MALARIA 3 page

The prevention of resistance. Resistance develops most rapidly when a population of parasites encounters sub-therapeutic concentrations of antimalarial drug. These act as a selective pressure filtering out the more resistant parasites within the infecting population. Selection is most efficient when single point mutations confer high level resistance. The mutations which confer reduced drug susceptibility within an infecting parasite population are thought to occur independently of drug pressure. Drugs with long terminal elimination phases, such as mefloquine, are particularly vulnerable because sub-therapeutic concentrations may occur for weeks or months after a single therapeutic dose. Selection for resistance in microorganisms is greatest at "intermediate" levels of drug activity (generally between 20 % and 80 % of maximum effect). Although chloroquine has the longest of all the elimination phases (terminal half-life 1-2 months), the blood concentrations during the terminal phase are very low and may lie below the "sensitive" part of the concentration effect relationship where selective pressure is greatest.

The pharmacological characteristics which predispose a drug to the development of resistance are weak intrinsic activity with a "flat" dose-response or concentration effect relationship, single or double point genetic mutations which confer marked reductions in susceptibility, and a long terminal elimination phase during which blood concentrations fall slowly down the concentration effect curve for the infecting population of parasites.

Initially at low levels of resistance selection occurs only from newly acquired infections, but, as resistance worsens, some of the primary infections are able to survive the initial therapeutic onslaught and to recrudesce subsequently. These are by definition the most resistant parasites, and they are preferentially transmitted because gametocyte carriage is more likely during the recrudescent infection. The chances of a resistant mutant parasite surviving can be reduced considerably if a second drug, with an independent locus of antimalarial action, is added. Escape would now require two simultaneous but independent mutational events. Mutations are rare events and the chance that two independent mutations would occur in the same parasite is the product of their individual mutation frequencies. This rationale for combination chemotherapy in malaria was applied originally to mefloquine/sulphadoxine/pyrimethamine but it did not work because of the pharmacokinetic mismatch between the three compounds, and because where it was introduced in Thailand in 1984, P. falciparum was already highly resistant to both pyrimethamine and sulphadoxine. Combinations of artemisinin derivatives with slower acting and more slowly eliminated antimalarials are particularly effective because of the considerable biomass reduction achieved by artemisinin

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compounds with a treatment course as short as 3 days (circa 108 - fold reduction in parasite numbers). This ensures that there are relatively few parasites (maximum 105) remaining for the second, weaker drug to eliminate. Furthermore, these parasites are exposed to maximum concentration of the second drug. The artemisinin derivative is also "protected" by the second drug. This would argue for combining an artemisinin derivative with all slowly acting antimalarial drugs.

Prophylaxis

Because of increasing drug resistance, alternative measures such as reducing vector-human contact are progressively more (rather than less) important. Insecticide-impregnated bed nets (with permethrin or deltamethrin) markedly reduce intradomi-ciliary vector populations, and should offer significant protection against the risk of malaria. Alternatively, insect repellents such as diethyltoluamide (DEET) may also reduce the risk of transmission and infection.

Because malaria does not produce immunity, there is no model of effective immunity to plasmodial infection, and no guarantee that numeral or cellular immune responses to specific antigens will protect against either infection or disease. In fact, one of the major unsolved questions is whether different mechanisms may be responsible for protection from infection vs. disease.

Control questions:

1. Source of malaria infection and mechanisms of transmission.

2. Types of malaria infectious agents.

3. Cycles of plasmodium malariae development.

4. Tissue shizogony, its duration during different forms of malaria.

5. Red blood cell's shizogony, its features at different forms of malaria.

6. Technique of preparation of "thick drop" method.

7. Pathogenesis of malarial attacks.

8. Types of temperature curves at different forms of malaria.

9. Clinical manifestations of malaria.

10. Outcomes of malaria.

11. Parasitosis and its epidemic value.

12. Differential diagnosis of malaria with leptospirosis and viral hepatitis.

13. Complications of malaria.

14. Medical treatment of malaria.

15. Prophylaxis of malaria.

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PLAGUE

Plague is an acute infectious disease caused by Yersinia pestis with severe intoxication, fever, affection of lymphatic system and lungs. It belongs to the group of the extremely dangerous infections (quarantines).

Historic reference

Many researchers of the history of medicine relate the plague epidemics to the most ancient times of the human history. The information about mass mortality, mentioned as a punishment of Jehova for the people's sins is the main argument for such conclusions. Now it is hard to say if they were really plague epidemics or other infectious diseases. In the historic times a mass disease, described by Fukidid (430-426 BC), was considered to be a plague epidemic, now it is looked a as a typhus epidemic. The old foreign researchers of plague consider an epidemic described in the book of Moses and in the books of Judges and Prophets as a plague epidemic. At the times of the exodus of the Jews from Egypt (about 1320 BC) people of Palestine came back to the God of Israel carrying 5 golden images of tumours (bubos) and 5 images of mice - showing the connection of the human disease with rodents.

Later there were many indications showing that the plague in Egypt existed from the ancient times. However the first doubtless information about plague in Egypt was found at Ruth from Efese at the time of emperor Troyan (98-117 AD) in which the outbreaks of bubonic plague with high mortality in Livia, Egypt and Syria were described, that epidemic took place at those times and earlier starting from the end of 3rd century DC. Apparently, the word "plague" comes from the ancient Arabic word "jumma" which means "bean".

During the last 2000 years, Y. pestis has caused social and economic devastation on a scale unmatched by other infectious diseases or by armed conflicts. It is generally considered that there have been three world pandemics of plague and credible estimates indicate that together these resulted in 200 million deaths. During these pandemics, the disease occurred in both the bubonic and pneumonic forms. The first of these, the Justinian plague, occurred during the period AD 542 to AD 750. This pandemic is thought to have originated in Central Africa and then spread throughout the Mediterranean basin. The second pandemic started on the Eurasian border in the mid-14th century. It is this pandemic which resulted in 25 million deaths in Europe and which is often referred to as the "black death". This pandemic lasted for several centuries, culminating in the Great Plague of London in 1665. The third pandemic started in China in the mid-19th century, spread East and West, in 87 ports, in almost all continents.

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Eight epidemic breakouts of plague have been registered in Odessa. The biggest epidemic took place in 1812, when about 3,000 people fell ill and more than 2,000 people died. All the dead people were buried behind the first Christian cemetery, where there is still a hill called a plague hill or just "chumka". The last epidemic of plague in Odessa took place in 1910, when 141 persons fell ill and 43 of them died.

Professor V.Stefansky - the first head of the chair of infectious diseases in Odessa medical institute was one of the pioneers of using serum for the treatment of sick people.

Current incidence of plague

World Health Organization (WHO) figures indicate that there is still a public health problem from plague, especially in Africa, Asia and South America and plague, cholera and yellow fever are the only internationally quarantinable infectious disease. As a class 1 notifiable disease, all suspected cases must be reported, and investigated by public health authorities and confirmed cases must be reported to the WHO in Geneva, Switzerland. During the period 1967-1993, the average worldwide incidence of plague was 1,666 cases. Although the incidence trend was downwards until 1981, there has been an apparent increase in the incidence of disease over the last decade, possibly because of more efficient diagnosis and reporting of cases. Even today, many cases of plague are not diagnosed and it is likely that the true incidence of disease is several times the WHO figures.

The Indian outbreak of plague in 1994. Despite the high incidence of plague in India during the first half of this century, the number of cases had declined since 1950, and the last recorded case occurred in 1966. However, between August and October 1994 two outbreaks of suspected plague occurred. One of bubonic plague in the Beed District of Maharashtra State, and the other of pneumonic plague in the city of Surat in Gujarat State. The Surat epidemic caused panic throughout India, resulting in a mass exodus of up to half a million people from the city, and attracted international media attention.

At the peak of the epidemic, over 6,300 suspected cases were recorded. However, official figures released later indicated that only 876 presumptive cases of plague were identified (by serological testing for antibodies to Y. pestis) and there were 54 fatalities. The cases were confined to six states in central and western India; none of the suspected cases in other states, such as Bihar, Punjab, Rajasthan and West Bengal, had positive serological markers for presumptive plague.

During the outbreaks, one of the major problems was the failure to collect systematically clinical samples for analysis. Routine tests to confirm a diagnosis of plague were not carried out and pure isolates of Y. pestis were not cultured from blood, sputum or autopsy samples. As a result, the exact nature of the outbreaks in Maharashtra and Surat has provoked controversy and alternative causative agents have been proposed. To address concerns, a team of experts

Plague

from the WHO visited India in October 1994. Although the WHO team was unable to isolate Y. pestis from clinical samples, it established that there was clinical, epidemiological and serological evidence of an outbreak of plague.

In response to the crisis, the Indian government constituted a Technical Advisor Committee (TAC) in 1994 "to elucidate the factors responsible for the current outbreak of plague and its spread". In clinical and environmental studies coordinated by the TAC, pure Y. pestis was isolated from the sputum of 11 pneumonic plague cases in Surat, and the tissues of 6 rodents trapped in Beed and 1 rodent trapped in Surat. The biochemical, genetic and immunologic similarity of the Surat and Beed isolates suggested that they arose from the same Y. pestis strain and, for the first time, provided evidence that the outbreaks were linked.

The TAC also conducted studies to identify the events leading up to the epidemics. In the Beed District of the Maharashtra State, the seeds of the outbreak were laid in October 1993 when the residents of Mamla village abandoned their homes in fear of tremors associated with a major earthquake in the neighboring districts of Latur and Osmanabad. Large quantities of grain remained in the homes, which provided a source of food for domestic rats leading to a population explosion and a rodent epizootic of plague. The initial source of human infection was the wild rodent population located in habitats surrounding the village. During August 1994, a heavy flea nuisance and "rat fall" was reported in the village and. shortly afterwards, the first cases of bubonic plague occurred.

The origin of the pneumonic plague outbreak in Surat is less well understood. Monsoon flooding occurred in the city in the first week of September 1994 causing people to leave their homes. Although such disruptions to the local ecological balance are known to contribute to plague outbreaks, there is no evidence that this occurred in Surat. The index case locality of the pneumonic plague outbreak was traced to Laxminagar colony in the north of the city and, although the origin of the disease remains obscure, the most likely scenario is that an individual with pneumonic plague who travelled from the Beed district to Surat was the source of the epidemic.

Etiology

Yersinia pestis (Bacillus pestis), the etiological agent of plague was first described by A. Yersen in 1894 in Hong-Hong, the International committee of systematization of bacteria (1982) referred it to Yersinia genus together with bacillus pseudotuberculosis and yersiniosis.

In its characteristic form this organism is a short, oval bacillus with rounded ends. In the tissues a typical capsule may be observed; in cultures grown at 37 °Ñ material can be demonstrated by means of India ink preparations, but it no well-defined.

The organism is Gram-negative, and when stained with a weak stain (e.g. methylene blue) shows characteristic bipolar staining which is an important feature in identification.

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In culture the plague bacillus is less typical Longer forms are frequent and polar staining is less obvious. Pleomorphism is marked especially in old cultures, and involution or degeneration forms are particularly noticeable. These are markedlly enlarged, stain faintly and include globular, pear-shaped, elongated or irregular forms. In fact the microscopic picture of an old culture often suggested that of a yeast or mould. Involution in culture can be hastened by the presence of 3 % sodium chloride and this has sometimes been utilized in identifying the organism.

In fluid culture the bacilli tend to be arranged in chains. The organism is non-motile and non-sporing.

Epidemiology

Rodents are natural reservoir for plague infection. Yersen was the first to notice the connection between a rats plague epizootic and a human epidemic. Bacillus pestis carriage was proved for black and gray rats and for such steppe rodents as gophers, marmots, sandworts, small mousekind rodents and others. There are almost 300 species and subspecies of basic sources and keepers of plague infection. Besides, during an epizootic among rodents, there can be found other mammals contaminated with plague - polecats, shrews, foxes, monkeys (makaky genus), domestic cats, one- and two-humped camels. Epizootics among rodents are kept by different species of fleas - carriers of plague infection.

It is now known that plague is not communicable from animal to animal by simple contact, but is readily communicated by fleas, which bite man, dogs and other animals. These act as passive intermediaries and carriers of the bacillus. Y. pestis multiplies in the stomach of the flea, retaining its virulence for over twenty days and is then passed out in the feces, so that the flea serves not only as a carrier,but also as a multiplier of the germs.

Especially convincing are the experiments of the Indian Plague Commission, which clearly showed that, if fleas are excluded, healthy rats will not contract the disease, even if kept in intimate association with plague-infected rats. Young rats may even be suckled by their plague-stricken mothers and remain healthy. It suffices to transfer fleas from a plague-infected to a healthy animal, or to place the latter in a room in which plague rats had died recently and had been subsequently removed. The fleas that have left the body of the dead rats,remaining in the room, convey the bacillus. An animal placed on the floor cannot be infected, if the precaution is taken to surround the cage with "tangle foot", so as to keep off the fleas.

Martin and Bacot found that a proportion of the fleas fed on plague-infected rats develop a peculiar condition of stomach and esophagus, which become blocked with blood-clot containing a pure culture of Y. pestis. When such a flea feeds on a normal rat, part of the culture regurgitates and communicates infection. At the same time bacilli are passed in the feces and may infect through any existing abrasion. They further observed that the "blocked" fleas died very

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rapidly, apparently of thirst, if placed in a warm, dry atmosphere. There is apparently little difference between wild rodent and domestic rat fleas in the readiness of infection. The life-span of the infected flea is comparatively short, about 3-2 days.

In temperate climates fleas are most numerous during the warmer weather, hence, summer and autumn are the bubonic plague seasons. In warm climates bubonic plague is most likely to become epidemic when temperature ranges between 10 °Ñ and 30 °Ñ - temperatures favorable to the multiplication and activity of the flea. Temperatures over 30 °Ñ are unfavorable, especially if the atmosphere is dry. The flea, then, communicates plague either by its fouled mandibles, by regurgitation, in the act of sucking, or by provoking scratching and consequent inoculation of the bacilli deposited in its feces.

In ordinary circumstances the rat-flea completes its developmental cycle in from fourteen days to three weeks, but in warm damp weather this may be shortened to ten days. It requires ideal tropical conditions for propagation. The average life of a flea, separated from its host, is about ten days, but it is capable of remaining alive without food for two months, should the temperature of the air be low.

Apart from the very serious danger arising froin vermin infected with chronic plague, which may hang about a house, the house itself does not retain the infection for any length of time. The Plague Commission has shown that floors of cow-dung contaminated with Y. pestis do not remain infective for more than forty-eight hours and that floors of "chunam" cease to be so in twenty-four hours.

Evidence of rat-mortality is not always conspicuous, even when the epizootic is severe. Dead rats may not be found in the open, but many may be discovered if search is made in the right places. Black rats which live in the roofs of tropical houses usually fall down on to the floor when stricken with plague.

Other means of infection. Human infection, however, is not always transmitted by fleas. In a small percentage of the bubonic cases, infection occurs from exposure of abraided surfaces of the skin to the plague bacillus. Instances of such infection have occurred in barefooted individuals with small wounds of the feet from walking on floors or stepping on material infected with plague bacilli, or through abrasions on the hands of those who have performed autopsies on or handled the bodies of those who have died of plague, or who have shot and skinned rodents infected with plague.

Infection in primary human septicemic plague is usually acquired through the mucous membranes, particularly of the mouth and throat and the conjunctivae. Particles of infected sputum which have been accidentally coughed into the eye have produced human septicemic plague. Animals such as monkeys may be given primary septicemic plague by instilling a few drops of a culture of Bacillus pestis in the eye, or by rubbing a small amount of the culture on the mucous membranes of the gums without producing visible erosions. Infection of the mucous membranes of the mouth may occur also in man through the hands conveying infection, as might occur in individuals who have shot or skinned infected rodents.

Infectious diseases

There has been "an outbreak of septicemic plague reported in Ceylon in which there was an absence of plague in rats. The infection was possibly transferred directly through human fleas or bedbugs.

In epidemics of primary pneumonic plague, infection does not occur as in bubonic plague through the agency of heavily infected fleas, or through the skin, but directly from man to man airborne through droplets of infected sputum expelled by coughing, as was conclusively shown by Teague and the writer in the Manchiirian epidemic. In no other infectious disease have such enormous numbers of uniformly highly virulent microorganisms been demonstrated in the droplets of sputum coughed up by patients with primary epidemic plague pneumonia.

It is a matter of experience that the transference of plague from place to place generally occurs from infected rats or infected fleas which have been transported by ships,though sometimes by rail and other conveyances. A case of bubonic plague in a ward with other patients would not be a source of danger, provided there was freedom from fleas and that no plague patient developed a secondary pneumonia. It is very doubtful as to human infection ever taking place by way of the alimentary canal, although there is some evidence that rarely the tonsil may be primarily involved. Monkeys are very susceptible to plague, but no epizootics among them have been recorded.

Pathogenesis

When flea ingests blood meal from bacteremic animal infected with Y. pestis, the coagulase of the organism causes the blood to clot in the foregut, leading to blockage of the flea's swallowing. Yersinia pestis multiplies in the clotted blood. During attempts to ingest a blood meal, a blocked flea may regurgitate thousands of organisms into a patient's skin. The inoculated bacteria migrate by cutaneous lymphatics to the regional lymph nodes. The flea-borne bacilli possess a small amount of envelope antigen (fraction 1) and are readily phagocytized by the host's polymorphonuclear leukocytes and mononuclear phagocytes. Yersinia pestis resists destruction within mononuclear phagocytes and may multiply intracellular^ with elaboration of envelope antigen. If lysis of the mononuclear cell occurs, the bacilli released are relatively resistant to further phagocytosis. The involved lymph nodes show polymorphonuclear leukocytes, destruction of normal architecture, hemorrhagic necrosis, and dense concentrations of extracellular plague bacilli. Transient bacteremia is common in bubonic plague, and in the absence of specific therapy, purulent, necrotic, and hemorrhagic lesions may develop in many organs. Hypotension, oliguria, altered mental status, and subclinical disseminated intravascular coagulation (DIC) may be noted and are attributable to endotoxinemia.

Anatomic pathology

The chief points noted in a plague autopsy are:

1) The marked involvement of the lymphatic system as shown by intense congestion and hemorrhagic edema of the lymphatic glands. Not only are the

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glands involved tributary to the site of inoculation, thus forming the primary bubo, but there is secondarily more or less inflammatory change in many of the lymphatic glands of body. There is also a marked periglandular edema, with hemorrhagic extravasations of the connective tissue surrounding the primary bubo, this mass being made up of a group of glands matted together by this periglandular exudate.

2) The marked destructive effect of the toxin of the plague bacillus, upon .the endothelial cell lining of blood vessels as well as of lymphatic ones. This causes the extensive blood extravasations so characteristic of plague as shown by petechial spots, not only of the skin, but of the serous and mucous membranes as well throughout the body.

There is a general congestion of all organs of the body. The meninges of the brain are deeply congested and there may be hemorrhagic extravasations in the brain substance itself. However meningitis has been reported only in a few cases. The spleen is generally markedly congested and enlarged to 2 or 3 times its normal size. There may be hemorrhagic extravasations throughout the spleen pulp. The bacilli are chiefly scattered throughout the venous sinuses. There is also active congestion of the liver. The kidneys are intensely congested, hemorrhages beneath the capsule are usual, and we often find hyaline fibrin thrombi in the tufts of the Malpighian bodies as was emphasized particularly by Herzog in Manila. The plague toxin has a marked effect on the cardiac muscle so that we usually find dilatation of the right side of the heart with fatty degeneration of the muscle fibers. In a study of the pathology of primary pneumonic plague. Strong noted pericardial and pleural ecchymoses with fibrinous pleurisy over the affected lung areas. The process was at first lobular, but later might involve the entire lobe. There was marked congestion of the bronchial mucosa with involvement of the bronchial glands. The larynx and trachea are also intensely congested. Microscopically there is a distension of the alveoli and bronchial passages with a hemorrhagic exudate. There is practically no fibrin in the alveolar exudate. The process seems to extend by continuity along the bronchi and bronchioles. Plague bacilli pack the exudate found in the bronchi and bronchioles. In a report on the autopsy findings of septicemic plague in Ceylon in cases where plague bacilli were demonstrated in smears and cultures from spleen and blood, Castellani noted especially meningeal congestion and some splenic enlargement.

Clinical manifestations

Incubation period. The incubation period of human plague varies usually from 2 to 10 days, but is generally from 3 to 4 days. In primary pneumonic plague it may not be over 2 or 3 days.

Symptoms and course of bubonic plague. In bubonic plague premonitory symptoms are not usually observed, though occasionally there may be 1 or 2 days of malaise and headache. The onset, except in mild cases, is usually abrupt, with fever commonly accompanied by a moderate rigor or repeated shivering.

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The temperature rises Vapidly to 39.4 °Ñ or 40 °Ñ, sometimes even reaching 41.7 °Ñ. The pulse becomes rapid and the respirations increased. There is headache which is usually severe and mental dullness, and this condition is generally followed by mental anxiety or excitement. The patient may become maniacal. The skin is hot and dry, the face bloated, the eyes injected, and the hearing dulled. The tongue is usually swollen and coated with a creamy fur, or later with a brown or black layer. The symptoms usually complained of within the first 24 hours are very severe headache and backache. Burning in the throat or stomach, and nausea and vomiting may occur. Constipation is present as a rule. The pulse is either very small and thread-like or full and bounding. At times there may be acute delirium; at others, lethargy and coma. In children, convulsions usually occur. The urine is scanty and generally does not contain more than a trace of albumin and no casts. Later in the disease the albumin may increase somewhat, The high febrile stage lasts from 2 to 5 days or longer. The decline in temperature may be sudden or gradual. Cases that do well usually show a gradual fall of temperature, and after 14 days the temperature may be subnormal. Buboes, inflammatory enlargements of the lymph glands are sometimes the first sign to attract attention by their pain. They more often make their appearance from the second to the fifth day after the onset of the fever. The temperature frequently shows a decline when they appear. The affected gland is often hard and painful to the touch. In fatal cases, it may retain these characteristics; in others it suppurates. The average size of the bubo is from a walnut to an egg. Buboes appear in 75 % of the cases. In the cases in which buboes are present, they occur in the inguinal glands in approximately 65-70 %, in the axillary - 15-20 %, and the cervical - 5-10 %. Carbuncles appear in about 2 %, in which there are reddened indurated patches of skin,which subsequently necrose. The spleen is frequently moderately enlarged, but often cannot be palpated. Hemorrhages from the stomach and intestine are not uncommon, and when the disease is complicated with the pneumonic form they may occur from the lung. Epistaxis is also not infrequent. The blood usually shows a leucocytosis of forty thousand or more the increase being in the polymorphonuclear leucocytes. The plague organism can be isolated front the blood in about forty-five per cent of the bubonic cases.

Date: 2014-12-21; view: 894