ñ, 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 deased the patient may feel- exnausrea,DUX 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, Birma, 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

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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 Beam (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 °Ñ 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 °Ñ. 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.

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 °Ñ. 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. 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.

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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.

Quartan malaria nephrosis. Although kidney changes are associated with subtertian malaria,nephrosis is commonest in countries where the quartan parasite predominates.

According to Giglioli both sexes are susceptible, and especially children, in whom quartan malaria is most common, but in adults males predominate. He regarded albuminuria in a febrile attack as an indication of parenchymatous nephritis; Goldie, on the other hand, took a less serious view and considered the pathological picture as one of nephrosis and due to the production of malarial toxin's over a long period.

Additional evidence of the association of the quartan parasite with nephrosis comes from Bruce-Chwatt and others in Nigeria and Giglioli in Guiana who have shown that this serious complication in children has disappeared since the success of DDT suppression campaigns.

Course of ovale tertian malaria. This type closely resembles benign tertian and the attack may be ushered in by an initial remittent phase; but, generally speaking, the attacks are sudden, short and mild, and not accompanied by any grave degree of anemia, whilst the rigors are more apt to take place; during the evenings. Rheumatic-like pains in various parts of the body, especially the lumbar region, are characteristic, and sometimes pain referred to the appendix may suggest appendicitis. There is usually no excess of urobilinogen in the urine. Occasionally severe infections are encountered, with rigors, a temperature of 40.6 °Ñ, irregular tertian periodicity and persistent headache. It may evince considerable latency. Recurrences have never been observed. Peaks of fever are not usually as high as in benign tertian.

Course of subtertian or malignant malaria. There are probably many strains of P. falciparum differing from one another in virulence as James has shown with his Sardinian strain. Herpes labialis is commoner with this form.

In distinguishing subtertian malaria the rigor stage is relatively less marked, or may be absent entirely. The primary attack begins with a sense of chilliness. The hot and sweating stages are more prolonged and liable to be followed by an adynamic condition, together with vomiting, intestinal irritation, bone pains, anorexia, headache and supra-orbital neuralgia and a degree of moderate sweating. After apparent recovery from fever there is a tendency to recrudescence at shorter

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intervals than in benign tertian. Subtertian fevers are accompanied by rapid hemolysis toxemia and succeeded by marked cachexia. The underlying pathology is due to the sporulation of parasites in the internal capillaries so that, at any time during the course, and especially in primary infections, symptoms of the gravest character may appear. The tendency for successive paroxysms to overlap, or to become subintrant, is marked. When intermissions are distinct the crisis is what is called "a double crisis". Thus, when the fever has attained its apparent fastigium, there is a drop of one or more degrees of temperature - a false crisis

- followed by a fresh rise which is then succeeded by a true crisis. This peculiar

phenomenon has been attributed to the presence of two generations of parasites

in the blood, one of which matures somewhat later than the other; it occurs

ordinarily in one other tropical fever: kala-azar. Such an infection may therefore

produce a quotidian typhoid-like temperature chart. Even at this stage the

temperature may not exceed 39.4 °Ñ - 40 °Ñ. The liver is usually enlarged and

tender, especially in the region of the gall-bladder which itself is generally swollen

and turgid with bile, as the result of extensive hemolysis. These phenomena may

give rise to the impression of gallbladder disease.

Though this fever may be justly regarded as dangerous to life, yet it is singular that subtertian parasites may exist in the blood for months without seriously interfering with health. Sometimes attention is drawn in other directions

- to edema of legs, diarrhea, dyspepsia or some other apparently small complaint,

quite unconnected with malaria - and these may appear in men returning from

West Africa in whom the first symptoms of ill-health may be noted after several

weeks' residence in a temperate climate.

Manson said "What one sees in the peripheral circulation is only a reflection of the drama which is occurring in the internal circulation".

Bilious remittent. One type of subtertian fever - bilious remittent - has long been recognized on account of the bilious vomiting, gastric distress, sometimes bilious diarrhea, sometimes constipation, which accompany the recurring exacerbations. It is further distinguished by the pronounced icteric or, rather, reddish yellow or saffron tint of skin and scalars - a tint derived, probably, not from absorption of bile as in obstructive jaundice, but from modified hemoglobin (serum bilirubin) free in the blood or deposited in the skin and sclerotics. Sometimes cases are seen with intense icterus, high serum bilirubin and jaundiced sclera, without splenomegaly,but with large numbers of parasites in the peripheral blood. This type may be readily mistaken for various forms of obstructive jaundice.

Pernicious attacks. The French neatly designate these acces pernicieux. They characterize subtertian infections, and may supervene in apparently mild cases and carry off the patient with horrifying suddenness - as suddenly as an attack of malignant cholera. Pernicious attacks are apt to develop in drug addicts. They are classifiable into: (1) septiccemic (or toxemic) type, accounting for about 30 %, with numerous parasites in the blood, death taking place from

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cardiac-failure; (2) cerebral, accounting for some 55 %, ending usually in coma, in which, compared with other forms, parasites are usually very scanty in the peripheral blood; (3) algid, with subnormal temperatures and a clinical syndrome resembling that of shock, accounting for some 14 %, and finally (4) renal, with edema and nephritic signs which amount to about 1 % of the total. Field found that the case mortality rates rose significantly when the patient, before treatment, showed 100,000 parasites per mm3 of blood.

Cerebral forms.

In the course of what seems to be an ordinary malarial attack the body-temperature, instead of stopping at 40 °Ñ or 40.5 °Ñ, may continue to rise and, passing 41 °Ñ, rapidly mount to 42 °Ñ (or even, rarelly, to 42.5 °Ñ). The blood shows hyperinfection with P. falciparum and more than 5 % of erythrocytes are infected and most contain about two parasites in each corpuscle. The patient, after a brief state of maniacal or, perhaps, muttering delirium, becomes rapidly unconscious. The pupils are dilated and the corneal reflex absent. The fundi are usually normal. The skin is hot and burning. The legs are usually spastic. Fever sores (herpes labialis) are often observed around the lips and mouth. There is an almost distinctive facies. The pulse is rapid and dicrotic, and there may be generalized muscular twitchings. Splenic pain may be present. At first there is a disorientation with motor aphasia. Incontinence is usually a dangerous sign. Changes in behavior, such as insolence or insubordination, may often be encountered in the early stages, excitement, mania and coma then follow.

Ñîòà. Sometimes the patient, without hyperpyrexia (the temperature perhaps not rising above, or even up to 40 °Ñ), 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, 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).

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

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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 bloodstream 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

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, kaia-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 m^ny obscure and ill-defined conditions.

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Treatment

At cupping of fever attacks at any kind of a malaria there are used preparations with shizotropic action: chingamin (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 there is used chingamin diphosfat during 3 days more often: in 1 day 1.5 gm (at once 1 gm and in 6 hours the others 0.5 gm), in 2nd and 3rd day - unitary 0.5 gm. The serious form of a tropical malaria demands prolongation of treatment course by chingamin 2 days 0.5 gm 1 time a day. If plasmodiums are refractory to chingamin,indicate quinine dichlorid 2 mL

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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 gm of sulfadoxin and 0.025 gm 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 primachin is indicated 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 a solution of quinine dihydrochlorid is used. The next days indicate the preparations per os. Simultaneously desintoxication therapy with reopolyglycin, polyglucin, albumin, rheogluman, polyionic solutions is performed. The total quantity of infused liquid should not exceed 1500 mL. There may be infused 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, cordiamin, corglykon or strophanthin, phenylephin hydrochlorid,

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prednisolon, and also reopolyglycin, quartasol or another polyionic solutions should be infused. In case of development of serious anemia the blood of the same group, blood plasma may be transfused.

Individual chemioprofilaxis is carried out for the persons leaving in the endemic regions. For this purpose chingamin 0.5 gm once a week is applied, 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 gm per day during 2 weeks is carried out.

Severe malaria.

Drug resistance has narrowed the therapeutic options in severe malaria. Chloroquine should no longer be used for severe malaria outside the few areas where sensitivity is retained. For nearly all the tropical world, the choice now lies between quinine (or quinidine) and either artemether or artesunate. The artemisinin derivatives are more rapidly parasiticidal than quinine, and safer in severe malaria (they do not cause hypoglycaemia), but to date large randomised trials have largely involved artemether which is relatively slowly absorbed particularly in severe malaria. These have not shown significant benefit in terms

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of mortality for artemether. Although there has been some evidence of a decline in the efficacy of quinine in severe malaria in southeast Asia,these recent large randomised comparative trials with artemether have provided reassuring evidence that the mortality with quinine treatment is not rising significantly.

Date: 2014-12-21; view: 919