DIPHTHERIA

Diphtheria is an acute infectious disease caused by Leffler bacilli, transmitted mainly in an air-drop way and characterized by the symptoms of general intoxication, local inflammation of the mucous membranes mainly with the formation of fibrinogenous fur and typical complications on the part of the nervous system, cardiovascular system and excretory system.

Historic reference

Diphtheria belongs to the most ancient epidemic diseases of mankind. Homer and Hippocrates mentioned this disease. Artemey Kapadokes gives the extremely detailed descriptions of diphtheria under the title of the Egyptian Syrian ulcer about 19 centuries ago. The records of diphtheria were found in the Middle Ages.

The first writer who gave the classic description of diphtheria and mainly its pathologic anatomy basics was Bretonno; he also proposed the term "diphterit" from the Greek word "diphtera" (membrane). Bretonno's student Truss elaborated the doctrine about the specific nature of diphtheria as an infectious disease,he was the first who proposed the word "diphtheria" for the title of the disease,instead of Bretonno's anatomical term "diphterit". Klebs and Leffler, who received clean diphtheria bacilli on blood serum, discovered diphtheria pathogen in 1883-1884. Ru and Yersen received diphtheria toxin and studied its qualities in 1888-1900; Bering and Ru made the discovery of antitoxin in the form of antidi phtheria serum in 1894. The idea of active immunization against diphtheria belongs to Bering.

Klebs discovered the diphtheria pathogen Corynebacterium diphtherias in

the sections of diphtheria membranes in 1883. In 1884 Leffler extracted it in

clean culture and infected a number of animals, among which Guinea pigs turned

out to be responsive to the infection. .

Etiology

The distinctive quality of the diphtheria microbes is their polymorphism. Gram-positive coloring and the typical location of rods in the form of "bristling fingers" or V-figures. The diphtheria microbes are immobile,they don't produce spores, and do not have capsules or flagellums. They are usually situated one by one, however, in the diphtheric membranes and clean cultures they are often found in the form of assemblage resembling a constitution of felt.

On the Lefler medium the diphtheria microbes yield the best growth (colonies) during 16-20 hours; the growth can be observed even in 6-8-10 hours after sowing.

All aniline paints can tincture diphtheria microbes. They are well tinctured by Neisser's method. The diphtheria pathogens located in membranes do not die

Diphthe-ria

at a temperature of 98 °Ñ within one hour. The clean culture can survive at a temperature of 60 °Ñ only within several minutes. However, at low temperatures, absence of light and moisture the diphtheria microbe is not destroyed for a long time (even below 0 °Ñ); it can tolerate even freezing and thawing. At the same time straight sunlight kills it comparatively fast.

The main biological quality of the diphtheria microbe is its capacity to produce toxin (exotoxin) that causes the pathogenicity of this microbe.

Epidemiology

The source of diphtheria is a person in whom it is manifested in various clinical forms - from serious toxic forms up to the deleted ones and healthy bacteria-carrying. There are infrequent reports on people being infected with diphtheria from animals.

The duration of the microbe vegetation in the organism and the terms of purification mostly stipulate the epidemic danger of the bacteria-carrier as a source of infection; In practice it is difficult to determine the true duration of bacteria discharge because of the absence of precise information about its beginning.

The most epidemically dangerous are the bacteria-carriers who discharge microbes for a long time (up to 1 month and longer), it is more often observed in patients with chronic diseases of the upper respiratory tracts particularly with tonsillitis.

It is known that the diphtheria infection is transmitted in an airdrop way, which is inherent for the majority of respiratory infections. Nevertheless it is necessary to briefly mention some aspects of the transmission mechanism, particularly the pathogen survival rate in the environment. Various enviromental factors can influence the transmission of the diphtheria infection,however,they play a small role and more often have casuistic nature. The leading role in the epidemiology of diphtheria belongs to the drop mechanism of the transmission.

The periodicity and seasonal prevalence of the case rate are characteristic of diphtheria as an infection with a dropping mechanism of transmission. These epidemiological peculiarities were more considerably expressed during the pre-vaccinating time when the periodic growth of the sickness rate was observed every 10 years.

The autumn-winter seasonably is characteristic of diphtheria. In the 20s -50s the specific prophylactic agents of diphtheria were introduced into the practice of public health services of many countries, it resulted in the considerable decrease of the sickness rate. The diphtheria sickness rate decreased considerably fast in the USA, Canada and most countries of Europe.

Diphtheria used to be one of the major causes of children's mortality a century ago. Even in the 1920s the incidence in the USA and Canada was approximately 150 cases per 100,000 people, but decreased to 10/100,000 in the 1940s.The introduction of immunization resulted in the decrease of the

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yearly number of notified cases to single figures in most Western countries, in the USA a total of 1,288 cases were reported during 1971-1981, compared to, only 40 cases in 1980-1993. In England and Wales, there were 800,000 notifications of diphtheria during 1920-1934 with 50,000 deaths. The number of cases decreased from over 40,000 in 1940 to 37 in 1957, and during the period of 1970-1994 only 124 cases were identified. In some countries, including Finland and Sweden, decades passed without any cases after the implementation of diphtheria vaccinations in the 1950s. Reduction in the number of diphtheria cases has also taken place m the developing world,but the cutaneous forms of the C. diphtheriae infection especially still remain endemic in several tropical countries.

The factors leading to the start of diphtheria epidemics are poorly understood. The last major epidemic in Europe, before the current one, occurred in the 1940s. In 1943 the annual incidences per 100,000 population were as high as 212 in Germany, 760 in Norway and 622 in the Netherlands. It has been estimated that in 1943 there were 1 million cases and 50,000 deaths due to diphtheria in Europe. Limited epidemics have thereafter been reported both in developing (including China, Tajikistan, Ecuador, Jordan, Lesotho, Sudan, Yemen and Algeria) and industrialized (USA, Sweden, Germany) countries. These epidemics have all been local and relatively small; numbers of cases have varied from a few to a few hundred. The carriage rate of C. diphtheria even,in the proximity of the patients, has been low, and no significant spread of the infection has occurred in the general population. Since 1990, a massive epidemic has prevailed in Eastern Europe, mostly in the Russian Federation, Ukraine and their neighboring countries. A smaller epidemic occurred previously in 1983-1985, when the annual number of cases in the Soviet Union exceeded 1,400 - being less than 200 in preceding years. After a few-years of low incidence, rates per 100,000 population started to increase from 0.5 in 1990 to 10.2 in 1993, 26.9 in 1994 and 24.2 in 1995. Especially in large cities, the rates were high (St. Petersburg, 52.5/100,000 and Moscow, 47.1/100,000). In some areas the incidence rate even exceeded 100/ 100,000. Over 63,000 cases were reported from Russia in 1990-1994. Thereafter, the epidemic started to decline and, in 1996, the incidence was only 9.2/100,000.

Another country suffering badly from the epidemic is Ukraine. The annual number of diphtheria cases remained below 100 until the end of 1980s,but increased rapidly thereafter. The incidence rates increased from 0.1/100,000 in-1989 to 5.7 both in 1993 and in 1994. The total number of cases in Ukraine between 1990 and 1994 was estimated at nearly 9,000. Reflections of the epidemic can also be seen in other countries close to Russia and Ukraine, although the numbers are smaller. In 1994, Belarus reported 230 cases (incidence 2.5/100,000), Estonia 7 (0.4), Latvia 250 (9.6), Lithuania 31 (0.3), and Moldova 372 cases (8.6/100,000). Case fatality rates in this epidemic ranged from 3 % to 21 % in different countries.

Features that might be important in understanding the dynamics of the epidemic and its prevention have been studied. The most important is the high

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percentage of adults, 60-77 % of cases. This is, in contrast with the experience from the prevaccination period, when the corresponding figure used to be below 30 %. Certain groups at increased risk were suggested: medical staff, teachers, vendors, transport employees, food handlers, and military personnel.

No significant spread occurred outside the countries of the former Soviet Union. The European Union countries reported only a few cases of diphtheria during the period of this epidemic. In 1990-1996, there were 27 cases in Germany, 33 in the UK, 3 in Belgium, 10 in Finland, 3 in Greece, 4 in Italy, 2 in the Netherlands and 3 in Portugal. 23 of the 85 cases in EU countries could be linked epidemiologically to Eastern Europe. None of the other EU countries reported cases in this period.

Pathogenesis

The diphtheria infection develops only in case of the parenteral entering of poison into the organism.

Implanting in the organism through covering tissues the diphtheria pathogens form local foci of histic damage. More often it happefis on the mucous membranes of the stomatopharynx, nasal-courses where the microbes utilize slime as a medium, less often the foci develop on the skin and even less often on the mucous membranes of an eye and vulva-vaginal area. Alongside with classic exotoxin, which is a true lethal factor,the diphtheria microbes in the zone of inoculation produce numerous solvable local-acting factors (hyaluronidase and neuraminidase) damaging the cells and facilitating the diffusion of bacteria and toxins in the tissues.

That is why the damage of almost all tissues is observed in the inoculation zone including the mucous membranes, skin, muscles, and nervous fulcrums. Hyperemia, retardation of the blood flowand sharp rising of the permeability of hysto-hematic barriers promote the formation of exudate which is rich in protein and fibrinous membranes in the damaged tissue area.

At the intranevral injection the diphtheria toxin causes the primary lesion of oligodendrocytes (Shvann cells) and myelin with the subsequent development of the sectidnal demyelination in area of inoculation.

The local cytopathogenic effect of the toxin is determined by the rate of the poison entering the tissues, by the toxin-aggregating capacity of the cells and the availability of the microbial spreading factors (neuraminidase, hyaluronidase). If poison enters slowly, there appear conditions for the manifestation of its local cytotoxic action in the area of inoculation, but if the toxin concentration in this area increases rapidly, then in a short time the "threshold" dose is accumulated, and in case of its exceeding the poison is reabsorbed in the circulation system and already has a predominantly systemic pathogenic effect.

In the blood the toxin contacts with globulins, and at a greater saturation with albumines. The poison forms complexes with hemolysins and hemagglutinins.

The process of the poison fixation in tissues is not accompanied by any disorders of proteins, carbohydrates and fat metabolism. After the completion of

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the latent stage and the development of the characteristic symptoms of toxic diphtheria the patients have only a mild increase of the sugar content in the blood without changing the tolerance to galactose and levulose.

There is noticeable weakening of phosphorylation processes in toxic diphtheria. The changes of oxidative phosphorylation in mitochondrions are not the result of the toxin direct pathogenic action, but the indirect one through the neurohumoral part including the sympaticoadrenal system.

The results of research of the metabolism violations in toxic diphtheria of the humans and animals are the evidence of the absence of specific changes of carbohydrates, proteins and fat metabolism in dynamics of the disease up to the fatal outcome. The nature of these violations is similar to the damages caused by any pathogenic matter with general toxic properties.

Anatomic pathology

Fibrinous inflammation is the pathomorphologic manifestation of the macro-and microorganism interaction in diphtheria. The form of this inflammation directly relates to the constitution of the affected mucous membrane. If the process develops on the mucous membrane covered with the single-layer cylindrical epithelium (for example in the respiratory tracts), croupous inflammation develops; the cover that develops includes a necrotic epithelial layer. The cover is not firmly connected with the underlying tissue and can be easily separated from it. If the process develops on the mucous membranes covered with a multilayer flat epithelium (lumen of fauces, pharynx), it is not only the epithelial layer that necropsies, but partially the joint tissue basis of the mucous membrane (tunica propria mucosae). A thick fibrinous cover develops, it can be hardly removed from the underlying tissues. It is diphtheria inflammation.

The regional lymph nodes get involved in the process: they are enlarged owing to the expressed plethora, edema and the proliferation of the cell-like predominantly reticuloendothelial elements. Local necroses develop in them. In the toxic form of diphtheria develops the edema of the fauces mucous membrane, pharynx, and also the edema of cervical fat in the immediate proximity of the affected regional lymph nodes. In the basis of this edema there is a serous inflammation in the form of numerous cell-like infiltrates.

The diphtheria intoxication is characterized by the affection of the nervous system (mainly the peripheral nerves of the sympathetic ganglions), cardiovascular system, paranephroses and nephroses.

The changes of the peripheral nerves are manifested by multiple toxic parenchymatous neuritis, in diphtheric polyneuritis the process can spread on the intraganglion fibers of intervertebral nodes and their cranial homologues.

The cardiovascular system is considerably affected in the diphtheria intoxication. The vessels affection is mainly manifested in their paretic dilatation with the symptoms of stagnation which can transform into stasis. The deep

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degenerative changes are observed on the part of myocardium. The changes of myocardium in the hearts of children who died on the 3-5-th day of the third degree toxic diphtheria or hemorrhagic diphtheria were manifested only in expressed plethora, an edema of the intermuscular tissue with frequent hemorrhages: the fibrinous degeneration of the vessels walls was constantly observed.

The typical picture of diphtheria myocarditis (hyperemia, hemorrhage, the cell-like infiltration) was observed in children who died during the 2-3rd week of the disease. As a rule, the conductive system of the heart is also affected. The simultaneous affection of the cardiac muscle, nervous system (sympathetic system), which enervates the vessels and stipulates their tone, the violation of the paranephros function results in cardiovascular weakness, which is so characteristic of the serious forms of diphtheria. Depending on these lesion combinations,the phenomena of either cardiac or vascular weakness can dominate. The degenerative processes in epithelia of canaliculi develop in the kidneys, it looks like nephrosis.

Clinical manifestations

The incubation period,as in the other forms of diphtheria,lasts from 3 to 10 days. The disease has either an acute, sudden, or step-by-step oncoming with hardly noticeable symptoms, in the first case the temperature immediately rises up to 38-39 °Ñ, there is a headache, malaise. In the second case a child develops poor appetite, flaccidity, slight temperature rise (37.5-38 °Ñ) during several days. Quite often even senior children do not complain of a sore throat or the pain is insignificant, and if the doctor is not in the habit of examining a throat in each patient with a fever, diphtheria in such cases is not revealed by the parents and the doctor as well. If the patient is examined during the first day of the disease it is possible to notice a slight pulse acceleration, which correlates with the temperature; the cervical glands are usually slightly enlarged on one side, painful at pressing. The tongue is furred, the tonsils are swollen either both or mostly, one of them, turn red, but the erythema is strictly localized and does not spread on the uvula and soft palate as in scarlatina. It is possible to discover fur on the reddened tonsil, during the first hours of the disease it looks like a mild combustion of the mucous membrane or a heavy-bodied web grid; it is possible even to remove it by a cotton plug but a new one appears on its place extremely fast, and it cannot be removed any more. By the end of the first day or by the beginning of the second day the fur gets a characteristic diphtheria cover properties: it is dirty-gray or yellowish, rather thick, rises above the mucous membrane surface, it cannot be removed without bleeding; plenty of fibrin and diphtheria bacilli can be discovered under the microscope in it. The manifestations of the general intoxication remain insignificant: a headache, malaise, poor appetite. The borders of the heart are normal and the tones are clean. The pulse is accelerated; the blood pressure is in the normal range or slightly heightened. The liver and spleen are not changed; the urine does not contain protein. There is moderate leukocytosis (10,000-12,000) and neuthrophylia

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in the blood. The following course of the disease can be diverse. Nowadays, when the serum treatment is widely applied, the natural course of diphtheria can be observed very seldom. Therefore, it is necessary to distinguish the diphtheria course during serum treatment and without it.

If serum is injected, sometimes within the first day there is no essential change in the patient's condition: the temperature remains elevated, the general condition is also abnormal, fur can even increase. But as a rule, there is a sharp improvement in 24 hours: the temperature critically drops, sometimes down to normal, the child becomes vigorous and cheerful, the appetite improves, the cervical glands-get smaller, the fur changes its appearance: it becomes more porous, it looks as if it is uplifted above the mucous membrane, there is a girdle of sharply expressed erythema on the edges, the diffusion of the fur, is intercepted. Within the following day and night the considerable part of the fur disappears, in 2-3 days the fauces completely refine, and the child recovers. If serum is injected in time, the consequences of the intoxication (paralyses, heart weakness) don't usually develop.

There are also cases when the temperature drops on the 3-5th day and the fur also disappears rather fast without any serum treatment. But such cases are an exception. In most cases the disease progresses, the fur covers both tonsils, it can spread to the uvula and aerofoil; the cervical glands are enlarged, painful, but there is no edema of the cervical cellular tissue and fauces. There are sometimes traces of protein in urine. The temperature is of the remittent (febris remittens) or improper type and lasts during 7-12 days. The fur disappears slowly without any ulcerations or detects of the mucous membrane. The disease ends on the 7-15th day; the isolated paralyses (paralysis of the soft palate) and unexpressed cardiac disorders are sometimes observed.

In the eases when the disease is not treated with serum, it is impossible to be sure in the complete recovery of the patient even if the process stops and the fur disappears. The fur sometimes appears again and can spread to the nasopharynx and nasal cavity or the process goes downwards to the larynx.

Diphtheria of the fauces and diphtheria of the nose.

The transfer of the process from the tonsils to the nasal cavity is implemented either directly or skipping the soft palate and pharynx,the process affects the nasopharynx and rear parts of the nose. Such transfer is usually observed not earlier than on the 3-5th day of the disease and is accompanied by a new temperature rise, and deterioration of the general condition, and there are characteristic symptoms indicating the affection of the nasopharynxes and nasal cavity. The voice becomes nasal, the mouth is open, the tongue is dry and coated with peels, a slimy at first and then sanious discharge comes out of the nose, and frets the skin 'around the nostrils and on the lips. An abundant purulent discharge can also be seen on the rear wall of the pharynx. Not only the submandibular lymphatic glands, but also the lymphatic glands situated around m. sterno-cleido-mastoideus swell up a little on-the neck. If the process has gone far and has

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affected the forefronts of the nose, it is possible to see the covers without any instruments having cleared the nose entrance from purulent discharge and peels. The spreading of diphtheria on the nose worsens the prediction,as sometimes an edema of the cervical cellular and the symptoms of general intoxication accompany it, i.e. the widespread diphtheria changes into toxic one. In other cases the process can proceed to the nasal sinuses and middle ear. Clinically this transfer can remain unnoticed or corresponding symptoms may appear (edema of blepharous and the back of the nose, discharge form the ears). Whether this transfer is caused by the diphtheria infection itself or a mixed infection plays some role (streptococcus, pneumococcus), — it is not always possible to find out (the information on primary diphtheria of the nose can be found below).

Diphtheria of the fauces and diphtheria of the mouth.

If the process spreads to the oral cavity, dirty-gray densely sitting covers develop on the palate (Fig. 13),on the mucous membrane of the lips and cheeks, and also on the tongue. The bacteriological research discovers Leffler's bacilli in the covers.

The clinical symptoms: abundant salivation, smell from the mouth, painful mastication and swallowing, large swelling of submandibular glands. The covers disappear slowly leaving the ulcers that do not heal for a long time.

The diphtheric affection of the larynx and respiratory tracts is known under the name of a croup.

Croup (true,diphtheric) can be secondary,if it develops after the affection of the fauces or the nose, and primary - at the primary localization of the diphtheria process in the larynx.

The course of croup can be divided into three stages.

1. A croup cough stage. The first symptom indicating the starting affection of the larynxes is sharp loud cough, which becomes rasping, barking very soon. Senior children complain of the sense of smart and pressure in the larynx; the palpation of the larynx appears to be painful. At the same time the voice becomes hoarse, unclean, and then completely silent (aphonia). At the examination with a laryngeal mirror it is often possible to see an edema and hyperemia of the epiglottis, and often there are no covers at this stage. This period lasts 1-2-3 days and develops into a second stage.

2. A stenosis stage. The respiration becomes labored, unclean; at each inspiration the sawing or whistling sound is audible. This sound is weak at the beginning and audible only during exaltation and the child's cry, then it becomes sharp, constant and is audible from the distance. Another symptom is the larynx narrowing — retraction of compliant, weaker places of the thoraces. As the insufficient amount of air enters the lungs through the narrowed glottis, the intrapulmonic pressure becomes lower than the atmospheric one and under its influence- the compliant places of the thoraces — the supraclavicular and bulbar-fossas; intercostal spaces, anticardium - are more or less sharply retracted at

1.

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each inhalation. At first a child is quiet,satisfactorily manages the air deficiency. Then the oxygen deficiency develops - the child becomes restless, rushes in bed, jumps up, grasps the handles of the bed, wants to be held in his mother's arms, showers his head to the back. The auxiliary muscles start to work - intercostal, mm. sterno-cleido-mastoidei, mm. scaleni. The sterno-clavicular muscle appears to be noticeably tight at the palpation during an inhalation. When the child is in such a condition,injecting the serum and providing the adequate treatment (an operation and other treatment measures; (see treatment of croup below) can save him. If the disease has its natural course, the condition improves and the stenosis easies in the extremely infrequent cases when the cover disappears; in most cases the disease reaches its last stage.

3. An asphyxia stage. In the struggle with stenosis the child exhausts, the respiratory muscles get tired. The child becomes calm, sleepy, he inditfferently lies in bed. The respiration is accelerated, but it is superficial, the retractions are already not so visible. The lips,tip of the nose and nails become blue,the face turns pale,sweat quite often appears on the forehead. The extremities are cold, the pulse is very rapid, thready, sometimes paradoxical (abasement of the pulse wave during the inhalation). From time to time there are attacks of acute dyspnea - the child jumps up, rushes because of air-deficiency, the eyes express fright, the face becomes cyanotic; sometimes such attacks result in the immediate death; in other cases the child dies after a more or less continuous agony with the symptoms of exhaustion of respiratory and circulation centers.

Toxic diphtheria.

The typical form sometimes develops on the 3-5th day of the disease from the localized form when the process affects the nasopharynx and oral cavity, more often it develops as it is from the very beginning. In this case the disease has an acute oncoming, which is more rapid than in localized diphtheria. The temperature immediately rises up to 39-40 °Ñ, there is a headache, repeated vomiting, sometimes abdominal pains. Senior children complain of a pain at swallowing. The pulse is rapid: 140-160 beats per minute, the face is pale, there is malaise, sleeplessness, sometimes exaltation. The submandibular glands are enlarged, painful; it is possible to see a quaggy pasty edema of the cellular under the low jaw angle, usually on one side; sometimes an edema develops only on the second day.

At the mouth examination you can see that the tongue is dry and furry, the fauces are dark-red and hydropic; there is usually dirty-gray fur on one tonsil, it cannot be removed by a cotton plug. This fur affects the entire tonsil, passes to the uvula, sometimes to the soft palate extremely fast, within several hours. On the second or third day the disease is in full swing, and it is not difficult to clinically diagnose toxic diphtheria. The temperature remains high: 39-40 °Ñ. The face is pale, pathy. There is sanious fluid discharge from the nose, it frets the skin. The mouth is open,the lips are dry and cracked; the smell can sometimes be sensed even from the distance. The respiration is hoarse, the voice is muffled, with a strong nasal tone. The

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glands are enlarged even more, but it is more difficult to palpate them because the edema of the fat cellular takes a considerable part of the neck (Fig. 13). The glands are not so tight because of the edema of the cellular, as compared with scarlatina. Thick, dirty-gray covers are not only on the tonsils and uvula, but also on the mild and firm palate; the edema of the whole fauces is considerably expressed; the uvula is especially edemic and enlarged; it is squeezed and strangulated by the enlarged tonsils, sometimes it is twisted backwards, so that the back wall of the pharynx is not visible. As a result of such swelling of the fauces the respiration becomes labored, stenotic (stenosis of the pharynx). The swallowing is extremely painful, and the feeding of the patient becomes difficult. Simultaneously with worsening of the local process the phenomena of the general intoxication also increase: the pulse is rapid and weak, the heart sounds are dummy, the blood pressure is low; there is protein in urine, sometimes cylinders; general malaise is considerably expressed. There is considerable leukocytosis in the blood (up to 15-20 thousands) and neutrophilia.

Complications

The most frequent diphtheria complication for adults is myocarditis. The affection of the heart is especially typical for the toxic forms of the disease.

The severe form of myocarditis develops only in the patients with toxic diphtheria (except subtoxic) at overdue (after the 5th day of the disease) specific treatment and is always accompanied by complications on the side of the kidneys and nervous system.

The complications caused by the affection of the nervous system are observed less frequently. In the mild forms of diphtheria (localized,wide-spread) the adults develop only the soft palate paresis - mononeuritis, which has an easy short-term course (no more than 10-14 days), characterized by a snuffling voice and chokes while eating liquid food. In more than 1/3 cases toxic diphtheria is complicated by polyneuritis in various combinations and polyradiculoneuritis. Among the cranial nerves the IX, X, III, VII, XII pairs are affected more often, it results in paresis or paralyses of the soft palate, pharynx, tongue, accommodation paresis and mimicry affection.

The severe forms of polyradiculoneuritis develop only in patients with concomitant alcoholism, they are characterized by deep wide-spread paralyses of the extremities, body, neck, respiratory muscles in combination with the affection of the cranial nerves, resulting not only in the long-lived disorders of the working capacity,but also in lethal outcomes,even in subtoxic diphtheria.

One or two-sided focal pneumonia quite often develops at the early stage of the disease in toxic diphtheria.

Diagnosis

The modern microbiologic diagnosis of diphtheria is based on the clean culture isolation and identification of the pathogen by the cultural-morphological, biochemical and toxicogenic properties. Thus, it is necessary to strictly observe

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a number of conditions. The 'slime from the stomatopharynx and nose as well as the secret from other areas of the pathological process localization are collected by separate wads before eating or after it but not earlier than in 2 hours, and also before gargling and other kinds of treatment (drops, ointments, wads).

Taking the material for research correctly is of great importance. In the stomatopharynx slime is taken from the tonsils, palatal aerofoils, uvula and trailing wall of the pharynx by rotary movements of a wad obligatory with the help of a glass spreading rod, not touching the mucous membrane of the cheeks and tongue. If there is fur of fibrinous nature, the material should be taken both from the affected tissues and the healthy tissues adjacent to them. A small part of the removed coat, which is carefully ground between glasses, or a smear taken by a separate wad are sent to the laboratory for the direct bacterioscopic investigation. The scooping of the material from the nose should be done after the careful preliminary purification of it from the slime by a dry cotton plug or after blowing the nose.

Though the streamlining of some stages of the bacteriological research accelerates the terms of carrying out an analysis to some extent, they all remain rather prolonged and do not guarantee the early diagnostics of diphtheria.

Serological, immune-chemical and the immunological methods play a more and more relevant role in the diagnostics and epidemiological evaluation of the disease. On their basis are designed the accelerated methods of discovering diphtheria toxin in clean and blended cultures in case of growing them in liquid mediums and other substrates.

The serological tests are applied to study collective immunodeficiency. RDGA is the most accessible,simple and quite informative.

Differential diagnosis

The diagnosis of diphtheria of any localization is quite difficult, as it is similar to many diseases of the infectious and non-infectious origin. The number of diagnostic mistakes increased in the period of diphtheria elimination, at a sporadic case rate, as the vigilance towards this infection vanished. The mistakes are the most frequent in diagnosing diphtheria of the stomatopharynx — the most widely spread form of the disease.

The localized form of diphtheria of the stomatopharynx is the most difficult for the clinical diagnostics. The disease should be suspected if there is dense and nitidous fur situated on the domed surface of the tonsils, their swelling, which corresponds to the area of the fur, limited hyperemia of the mucous membrane in the form of a thin rim with a cyanotic shade. The diffuse bright hyperemia, which affects all the departments of the stomatopharynx, is not characteristic of localized diphtheria. The absence of the tonsils edema in case of vast fur on them testities against diphtheria. While observing the patients it is possible to notice other symptoms, which help to diagnose the case. So, such symptoms as a short-living (1-3 days) fever, the absence of pain at swallowing in 2-3 days with the remaining fur are characteristic of localized diphtheria of the stomatopharynx.

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It is necessary to remember that in the patients suffering from chronic tonsillitis the symptoms of diphtheria may be distorted. In such patients the fever remains long, the fur is situated in the hypertrophied tonsils lacunas, and the hyperemia of the mucous membrane is of a diffuse nature. If there are no convincing symptoms of angina in the patient who is in the diphtheria focus,it is necessary to diagnose diphtheria even if there is no bacteriological confirmation of the diagnosis.

In comparison with other diseases,localized diphtheria of the stomatopha-rynxes should be differentiated from follicular and lacunar angina of the streptococcal and staphylococcal etiology more frequently. The considerable intoxication (malaise, weakness, joint aches, headache) is characteristic of these diseases even if there is slight fur on the tonsils. The fur that is located on the lacunas and has a quaggy,viscid consistence,yellow or virescent color is different too. The fur is localized or solid, usually dull and can be easily removed by a glass spreading rod. The hyperemia of the mucous membrane is more often bright and diffuse. The appearance of the patient is also different: palenesses characteristic of diphtheria,but feverish blush,shine in the eyes,brightness and dryness of the lips are characteristic of angina.

Ulcerus-necrotic angina of Simanov sky-Vincent's is quite often taken for diphtheria and vice versa. The peculiarity of this angina is the absence or minor expressiveness of intoxication. The temperature is subfebrile or normal, the pain at swallowing is slight. As a rule, the process is one-sided. On the tonsil develops the ulceration in the shape of a crater, coated by clotted fur of the virescent color. The areas of necrosis can also be found on the palatal airfoil, uvula or soft palate.

The angina form of tularemia looks like diphtheria by the form of the fur on the tonsils, but it differs by a rather late development (on the 3-5th day), absence of an edema of the tonsil, the ulcer-necrotic-nature of a lesion (the fur not only rises above the level of the healthy tissue, but is also located below it), a considerable increase of the regional lymph nodes that continue enlarging after the disappearance of tonsillitis.

Necrotic angina in scarlatina can be considered to be diphtheria owing to the vastness of the lesion areas and dense fur cohesion with die tonsils surface. However, in this case the affected areas of the tonsils do not rise above the level of the healthy tissue, the edema of the mucous membrane is insignificant, the hyperemia is extremely bright and at the same time has a distinct border. It is also necessary to take into consideration the patient's appearance: bright hyperemia of the cheeks and paleness of the nosolabial triangle. The development of the small-dot rash in the typical places for scarlatina solves the problem of the diagnosis.

Widespread diphtheria of the stomatopharynx is diagnosed easier than localized one: the spreading of the fur from the tonsils on the adjacent parts of the stomatopharynx - palatal aerofoils, uvula - indicates that the process is not ordinary. The edema of the mucous membrane testifies in favor of diphtheria. While diagnosing widespread diphtheria, it is necessary to be convinced of the absence of the hypodermic cellular edema of the neck not to fail to diagnose toxic diphtheria.

228 Infectious diseases

Toxic diphtheria of the stomatopharynx is characterized by in especially bright clinical picture, nevertheless, the greatest number of mistakes is made in both children and adults in this case. Apparently, the main cause of it lies in the fact that toxic diphtheria is a comparatively rare disease and the doctor lacks personal observations, which could help him to diagnose the disease. The main symptoms of the early period of toxic diphtheria are edema of the neck - hypodermic, cellular, edema of the stomatopharynx mucous membrane and widespread fur on it.

Contagious mononucleosis should sometimes be differentiated from toxic diphtheria. The resemblance is explained by the fur on the tonsils that has irregular depth irregular consistence of the neck hypodermic cellular above the enlarged lymph nodes. In contrast to toxic diphtheria contagious mononucleosis develops step-by-step,the quaggy fur on the tonsils occurs not earlier than on the 3-4th day, it can be rather easily removed by a glass spreading rod and is triturated. A long-lived fever, polyadenitis with primary enlargement of the posterior neck lymph nodes, hepatolienal set of symptoms and characteristic pattern of the peripheral blood, in which one the uninuclear cells dominates, — testify in favor of contagious mononucleosis.

Treatment

Hospitalization of patients is obligatory. In case of a toxic diphtheria patients transport only laying. The severe confinement bed regime is necessary during 20-25 days, then at absence of complications the patient allow to sit and gradually dilate impellent regime. At mild forms (localized diphtheria of pharynx,diphtheria of nose) duration of confinement bed regime is reduced up to 5-7 days. In the acute period of disease fluid and semifluid nutrition is necessary. Treatment may be specific and pathogenic.

Specific treatment will carry out by high purified horse hyper immune serum. For prevention of anaphylactic reactions infuse serum by Bezredko method. First of all 0.1 mL diluted 1 : 100 of serum infuse intracutaneous of forearm. If after 20-30 min on a place of injection there are not changes or the papule in diameter is not more than 0.9 cm, - reaction is negative, and infuse 1 mL of undiluted serum sub dermal, and at absence of reaction - after 30 min all prescript dose in muscle.

At toxic diphtheria II-III stage and the hyper toxic form a serotherapy is carried out necessarily, under protection of hormonal preparations, and sometimes - narcosis. In case of positive intradermal assay or at presence of anaphylactic reactions further subdermal infusion of serum only behind unconditional indications. Serum in dilution 1: 100 is infused in a sub dermal fat of brachium in doses 0.5, 2, 5 mL consecutive with intervals 20 min. At absence of reaction to previous dose infuse 0.1 mL of undiluted serum subcutaneously. If reaction is not present, through 30 min infuse all prescribed dose subcutaneously. In unusual cases serum is infused under narcosis.

Diphtheria 229

Antitoxic serum neutralizes only a toxin, which circulates in a blood, and does not influence on fixed in tissues. Therefore specific treatment may be carried out as soon as possible (optimum in 1 — 3 rd day of disease).

The form of diphtheria determines doses of serum for the first introduction and course of treatment.

At late (after 2nd day of disease) beginning of treatment of patients with the widespread or toxic form the first dose of serum should be increased. The form of disease also determines frequency rate of infusion of serum. In case of localized diphtheria of a throat, nose, rare localization of process and early serotherapy is possible to be limited by disposable infusion of serum. If diphtheria of throat is widespread, infuse serum during 2-3 days (at the toxic form -through every 12 hours). The first dose makes 1/3 - 1/2 course; in first two days patient may receive 3/4 of course doses.

Serum dose depends on toxicosis stage, process spread and lesions localization; it fluctuates in limits of 5 through 500,000 units,

Usually the course of serotherapy lasts no more than 3-4 days. Indications for stopping of serotherapy are disappearance or decreasing of spot, edema of pharynx and hypodermic fat of the neck, at croup - complete disappearance or decrease of stenotic respiration. At suspicion on toxic diphtheria serum should be infused immediately; at localized form - it's possible waiting for results of bacterioscopy, otolaryngology examination etc., but under condition of constant surveillance in hospital; on diphtheritic croup - infusion of serum is obligatory if this diagnosis is not refused after carrying out of intensive cure during 1-1.5 hours.

In order to intensify action of serum, infusion of 25 % solution of magnesium sulfates intramuscularly once a day right after beginning of serotherapy is recommended.

Pathogenetic treatment is directed on desintoxication, restoration of hemodynamic and elimination of adrenal gland insufficiency. Desintoxication therapy provides intravenous infusion of 10 % solution of glucose with insulin, albuminous preparations and colloid solutions in the ratio 1:1. A liquid is infused at the rate of 20-30 mL/kg of mass. Diuretic agents, are indicated under the control of arterial pressure and diuresis.

For improvement of tissue metabolisms cocarboxylase, acidum ascorbinicum, a nicotinic acid, ATP are indicated. The nicotinic acid decreases also an influence of diphtheritic toxin, and ascorbic - stimulates imunogenesis and function of cortex of the adrenal glands.

Prednisolonu m (2-3 mg/kg) or hidrocortizonum (5-10 mg/kg per day) are prescribed to the patient with widespread and toxic forms of diphtheria with the purpose of replaceable, anti-inflammatory and hyposensibilisative treatment for 5-6 days. In the first 2-3 days glucocorticoides are infused in vein, then per os. In case of hypertoxic and hemoragic forms the daily dose of prednisolonum is enlarged up to 5-20 mg/kg according to stage of shock.

230 Infectious diseases

At toxic form of diphteria, since the first day there is indicated 0,1 % solution of strychninum of sodium nitritum (0.5-1.5 mL subcutaneously) during 2-3 weeks and more. Strychninum stimulates tone of the central nervous system, stimulates respiratory and vasomotor centers, tones up sceletal muscles and a myocardium, stimulates oxidant-recreated processes in myocardium. Use of cordiaminum, corazolum raise a tone of organs of circulation. At cases of DIC for desagrigation, except reopolyglucini, indicate antihistamines, vasodilators, trentalum, ksantinol. For reception of anticoagulative effect infuse heparin (150-400 U/kg per day). Inhibitors of proteases are recommended.

Antibacterial therapy is prescribed with the purpose to eliminate Corynebacteria diphtheria and secondary flora. It is expedient to apply benzylpenicilini, tetracyclinums, cefalosporines, erythromicini.

Treatment of patients with diphtheria of larynx. Patogenic treatment is indicated: sibazonum (seduxenum). Oxygen therapy is provided. In case of a stenosis of larynx without respiratory failure the good effect gives a warm soda drink, sinapismuses. Hyposensibilisative preparations (dimedrolum, pipolfeni, tavegili) are used to decrease the edema of mucous, locally antiedema and anti-inflammative therapy in aerosols (inhalations) is prescribed.

Complex treatment provides also indication of glucocorticosteroides, in particular prednisolonum (2-3 mg/kg per day), which, except for antiinflammatory action, assist decrease of edema of larynx, reduce a permeability of wall of capillaries and exudation. Half of daily dose is infused intravenous or in muscle,the rest is given per os. After prescriptions desintoxicative therapy will carry out. Antibiotics of wide spectrum action are prescribed. If conservative treatment is not effective, operative measures are used.

Triad of signs is the indication to initial intubation (tracheostoma):

a) Paradoxical pulse (inspiratory asystolia of Raufus); b) sign of Baie: continuous contraction of sternocleidomastoideus muscles during inspiration; c) proof cianosis of labiums and face. In case of a localized croup - long nasotracheal intubation, at a wide-spread descending croup tracheostomy with the following drainage of trachea and bronchuses are indicated.

Treatment of complications. At myocarditis optimum duration of the bed period regime is near 3-4 weeks. There are indicated strychninum (a long course); solution of glucose with cocarboxylase, acidum ascorbinicum, ATP, calcium pangamatis, agents which influence on tissue metabolism (a methandrostenolone, a potassium orotatis). At serious and medium myocarditis prednisolonum per os and parenteraly (in a daily dose 40-60 mg) is recommended. Introduction of cardiac glicosodes is supposed only at manifests of heart insufficiency without disorders of contraction. Anticoagulants of indirect action are prescribed for prophylaxis of tromboembolitic complications (dicumarinum, neodicoumarin, pelentanum).

The patient with diphtheric polyneuritis should be treated with strychninum, vitamins of group B, glucocorticosteroides. In the recreating period an oxazili

Diphtheria

inside during 15-20 days, massage, medical gymnastics (cautiously), diathermy, galvanization,quartz are prescribed.

In case of respiratory muscles disorders antibiotics of wide spectrum of action are used in the maximal doses for prophylaxis of pneumonia. Patient can be transfer on apparatus respiration in conditions of departament of reanimation after indications. Proceeding from action of diphtheritic toxin as inhibitor of acetylcholinesterase, proserini at neurologic complications is indicated after fading acute displays of disease.

Treatment of toxygenic corinebacterias diphtherias carriers. At repeated allocation of bacteria - antibiotics of tetracycline lines, rifampicini are recommended. After a seven-days course usually there comes sanitation. The basic attention should be payed to chronic disease of nasopharynx. Treatment begins with fortifying (methyluracilum, pentoxylum, aloe, vitamins) and hyposensibilisative agents with physiotherapy ( ultraviolet radiation, ultrasound).

Duration of hospitalisation is determined by gravity of diphtheria and character of complications. If complications are not present, patients with the localized form may be discharged from the hospital at 12 - 14th day of disease, with spread form at - 20 - 25th (bed regime - 14 days). Patients with subtoxic and toxic forms should be on bed regime 25-30 days; they may be discharged at 30 - 40th day of disease. In case of a toxic II - III degree diphtheria and serious course of disease the regime lasts 4-6 weeks and more. The obligatory condition for patient's leaving the hospital with any form of a diphtheria is negative result of two control inoculations received with an interval of 2 days.

Prophylaxis

The major manifestations of diphtheria can be prevented in individual patients by immunization with formalin-inactivated toxin. Therefore, documentation of inadequate levels of antitoxin in large proportion of the adult population in North America and Western Europe has caused great concern that a toxigenic strain introduced into these populations could cause a major outbreak of disease. Serum antitoxin levels can be measured by toxin neutralization tests in rabbit skin, in Vero cell culture, or by hemagglutination, with roughly equivalent results. Concentrations of 0.1 - 0.01 (international units) generally are thought to confer protection. For example, data from a recent outbreak showed that 90 % of clinical cases had antitoxin levels below 0.01 IU/mL, whereas 92 % of asymptomatic carriers had liters above 0.1 IU/mL. Following immunization, antitoxin levels decline slowly over time so that as many as 50 % of individuals over age 60 have serum liters below 0.01 IU/mL. For this reason, booster doses of toxoid should be administered at 10-year intervals, to maintain antitoxin levels in the protective range.

Recommendations from the Immunization Practices Advisory Committee in 1991 are as follows.

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For children from 6 weeks to 7 years of age: three 0.5-mL intramuscular injections of (DPT) vaccine should be given at 4-8-week intervals, beginning at 6-8 weeks of age, followed by a fourth dose 6-12 months after the third.

For persons of 7 years or more: 0.5 mL Td (toxoid—adult) is given twice at a 4-8-week interval, with a third dose 6-12 months later. Because the pertussis component of DPT is responsible for most of its side effects, and the risk of pertussis is much less after age 6, that component of the vaccine is omitted. Moreover, because subjects over age 7 have a higher incidence of local and systemic reactions to the concentration of diphtheria toxoid in pediatric DPT vaccine (7-25 limit flocculation [Lf] units) and because a lower dose of toxoid has been shown to induce protective levels of antitoxin, the Td formulation of vaccine contains a maximum concentration of 2 Lf units of diphtheria toxoid. If the recommended sequence of primary immunizations is interrupted, normal levels of immunity can be achieved simply by administering the remaining doses without need to restart the series.

Booster immunizations: children who have completed their primary immunization before age 4 should receive a booster dose of DPT at the time of school entry. Persons above 7 years of age should receive booster immunization with Td at 10-year intervals. As a help to memory, this should be done at decade or mid-decade intervals (e.g., ages 15, 25, 35, etc., or 20, 30, 40, etc.). Travelers to areas where diphtheria is still endemic should be particularly careful to be sure their immunization is current. Although the recommended booster dose of 1.5-2.0 Lf units will increase antitoxin levels to above 0.01 IU in 90-100 % of previously immunized individuals, some authorities have recommended using 5 Lf units, because antitoxin levels remain above 0.01 lU/mL for a longer period than with 2 Lf units. Patients should receive toxoid immunization in the convalescent stage of their disease because clinical infection does not always induce adequate levels of antitoxin. Close contacts whose immunization status is incomplete or unclear should promptly receive a dose of toxoid appropriate for their age, and complete the proper series of immunizations. In addition, they should receive prophylactic treatment with erythromycin or penicillin, pending the results of pretreatment cultures. Given these preventive measures, the prophylactic use of antitoxin is considered unwarranted.

Control questions:

1. Source of infection and mechanism of diphtheria transmission.

2. Pathogenesis of disease and pathomorphologic changes.

3. Classification of clinical forms of diphtheria.

4. Clinical features of certain disease forms.

5. Clinic of the urgent states at diphtheria.

6. Complication of diphtheria.

7. Laboratory diagnosis of diphtheria.

8. Differential diagnosis of diphtheria.

9. Specific, etiotropic, pathogenetic and symptomatic treatment of patients with diphtheria.

10. Medical aid in case of croup,hypertoxic forms of diphtheria.

11. Principles of discharge of patient from hospital.

12. Prophylaxis and preventive measures in spot of infection outbreak.

10.

Rlckettsiosis

Date: 2014-12-21; view: 1748