Infectious diseases with
the dominant involvement of kidneys: leptospirosis, HFKS
(hemorrhagic fevers with kidneys syndrome). Hemorrhagic fevers: yellow fever,
Leptospirosis is an acute generalized infectious disease, characterized by extensive vasculitis, caused by spirochetes of the genus Leptospira. It is primarily a disease of wild and domestic mammals; humans are infected only through direct or indirect contact with animals.
A. Weil (1886) was the first who described leptospirosis as an independent disease, four cases with a high temperature, jaundice, hemorrhages and the renal affection.
R. Virchout (1865) considered the described disease as a kind of typhoid fever and called it “typhus biliosus” differentiating it from “katarrhalischen icterus“.
In 1888 in the book “Infectious Jaundice” S. P. Botkin’s pupil N.K.Vasiliev informed about twelve cases of a similar disease but did not paid much attention to the character of the temperature, the expressiveness of jaundice, the time when hemorrhages and the renal affection appear, he comes to the conclusion that the new disease is different from typhoid fever and catarrhal jaundice.
For a long time leptospirosis was divided into icteric and non-icteric forms. The first description of non-icteric leptospirosis was given by W. A. Bashenin in 1928, he suggested naming me disease “water fever”.
Leptospirosis is registered in many countries.
The leptospirosis pathogen belongs to the genus of Leptospira Nogychi and can be divided into 2 kinds - parasitic and saprophytic. There are hundreds of serotypes in each kind. The body of the leptospira consists of a long axis thread which is covered with a cytoplasmatic spiral that has a three-layer membrane (Fig.1). The average length of leptospiras is 10-14 mkm, the number of cons – 10-12. There are no spores or capsules. Leptospiras have energetic and complex movements. This explains their high invasive ability. Leptospiras do not get well painted with common aniline dyes. Some special liquid media containing animal (rabbit) serum are used to cultivate leptospiras. Leptospiras are unstable in the environment but are adapted to living in water.
The leptospira life time in water oscilates within wide limits – from several days to many months depending on pH, the salty composition and the microflora of the reservoirs.
It has been discovered that leptospiras have hemolysin and also lipases that can have a cytotoxic influence on the organs and tissues which are rich with lipids. There is endotoxin in the leptospira cells.
The modern classification of leptospiras is based on their antigenic structure. There have been discovered 200 serovars united in 25 serological groups.
There are two active serologic complexes among the antigens of leptospiras each of them has a complex set of components. One of them is situated on the cell surface and determines its typospecific qualities, the other - in the depth of the microbe and characterizes genospecific peculiarities of leptospiras.
The vital capacity of leptospiras in the environment depends on many factors. There is a considerable discrepancy in the whimsicality of leptospiras (the necessary conditions of their survival are high humidity, warmth, pH of the water and soil (7.0-7.4), the limited amount of salt). In the water of the rivers, pools, lakes and marshes leptospiras remain viable for 5-10 days but in the sea water they die in several hours. Leptospiras remain viable in the damp soil up to 270 days, in dry soil - not more than 3 days. Leptospiras can easily endure low temperatures and remain viable during prolonged freezing, however, they quickly die when warmed, dried if exposed to salt or acid.
Leptospirosis is a zoonotic infection. The source of the infection is animals wild, domestic and game animals (pigs, cattle, foxes, white foxes, nutrias and others). They form anthropurgias foci.
The small mammals who live in the forests, near the reservoirs (volemice) play the main role in maintenance the leptospirosis foci. Their infection takes a form of a symptomless chronic process in the kidneys. Leptospiras multiply in the tubules of the kidneys and go out with urine.
The natural foci are situated in low lying areas. They are marshes, flood-lands, water-meadows, the marsh-ridden parts of the rivers and irrigation system, overgrown with bushes and abundant grassy vegetation. The infection of people in the natural foci is of a seasonal character (June-September), it usually occurs during the agricultural work (mowing the meadows, collecting hay, growing rice, flax, hemp and other abundantly irrigated crops, felling and during hunting, fishing, gathering mushrooms, drinking water and washing with water from the contaminated shallow reservoirs). The morbidity in the natural foci has a sporadic or group character. The development of natural resources, unorganized rest result in the immediate contact of people with nature and create an opportunity for infecting people with leptospiras. The natural foci are the source of infection for the domestic animals.
In recent years the gray rat has been playing a more important part in the epidemiology of leptospirosis, its infectedness has been proved in many countries of the world. For a long time leptospirosis was considered a disease of big cities, mainly ports. However, in the present situation the intensive processes of urbanization, creation of large cattle-breeding complexes, growing rice and other elements of the economic activity of man gave changed the ecology of the gray rat, so the anthropurgias foci of leptospirosis can be both in the rural areas and in the cities.
The foci which appear in the cattle-breeding industries as a result of bringing animals that are leptospira-carriers or infecting the cattle, pigs m the natural foci in the pastures, watering-places play the most important part in the epidemiology of the disease. The agricultural animals often have leptospirosis in the obliterated, symptomless form. That is why the sick animals are not isolated in time, they excrete leptospiras into the environment and infect water, forage, pastures, soil.
In many big cities, especially ports, there is a high rate of leptospirosis among the gray rats. This is the reason for the citizens to fall ill with leptospirosis if due to their occupation they contact sinanthropos rodents or the things contaminated by them.
symptoms of leptospirosis among dogs had been described before the pathogen was
discovered and the term “leptospirosis” appeared. In 1898 in
The infection is mainly transmitted from animals to humans by water. The contact way is considerably less important. The transmission of the infection through food is rare. Humans can be infected while swimming in the reservoirs, drinking water from them or using it for economic needs, during different kinds of the agricultural work in the marsh-ridden places, when fishing. There have been described some cases of leptospirosis infection among the personal of the slaughter-houses, meat-packaging plants.
The sick rate rises up in June - September. In other months there are registered some sporadic cases that are not connected with the infection in the open reservoirs.
Leptospirosis can be referred to the professional diseases. The people who are involved in the agricultural work in the marsh-ridden places fall ill more often, they include cattle-breeders, the personal of meat-packaging plants, miners, dockers, plumbers.
There have been some cases when people fell ill after being bitten by a coypu rat, as well as the personal of the laboratories, who work with leptospiras. The susceptibility of people to leptospirosis is high. A typospecific immunity remains for a longtime after having the disease.
The pathogenesis of leptospirosis is characterized by changing several phases. The first phase includes the pathogen penetration and a short-time primary leptospiremia. The leptospiras penetrate the human organism through the skin of the mucous membranes, travel along the lymph tracts, penetrate the blood and then various organs - the liver, kidneys, adrenal glands, spleen, lungs and others. This phase lasts 7-20 days, it corresponds to the incubate period.
The second phase includes secondary leptospiremia, it coincides with the beginning of the clinical manifestations of the disease, the generalization of the process. The leptospiras penetrate the organs and tissues with the blood flow again, fix on the cell surface (especially, in the kidneys, liver, adrenal glands), can overcome the hametoencephalic barrier. The leptospiras do not cause a destruction and they do not parasites intracutaneously. They stick to the cell surface, can stay in the inter-cell space.
The third phase is a phase of toxinemia that is accompanied by an expressed fever. The most important pathogenic factor of this phase is capillary toxicosis. The rupture of the capillary endothelium results in the diapedesious hemorrhages into various organs and tissues. It is clinically manifested as a hemorrhagic syndrome. Thrombocytopenia plays a part in the origin of the hemorrhagic syndrome, it is connected with the influence of the leptospira lipase on the phospholipids of thrombocytes membranes and their gluing together with the formation of the primary thrombocytous congestion. The vessels of the liver, kidneys, adrenal glands get affected most of all, there may develop Waterhause – Friedrichen syndrome. The degenerative and partially necrotic changes of the liver parenchyma as well as hemolysis oferythrocytes under the affection of hemolysins are the cause of jaundice which has a mixed character.
The influence of leptospiras and their metabolites on the cellular wall results in the affection of the adrenal gland epithelium, all the cortical and subcortical layer of the kidney that results in the uropoiesis affection. There is a possibility of the development of renal insufficiency.
The fifth phase includes the formation of the sterile immunity. The tense humoral immunity is combined with the expressed local organic and cellular immunity. Then comes a stable recovery.
Leptospirosis is characterized by the affection of the capillary endothelium of a various organs and tissues. The walls of the vessels are fragile, their permeability is increased, this is accompanied with numerous hemorrhages in the kidneys, liver, lungs, endocardium and pericardium, mucous membrane of the gastroenteral tract. The liver is enlarged, plethoric and with smooth surface.
The histological investigation shows an edema of the interstitial tissue, dystrophy of the hepatic cells without an expressed cytoptesis of hepatocytes, biliary thromboses in the central zone of the lobules.
The most considerable changes can be found in the kidneys. The kidneys are considerably enlarged, there are such typical symptoms as a stroma edema, numerous hemorrhages, a sharply expressed granular degeneration of the convoluted tubules epithelium up to necrosis. The kidney affection in leptospirosis can be considered as nephrosonephritis.
There are hemorrhages in the adrenal glands, sometimes considerable. The muscle affection is also characteristic of leptospirosis, especially the affection of musculus gastrocnemius and musculus thoracic. There are hemorrhages of various sizes; an uneven swelling of the fibers, degenerative changes in the synapses of the muscular fiber and nerve, sometimes coagulation necrosis which causes myalgia.
Dystrophy and lipid dystrophy develops in the heart muscle, sometimes there is interstitial myocarditis. There are hemorrhages in the lungs as well as in other organs. There is often an edema of the meninx vasculosas.
The course of leptospirosis can be mild, middle-moderate and severe. The severity of the course depends on the microbe virulence, the dose of infection, the reactivity of the microorganism.
The main criteria of the severity are follows: the degree of toxicity, the expressiveness of the affection of the liver, kidneys, central nervous system, heart, adrenal glands, hemorrhagic manifestations.
There are cycles in the leptospirosis course. There is and incubate period, the beginning, height and convalescence.
The incubation period lasts 2-20 days (more often 7-10 days). The disease has an acute onset. The patient can indicate not only to the date but even the hour of the disease onset. The fever usually has a remitting or constant character, it lasts 5-9 days then it falls down in the form of accelerated lysis. There can be another wave (a relapse).
From the first hours the patients complain of intense headaches, pain in the muscles, especially, musculus gastrocnemius, the muscles of the scalp, neck, back and abdomen. In 1888 W. P. Vasiliev wrote that there is no such an intensive myalgia in the musculus gastrocnemius in case of any other disease. The abdomen pain can be so intense that there is a suggestion about an acute surgical pathology.
The symptoms of toxicity increase. The patients are flaccid, adynamic. The patients has a characteristic appearance - face is edemic, hyperemic, vessels of the scleras are injected (Fig. 2).
Fig.2. Scleritis in leptospirosis
There is often herpetic rash on the lips. In some patients (in 30 % cases) a polymorphic symmetric rash which stays for several days appears on the third - fifth day of the disease.
In some cases there is an enlargement and painfulness of the peripheral lymph nodes. The liver gets enlarged early, on the second-third day of the disease. Jaundice develops in the moderate severe - course as well as in the severe course. The liver has a dense consistence, it is painful at palpation. In a half of the patients the spleen gets enlarged.
There are considerable changes in the cardiovascular system: dull heart sounds, sometime relative bradycardia, arrhythmia, extrasystole. In case of an expressed toxicity the arterial pressure sharply decreases (up to collapse) as a result of a decrease of the precapilary arteries.
The initial period of leptospirosis is characterized by the peculiar changes in the central nervous system, in some patients there are such symptoms as disorders of the consciousness and even unconsciousness, cramps besides an expressed persistent headache, insomnia, delirium. In 10-40 % cases there are meningeal symptoms: rigidity of the occipital muscles, Kernig’s sign, Brudzinsky’s sign that are distinctly manifested on the fifth-eighth day of the disease. In such patients the spinal puncture confirms the diagnosis of serous leptospirous meningitis - cerebrospinal fluid flows out under an increased pressure, it is transparent. The microscopia of the cerebrospinal fluid shows leptospiras, during the regular one outside the dark field of vision - moderate lymphocytic pleocytosis. The amount of protein is increased. Leptospirous meningitis usually has a nonmalignant character, it usually lasts 8-10 days.
At the end of the first week, and sometimes earlier jaundice develops in some patients (12-20 %). The intensity of jaundice and its duration depends on the severity of the disease and can last several weeks (1-4). A moderate skin itching is quite possible. The urine is dark, the color of the excrements is not changed.
With the development of jaundice the condition of the patients usually worsens. The most severe manifestations of leptospirosis appear at the end of the first week - at the beginning of the second week of the disease.
The hemorrhagic syndrome appears on the seventh-tenth day: petechial eruption on skin, hemorrhages under the conjunctive, hemorrhages in the nose, gums, stomach, intestine, uterus. The hemorrhages can be repeated, massive and result in anemia. Many clinicians have observed that the expressiveness of the hemorrhagic syndrome corresponds the severity of leptospirosis and has a certain prognostic significance. The degree of the kidneys affection is even more significant while evaluating the severity of leptospirosis, the kidneys are always affected to some degree in leptospirosis.
From the first days of the disease there can be oliguria, moderate proteinuria, in the urine there are fresh erythrocytes, leukocytes as well as hyaline casts and the cells of the renal epithelium. The symptom of the kidneys affection become the most expressed from the seventh-tenth day of the disease. Oliguria can be followed by anuria, an acute renal insufficiency may develop, m spite of the development of an acute renal insufficiency, there is usually no edema and arterial hypertonia in leptospirosis. Sometimes an acute renal insufficiency develops very early, on the fourth day of the disease. It is an acute renal insufficiency resulting in uremia that is a frequent cause of the lethal outcome of the disease. If the therapy is timely and adequate, the kidneys affection in leptospirosis can be cured. Oliguria is followed by polyuria, and function of the kidneys gets gradually normalized.
The second week corresponds to the severity of disease. At this time jaundice becomes the most intensive, the hemorrhagic and meningeal syndromes increase or appear for the first time. The changes in the cardiovascular system increase: the pulse is rapid and weak, a systolic murmur is sounded in the apex cordis, there can be extrasystolia. The electrocardiogram shows diffusive changes of the myocardium.
At this period of the disease the infiltrates connected with the hemorrhagic foci are sometimes formed in lungs, this is accompanied by the sanguinolent sputum secretion.
By the end of the second week the condition of the patients improves. The headache and myalgia reduce, the jaundice intensity gradually decreases, a great amount of urine begins to excrete. The patients feel weak for a long period. The duration of the disease averages to 3-4 weeks. Some patients (20-60 %) may have relapses. In 5-7 days after the feverish period the temperature rises again, headaches and myalgia appear. The relapses and acute forms are not so severe as the first phase, as a rule. The temperature does not usually rises very high, the fever does not last more than 2-3 days. Some patients have 3-4 acute forms of relapses.
In leptospirosis the hemogram is characterized by the progressive anemia, a low reticulocytes number. In the patients with a hemorrhagic syndrome there is expressed thrombocytopenia, an increased period of the blood coagulability. Leukocytosis is a characteristic feature. The number of leukocytes increases up to 12-25x105 in 1 mkL. In the differential blood count there is neutrophilia with a shift to the left, expressed lymphopenia. The ESR reaches 40-60 mm/h.
The bilirubin amount in blood increases in case of the icteric form. The level of prothrombin may moderately decrease. The activity of transaminases is either normal or slightly increased on the tenth-fifteenth day of the disease.
The asthenovegetative syndrome is a characteristic feature of the convalescence period. Anemia and proteinuria remain for a long time.
Some patients have eye affections - uveitis, iritis, iridocvclitis that develop in 2 weeks and in several months after the onset of the disease. There can be other complications in the acute period - massive hemorrhages, an acute renal and hepatic insufficiency, uremia, myocarditis, an acute cardiovascular insufficiency.
It is quite difficult to diagnose leptospirosis, especially during the first days of the disease. The bacteriological method is of a little practical importance because leptospiras grow badly and slowly on the artificial media. The correctly taken epidemiological history plays the most important part in diagnosing leptospirosis. It is necessary to take into account the patient's occupation, his contact with agricultural animals, work in the meadows, swimming in the rivers and ponds, the existence of rodents in the surroundings. The epidemiological history not only determines the direction of diagnosis but gives an opportunity to control the environment. The following peculiarities of the clinical symptoms are taken into consideration: jaundice, accompanied by fever, myalgia, hematuria, hemorrhages. The diagnosis based on the clinical-epidemiological investigation, is confirmed by the laboratory data.
The materials used for diagnosing leptospirosis are blood, urine, cerebrospinal fluid.
The following methods of the laboratory diagnosis are used:
1. Bacteriological, bacterioscopic.
The bacteriologic investigation includes the primary microscopia of the initial material and its inoculation of media for acquiring the leptospira clean culture. The patient's blood serum, cerebrospinal fluid or urine are centrifuged. The fall out is investigated with microscope in a dark floor. Leptospiras are found as thin sinous mobile threads that look grayish -whitish on the dark background. That is necessary to note that the presence of leptospiras in blood is undoubtedly indicative of leptospirosis, but the negative result does not allow us to exclude the disease. The initial material inoculation of the water-serum medium consists of the native rabbit serum. The inoculation is incubated for 30 days at a temperature of 28-30 °C, the inoculation is examined on the dark floor of the microscope every 5-7 days.
The serologic investigations are done in the dynamics of the disease including the convalescence period. The reaction of the microscopic agglutination and lysis, as well as the complement fixation reaction are used to find antibodies in the serum of the sick people.
The reaction of the microscopic agglutination and lysis are done by a drop method with various serums of the patient’s blood and with those leptospira serotypes which can be found hi this area. The results of the reaction are taken into account with the help of a microscope with a dark floor. In the positive case there are phenomena of sticking together, the leptospira agglomeration in form of small “spiders” and different degrees of their lysis. The titer is considered to be diagnostic when the serum is diluted 1:50 -1:100.
The specific antibodies are discovered in the patient’s serum at the end of the first – the beginning of the second week of the disease. The antibodies can remain in patients for several years, that is why the investigation of the twin serums are of a great diagnostic importance.
Leptospiras appear in liquor later than in the blood, that is why its investigation (microscopia and inoculation of the same media as the blood) are done when there are symptoms of meningitis. Urine can be investigated from the first day to 3 months from the disease onset.
The guinea-pigs that are very sensitive to L. icterochaemorrahaigae are used as a model for the biological test. The animals are infected by injecting the infected material (blood, urine, cerebrospinal fluid taken sterile from the sick person) intraperitoneally, intracutaneously, intravenously, through the scarified skm and mucous membranes. The material is taken at the time when the bacteriological and bacterioscopic investigations are done. The animals die if there are leptospiras in the initial material.
However, in some cases there are diagnostic difficulties because of the polymorphism of the clinical picture, separate symptoms of which make it difficult to diagnose a disease (jaundice, fever, abdomen pain, myalgia, meningeal syndrome).
First of all it is required to differentiate the disease from flue, typhoid fever, hemorrhagic fever with a renal syndrome (HFRS), virus hepatitis, meningitis.
In case of flue the headache has a distinct location (in the superciliary arch area), there is no hepatosplenomegaly, jaundice. There are expressed catarrhal symptoms. The hemogram shows leukopenia, neutropenia, the ESR is usually normal. The fever last from 2-3 to 5 days.
If there are such symptoms as an acute onset of the disease, a high temperature, intense headaches, the appearance of the patients, the liver and spleen enlargement, it is necessary to differentiate leptospirosis from typhoid fever. However, the following symptoms are characteristic of the initial period of typhoid fever: Kiari-Avtcin’s sign, Govorov-Godolie’s sign, Rozenberg’s sign, and early increase of the spleen. There appears massive roseole-petechial eruption on the side surfaces of the breast, abdomen, extension surface of the extremities.
In HFRS there are no pains in the musculus gastrocnemius, there are such characteristic symptoms as loin pains, Pastematsky’s positive sign, petechial eruption located in the area of the shoulders and armpits. There is prolonged hypoisosthenuria, and in the urine fall out there are waxy casts, degenerative cells of the renal epithelium besides erythrocytes, hyaline casts. There is no jaundice and meningeal syndrome. The hemogram shows leukopenia at the increased ESR at the onset of the disease.
Virus hepatitis has a gradual onset, without chills, the temperature rises at the pre-icteric period. Muscle pains, scleritis, conjunctivitis are not characteristic of it. There are no meningeal and renal syndromes. The activity of transaminases is considerably increased. The hemogram shows leukopenia, low ESR.
If it is necessary to differentiate leptospirous meningitis form serous meningitis of another etiology, it is necessary to take into account the epidemiological history, pain in the musclus gastrocnemius; the development of the meningeal syndrome in 4-6 days after the disease onset, the simultaneous affection of the liver, kidneys; a hemorrhagic syndrome.
Among the most effective etiotropic agent there is combination of antibiotics and antileptospirosis immunoglobulin if they are indicated in an initial stage when Leptospires are in blood. Benzylpenicillin, Tetracyclin, Erythromicin and Streptomycin are indicated more often. The daily dose of Benzylpenicillin can be changed from 3 to 12 millions UN, however, the dose 6 - 8 millions UN is more often indicated per day (in a muscle). It dosage depends on gravity of the disease current. The maximal dose of a preparation is indicated at development of meningitis. Ampicillin, Oxacillin, Ampiox are effective semisynthetic Penicillins. Benzylpenicillin or semisyntetic analogue can be combined with Streptomycin. Tetracyclin is indicated 0.2-0.3 gm 4 times per day, it less often, than Penicillins, causes reaction such as Yarish-Gersgeimer, however strengthens a permeability of vascular wall and promotes development of a hemorrhagic syndrome. It is contrindicated at the icteric form of leptospirosis fever and development of renal failure. Treatment with antibiotics is carried out during all feverish period and 2-3 days of normal temperature. In case of occurrence of relapse a new course of an antibiotic therapy must be indicated.
Clinical observations of last years has testified the inefficiency heterogeneous antileptospirosis immunoglobulin, oppression of immune system by it. The allogenic donor immunoglobulin which is effective in the first 3-5 days of disease are applied in medical practice, has no side-effects. The preparation prevents development of acute renal failure.
With the purpose of desintoxication and improvements of microcirculation in a vein there are infused solution of glucose, Reopolyglucin, Rheogluman, Trisol, Quartasol, and ascorbic acid. Good desintoxication effect have the preparations that neutralize ammonia: an Ornithine, Ornicetil, Glutargin. At severe intoxication Prednisolon and its analogues are indicated. The initial dose of Prednisolon is 60-120 mg and more, it is used for short course, quickly reducing dose in process of clinical improvement. Enterosorbtion with using of granulated coal SKN, Sillard P, Enterosgel, Polyphepan can be effective. At the icteric form there should be prescribed diets ¹ 5, 5A, and at pathology of kidneys – a diet ¹ 7.
At the development of the Disseminated Intravascular Coagulation (DIC) carry out a complex of medical actions according to hematological research. At I stage (hypercoagulation) infuse in a vein Heparin 2500 UN 4 times per day, Reopolyglycin, Dipiridamol (Curantyl), Pentoxyfilin (Trental) Contricali in bottles, ascorbic acid 5 % solution in ampoules 1 mL: 5-10 mL 2 times per day. At II stages Heparin can be infused under the control of blood clotting time, other preparations (Reopolyglycin, Curantyl, Trental) - in the same doses, as at I stage of syndrome. At III stage of DIC infusing of Heparin is not indicated. At hypocoagulation there is indicated native plasma or Cryoprecipitat of plasma, trombocite mass. At hypofibrinolisis there are given acid aminocapronic, Contrical, Gordox, at secondary hyperfibrinolysis - synthetic antifibrinolitics, inhibitors of proteases - Streptokinasa, Fibrinolysin are indicated.
At the bleeding with a tamponade cold, and infuse Calcii chlorid, Vicasol, aminocapronic acid are used. Infusions of a blood plasma, a red cells mass, Albumin are indicated at bleeding. If hepatonephric insufficiency develops simultaneously plasma transfusion of blood with infusion of erythrocytar and trombocytar mass 2-3 times, and are used instead of albuminous preparations, a mixture of amino acids, for example Alveosin-Neo is recommended.
In occurrence of acute renal insufficiency (oliguria, hypoisosthenuria) there should be repeated lavages of stomach and an intestine 2-4 % solution of sodium hydrocarbonate, intravenous infusion of 40 % of glucose solution, Euphyllin, Mannit. At later infuse Furosemid (Lasix). At development of metabolic acidosis indicate Natrii hydrocarbonas and Tris-buffer. If medicamental therapy is not effective and oliguria stage lasts more than 3-4 days, there is a necessity in Plasmaferesis or Plasmasorbtion or Extracorporal dialysis by means of artificial kidney.
The deratization and sanitation veterinary measures the essential part of the prevention. Deratization is for decreasing of the activity of the natural foci (wild rodents control) and the sanitation of the anthropurgias foci (the sinanthropos rodents control).
One of the directions of leptospirosis prevention is the actions which break the transmission of the disease by water in the natural foci (mechanization of me agricultural work, the supplying of workers with water-proof clothes, a ban to swim in the infected reservoirs and to use unboiled water). Vaccination is recommended for the people who permanently stay in the natural foci. The people who belong to a group of high risk infection (cattle-breeders, veterinary doctors, the meat packing plant personal, night-men, deratizators) should be vaccinated with inactivated vaccine.
Group of acute natural foci diseases characterized by a general intoxication, fever, systemic lesion of small-sized veins with development of a hemorrhagic syndrome.
There are hemorrhagic fevers with a renal set of symptoms hemorrhagic fever with renal syndrome, Lassa, Ebîlà and Ìàrburg fevers, Yellow fever, caused by viruses of miscellaneous sets and labors.
The diseases are caused by RNA-containing
viruses of Bunyaviridae family: from Hantaan kind (HFRS), Togaviridae
- Flavivirus (Yellow fever), Filoviridae – (Ebola fever,
Source of hemorrhagic fever with a renal syndrome are mice-like (about 16 kinds), which are excreting the virus with urine, stool and saliva. Among the gnawers the transmissible way of causative agent is possible. The contamination of the person descends by air - dust, nutritional and contact pathes (routes). The transplacental transmission of a virus from the pregnant woman is possible. The probability transmission from the ill person is not fixed.
In the natural foci the source of an infection - multipapillary rat, and ill in the main (basic) visitants. For Ebola fever and Ìarburg the source of contamination in the nature is not known yet, probably, it is primacy. The relevant feature contagious hemorrhagic fever Lass, Ebola and Ìarburg - capability of transmission of a virus from the person. It results in originating intrahospital flashes, including among employees of hospitals and secondary diseases in monogynopaediums. The transfer (transmission) of the hospital causative agent from the person descends by an aerogenic way, and also at common use by subjects of household activities, at sexual contacts, is more often - at maintenance for ill, usage of not sterile medical instruments. The contamination is possible both in height of illness and in the period of a reconvalescence.
There are two forms of a yellow fever: a yellow fever of jungle (natural foci - monkey, hedgehogs) and urban yellow fever (source - ill person). Both are diffused by mosquitoes Haemagogus and Aedes (Fig.3). The contamination those at a puncture of the ill person are possible at the end of an incubation interval or per the maiden 3 days of illness. A sensibility of the people overall.
Fig.3. Yellow fever mosquitoes
Contagious hemorrhagic fevers Lassa, Ebola and Ìàrburg are usual for definite terrains of Africa. The cases of their delivery in countries of America and Europe by ill primacy and people are described, which one have caught and were in an incubation interval of illness. Yellow fever Peru is recorded in countries of Africa, and also in Bolivia, Brazil, and Columbiums. She falls into to conventional illnesses, the strife with which one is regulated by (with) international medico sanitary rules.
As the majority of causative agents hemorrhagic fever can be diffused with the help of the air drop, they are also potential agents of biological weapons.
After inoculation of organism of the person through an injured skin and mucous of respiratory tract or digestive tract the virus propagates lymphatic system, falls in a blood with the subsequent virusemia. The antipathy, histic destruction, and responses of an organism by the way immunopathologic processes, changes of a curtailing system of a blood, endocrine disturbance, development of acute renal failure develops. The virus causes a serious capillary toxicosis, multiple hemorrhages, hemorrhagic eruption, rising of a permeability of capillary tubes with an output for limits of a vascular bed of a fluid part of a blood, severe edema of tissues, violation of microcirculation, and dystrophic changes of internal organs of an internals.
Hemorrhagic fever with a renal syndrome. An incubation interval on the average 10-15 day (duration from 8 about 35 day).
The illness starts is acute with extremely
strong chills. Temperature of a body is increased till 39-40 °Ñ. The visual
disturbances, decrease of visual acuity, “mist” before eyes) complain on a
sharp headache, backache, muscles of extremities, photophobia. Arise nausea and
vomiting. At inspection ill mark paleness nasolabial triangle, hyperemia of a
face, necks, upper half of trunk. The palpebral fissures are narrowed down,
scleratis. A mucosa of an oral cavity and pharynx are bright red with
haemorrhages. The Kerning’s signs, Brudzinsky sign can be determined and stiff
neck. Fever 7-9 days is prolonged.
On 3-5th day of illness on a neck, lateral areas of a thoracic cell, in axillaries fossas, above clavicles occurs petechial eruption. It is sporadic the members small-sized, have the shape of sprockets and are assorted by the way of red or violet strias the eruption present during all feverish season (Fig.4). Then there are nasal, intestinal, pulmonary bleedings.
Fig.4. Petechial eruption
Cardiac sounds are dull; the initial tachycardia is replaced by a bradycardia, hypotonia. The phenomena of bronchitis are possible. Almost for all ill the signs of a lesion of the alimentary canal are watched: dryness of tongue, nausea, vomiting, inflation and abdominal pain without definite localization. For 25 % of patients enlarged a liver and spleen and the icterus are possible.
Leading is the renal syndrome patient shows the sharp back pain, positive sign Pasternatsky from both sides, development of an oliguria, and in sever cases - anuria and uremia. In height of illness find a proteinuria reaching 40 gm/l and higher, hematuria, hyaline and fibrinous barrels, augmentation of number of cells of a renal epithelium. In a blood is sharply raised the level of a filtrate nitrogen, urea, creatinine. In a hemogram: the moderate hypochromia anemia, leukocytosis with a neutrocytosis, thrombocytopenia, increased ESR.
Flow of illness is predominantly severe, lethality up to 6-8 %. There are also moderate, mild and deleted forms .
Congo-Crimean hemorrhagic fever. The incubation interval lasts 3-7 day. The illness starts with chills, hyperthermia till 39-40 °Ñ. There are pains in a head, joints and muscles, extremities and spin, gaste, repeated vomiting. Vessels of scleras and conjunctivas injected are provoked, their face, and neck, top of a chest hyperemic (Fig.5, 6). The mucosa of an oral cavity bloodshots with punctulate exanthema, the soft palate is hydropic.
The fever stays 7-8 days, for the majority an ill temperature curve double-peak, the decrease of temperature of a body with occurrence (appearance) of a hemorrhagic set of symptoms is characteristic.
Fig. 5. Skleritis
On 2-4th the day of illness on a skin of a lateral area of a trunk, inguinal and axillary areas, on a gaste and extremities petechias and eruption occurs. The eruptions are of the round or oval shape with legible contours of dark - cherry colour, peter on 5-8th day. Simultaneously with an eruption there are odontorrhagias, nose, mild, alimentary canal, and icterus. The condition ill is sharply degraded. The hyperemia of a face is replaced by paleness and îäóòëîâàòîñòüþ. It is marked sleepiness, adynamia, sometimes stiff neck, and Kernig’s sign. The liver enlarged, the icterus is possible (probable). The Pasternatsky sign is positive. Develop an oliguria, microhematuria, and proteinuria. In a peripheral blood: a leukopenia with a neutrocytosis, thrombocytopenia, augmentation ESR, on 2nd week of illness - relative lymphocytosis.
The illness can be mild, moderate and sever degree. The lethality reaches 40 %, predominantly owing to an infectious-toxic shock, massive bleedings, and hepatonephric failure.
Lassa fever. Incubation period lasts 3-17 day. The disease starts with a minor fever, malaise, muscle aches, and conjunctivitis. Step-by-step temperature reaches 39-40 °Ñ and develops representative pharingitis, more often ulcerative-necrotic. The ulcers have yellowish center with bright erythematic borders, are localized on a soft palate, tonsils and mucosa of a pharynx. In height of illness the meningeal signs is marked a strong headache, giddiness, sleepiness, at a normal structure of liquor, violation (disturbance) of consciousness. Are watched nausea, a vomiting, diarrhea, deaquation, abdominal pain and chests, tussis, the dysuric phenomena generalized lymphadenopathy, specially enlarged cervical lymphonoduses. It are marked a relative bradycardia, sometimes dicrotism of sphygmus. The liver enlarged. In the analysis of a blood - leukopenia with shift of the formula to the left, the thrombocytopenia, ESR is step-by-step increased till 40-80 mm/hour. In moderate and severe cases - moderate bleedings of miscellaneous localization and petechias an eruption on a skin and mucosa, less often - roseola, papule, and spot. In very sever cases develops an edema of a face and neck, exudates (pleural, pericardial, peritoneal). Considerably complicate flow of illness pneumonia, fluid lungs, uremia, and infectious-toxic shock. Lethality is up to 30-67 of %. In the period of a reconvalescence the palindromias, deterioration of hearing, baldness are seen an asthenia, sometimes. http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lassaf.htm
Incubation period of Ebola fever 7-14 day, Marburg fever - 4-9 days a beginning is acute, precursory symptoms serve conjunctivitis and exanthemas. Per the maiden days of illness there are a strong pain of a head, chills, fever till 39-40 °Ñ, dorsodynias, muscles, joints, the nausea, vomiting, often watery chair, that can result in a considerable deaquation of an organism. The ìàculo-papular eruption distributing to a neck and a face, upper extremities, breech is representative, further there is an eruption on palms and base surfaces. Is watched enantema on a mucosa of a mild and firm palate, ulcer. Dermatitis of a scrotum quite often develops. Enough often on the maiden week of illness the lymphadenitis in occipital, cervical, axillary areas is marked. The lymph nodules enlarged up to the pea size, mild, are a little morbid. From the 5-7-th of day of illness the hemorrhagic set of symptoms more expressed is affixed than at Lassa fever; for the women - parent bleedings, spontaneous abortions. The psychics, hyperesthesia, cramp is sometimes upset. Complications - bronchopneumonia, orchitis, panreatitis, uveitis. After petering fevers is long the external tags of illness - deeply sunk down of an eye, cachexia labored gait are saved. In a blood at first leukopenia, then leukocytosis with a left-shift, thrombocytopenia. Immediate causes of death – infectous-toxic shock, heart failure, cerebral distresses. Lethality - 30-90 %.
Yellow fever. An incubation period is 3-6 days. Distinguish two stages of illness. First stage is characterized by the sudden beginning with strong chills, fever repeated vomiting. Ill has pains in a head, back, lower back, bones. It are marked a sharp hyperemia and edema of a face and neck, eye injected by a blood. A mucosa of a or pharynx and tongue of bright red colour. The photophobia develops. Patients are irritable and are provoked. Pulse is fast. From the 3-rd day of illness there are yellow colouring of a skin and sclera, dot hemorrhages on a skin, are enlarged a liver and spleen. Then there comes a remission continuing 1-2 days. Temperature of a body is reduced up to the norm, the state of health is improved.
From the 5-th day of illness the condition of patient is sharply degraded (stage of venous stasis). Temperature of a body up to 40 °Ñ and above is again increased, there can be a delirium. The icterus rises. The face becomes pale yellow with cyanotic tint. Strengthen nausea and vomiting. Emesis masses are of dark brown or black colour. A feces are dark (melena). On a skin of a trunk both extremities there are petechias and ecchymomas. The copious nasal and parent bleedings, bleeding gums are observed. The nephroses - oliguria or anuria, blood and barrels in urine, azotamia are struck.
The tachycardia is replaced by a bradycardia (Faget’s sign). The arterial pressure is reduced. In the analysis of a blood a leukopenia - up to 1,5-2,0-10 /l, neutropenia. Encreased ESR. Are characteristic a hyperbilirubinemia (at the expense of both fractions of a pigment), enhancement of activity aminotransferase, in urine - bilirubin, urobilin, it is a lot of albumin, erythrocytes, leucocytes, barrels.
The fever stage lasts 8-9 days. The death can occure due to bleedings, shock, hepato–renal failure. The lethality makes 5-10 %, in the season of epidemics - up to 60 % and higher.
The abortive forms of illness without an icterus and hemorrhagic set of symptoms are possible mild, deleted.
The diagnostic hemorrhagic fever is carried out with allowance for of epidemiological anamnesis (seasonal prevalence, connection with the causative agent, contact with ticks, rodens and exotic animal) and representative clinical developments acute onset, fever, hemorrhagic syndromes. The diagnosis confirms virology and serological methods of research. Causative agent of Lassa fever, Ebola and Ìàrburg - on culture of cells Vero or on guinea pigs epidemic parotitises. “The Gold standard” - detection of RNA of the originator. For serodiagnosis will use RCC, RN, RIA, RIIF, IFA with double serums of patients, immunosorbent methods. With material of sick persons work only in the specially equipped labs, adhering to strick safety measures (Fig.7).
Fig.7. Specially equipped department for treatment
The differential diagnosis
As against hemorrhagic fever, for an ill flu the hemorrhagic developments are very seldom. The high contagiousness, more short feverish season(term), availability êàòàðàëüíîãî of a set of symptoms, Morozkin sign is characteristic for him(it). In outwashes with a slimy nasopharynx by a method find antigens of a virus of a flu.
The virus hepatitises often start step-by-step, with preicteric of the period, the flow which one is accompanied catarrhal,dyspeptic, asteno-vegetative syndromes. In height of illness are not watched a hyperemia and îäóòëîâàòîñòü of a face, ãîðÿ÷êà, îçíîá, lesion of nephroses. The hemorrhagic set of symptoms arises only at a very serious degree of illness.
The òyphoid-paratyphoid diseases have a gradual beginning, stepwise temperature rise, reference predominantly roseola eruption. Easy diagnostic confirming epidemiological anamnesis, research of a hemoculture, serological tests.
At a canicola fever the strong muscle pains, specially in èêðîíîæíûõ muscles are characteristic; a liver, often icteric forms(shapes) of illness with the sharply expressed hyperbilirubinemia practically always enlarged; in a blood on all stretch(extent) of illness - hyperleukocytosis with a neutrocytosis, shift of the formula to the left, very high ESR. The diagnosis confirms by the laboratory data - detection of the originator at a dark field method of a blood and urine, serological tests RMA with leptospira.
For a hemorrhagic vasculitis are characteristic long-lived recurrent flow, lesion of joints, and localization of an eruption on extensor surfaces of top and bottom extremities.
At Q fever are struck mild with development of a pneumonia, are enlarged a liver and lien.
For a malaria pathognomic representative attacks of a fever with definite periodicity. At examination find a splenomegaly, in a blood - malarial plasmodium.
The meningococcal infection contamination starts is acute, but in a clinical picture of the generalized form (shape) on the foreground more often the meningitis or sepsis with a copious hemorrhagic eruption acts, it is a lot of members of the star-shaped form (shape) with a necrosis of an epithelium. In the analysis of a blood a hyperleukocytosis with shift of the formula to the left, enlarged ESR. The diagnosis confirms by detection ìåíèíãîêîêêà in sowings from a nasopharynx, blood and liquor.
All sick are subject to mandatory hospitalization. The basis of treatment make desintoxication (i.v. 5-10 % glucose, polyionic solutions, 5 % donor Albuminum), glucocorticoids, strife with a hemorrhagic set of symptoms (Ascorutinum, Vicasolum, Dicynonum, Etamsylatum, calcium Dobesilat, Adroxonum, Acidum aminocapronicum; blood). In case of renal failure (for decreasing of remic intoxication a gastric lavage and intestine with 2 % sodium of Sodium hydrogenum solutions; at increasing of acute renal failure and infectious-toxic shock - extra corporal haemodialysis). Antiviral drugs per the maiden days of illness assign virolex, ribavirin, inducers of endogenic interferonogenesis (cycloferon, groprinosin), specific immunoglobulin or plasma. The antibiotics in case of bedding of a bacterial infection contamination.
Prophylaxis and measures in the locus
At hemorrhagic fever with a renal syndrome the preventive measures are directed on strife with the gnawers. Are offered inactivated cultural and cerebral vaccines (China, Russia, Japan), recombinant of a vaccine (USA, China), which one have appeared effective in endemial terrains. With this purpose carry out a disinfestation in the natural locuses, puttings, and also collect of tongs with animal and poultries. For a disinfestation will use gexachloran. In a burn-time in a field and on timber loggings it is recommended to use a special protective clothing and repellents.
Medical observation in the focus for 10 days. Conduct mandatory final disinfection with 3 % Chloraminum solution and chlorofos. For contact persons or one who was bitten by tongs in endemial districts enter a specific immunoglobulin i.m. in doses 5-7.5 ml for adult, 2.5-3.5 ml - for children. Apply a vaccine, inactivated by formalinum for specific prophylaxis of Congo-Crimean hemorrhagic fever.
Primary antiepidemic measures after
detection of sick with contagious hemorrhagic fevers Lassa, Ebola and
The specific prophylaxis contagious
hemorrhagic fever. The quarantine for arriving from epidemic areas lasts 17
day. In endemial districts of yellow fever vaccination of the population by an
An acute infectious disease of mammals, especially carnivores, characterized by central nervous system wrilation followed by paralysis and death.
Rabies in dogs and the importance of saliva in its transmission may have been recognized in Pharaonic times and in China at least seven centuries ago. But it now seems doubtful whether much-quoted passages from the Babylonian pre-Mosaic Eshnunna code (around 2300 ÂÑ) and those attributed to the Greek philosopher Democritus (500-400 BC) referred specifically to rabies Aristotle (322 BC) described rabies in animals but seems to deny that humans could be infected or could die from the disease. Celsus in "De medicina" (1st century AD) described hydrophobia in afflicted humans and recognized that the disease was spread by saliva, although his use of the Latin word "virus" did not imply a specifically infective origin. He discussed local treatment for the wound, including cupping, suction and cauterization, and the immersion of the patient in sea water. Other persistent myths that arose at that time were the idea that surgical excision of a dog's "tongue worm" (frenulum linguae) would protect it from rabies (as pointless and malicious an operation as that for "tongue tie" in children) and the belief that rabies could be generated spontaneously in dogs. In the sixteenth century, Fracastoro strengthened the concept of rabies as a contagious disease.
A scientific or experimental approach to rabies was delayed until 1793, when John Hunter published his very important paper, "Observations and heads of enquiry on canine madness." Hunter suggested that the transmission of rabies should be studied by inoculating saliva from rabid animals and humans into dogs and that attempts should be made to inactivate the "poison" in the saliva. These ideas may have inspired the experiments by Zinke (1804) and Magendie and Breschet (1813). Zinke used a paintbrush to introduce saliva from rabid dogs into incisions made in the skin of dogs, cats, rabbits, and chickens, which duly developed signs of rabies. In the same year Magendie and Breschet infected dogs with saliva from human patients with hydrophobia.
Galtier (1879) was responsible for an important technical advance. He found that rabbits could be infected with rabies and were far more convenient experimental animals than dogs. Pasteur adopted the use of rabbits in his studies of rabies beginning in 1880. He was the first to recognize that the major site of infection was the CNS. "Street virus" from a naturally infected dog was passaged through a series of rabbits to produce "fixed virus" with a consistent minimum incubation period of 6 or 7 days. Attenuation of the fixed virus was achieved by desiccation of rabbit spinal cord for up to 14 days. Pasteur was able to protect dogs from challenge by immunizing them with the desiccated material, and in 1885 he used his vaccine for the first time in Joseph Meister, a boy severely bitten by a rabid dog. In 1891 passive immunization, using whole blood from vaccinated dogs and humans, was studied by Babes and Cerchez. Negri (1903) described his diagnostic inclusion body, which allowed the laboratory diagnosis of rabies. The introduction of the more specific and sensitive immunofluorescence method by Goldwasser and Kissling in 1958 has now largely replaced the Seller's stain for Negri bodies. The nature of the infective agent was further elucidated by Remlinger (1903), who showed that it would pass through a Berkefeld filter. It was not until 1936 that the size of the virus was established by reliable ultrafiltration studies (Galloway and Elford), and it was first seen as a bullet-shaped particle by electron microscopy in 1962 (Almeida and colleagues).
Improvements in Pasteur's vaccine were achieved by Semple and Fermi, who killed the virus rather than attenuated it, and by Fuenzalida and Palacios, who developed a suckling mouse brain vaccine which carried a lower risk of neuroparalytic complications.
Successful growth of rabies virus in tissue culture was achieved by Kissling in 1958, leading to the development of human diploid cell strain vaccine by Wiktor and his colleagues in 1964 and of other safe and highly potent tissue culture vaccines. The use of passive immunization with equine hyperimmune serum has been vindicated by the famous natural experiment following an attack by a rabid wolf on 29 people in Iran in 1954.
The rhabdoviruses (Greek rhabdos—rod) are a group of about 140 RNA viruses of plants, arthropods, fish, reptiles, birds, and mammals. Rabies and its five related viruses constitute the genus Lyssavirus. The rabies virion is approximately 180 x 80 nm (Fig.8). The nucleocapsid consists of a single negative strand of helical RNA associated with three structural proteins: a nucleoprotein (N), a phosphoprotein (NS), and an RNA-dependent RNA polymerase (L). This is surrounded by a lipid-containing envelope including a matrix protein (M) and a glycoprotein (G) which forms spiky protuberances on the shaft and rounded end of the virion. This surface glycoprotein is the only molecule that induces neutralizing antibody and was therefore considered the only important constituent of vaccines. However, recent work has shown that the nucleoprotein is also capable of inducing protective immunity, although not by neutralization.
Fig.8. Agent of rabies (RNA-containing virus)
Rabies virus is rapidly inactivated by heat: at 56 °Ñ the half-life is less than 1 minute and, experimentally, the titer decreased by 105 infectious doses within 15 minutes. At 37 °Ñ the half-life is prolonged to several hours in moist conditions. The lipid coat of the virion renders it vulnerable to disruption by detergents and simple 1 percent soap solution. Forty-five percent ethanol, iodine solutions (with 1 in 10,000 available iodine), 3 percent sodium hydroxide, 1 in 1,000 ben-zaikonium chloride, chloroform, and acetone all inactivate the virus, but mereurochrome is ineffective.
Repeated intracerebral passage in animals of "street virus" from naturally infected animals results in a "fixed virus" of uniformly shortened incubation period and reduced pathogenicity which is used in vaccine production. Strains of rabies virus can now be identified using panels of monoclonal antibodies. Antigenic patterns show differences between vector species, for example distinguishing virus from North American insectivorous bats from fox, raccoon, and skunk strains occurring in the same area.
Wild or domestic animals occasionally carry the bat strains, indicating the source of their infection. The vector of rabies transmission to nonenzootic species can therefore be identified. Culture of virus is not essential, as monoclonal antibody typing is performed on the abundant nucleoprotein antigen in fixed brain impression smears. Some strains of rabies virus produce distinctive clinical manifestations, such as the sub-acute paralytic form of rabies in dogs in West Africa (oulou fato) and paralytic rabies transmitted to bovines and humans by vampire bats in Latin America and the Caribbean.
Rabies virus can be isolated and cultivated in a number of laboratory animals and continuous cell lines. The conventional method, by intracerebral inoculation of suckling mice, is sensitive but takes 2 to 3 weeks. Many laboratories are now using mouse neuroblastoma cell cultures in which the virus can be identified in 3 to 4 days.
Rabies is enzootic in mammal populations in most countries.
Rabies-free countries include the British Isles, Norway, Sweden, Iceland, Mediterranean and Atlantic islands, Australia, New Guinea,
Domestic dogs, and to a much lesser extent cats, are the main reservoir of urban rabies, which is responsible for more than 90 % of human cases worldwide. However, in countries such as the United States, where control of rabies in domestic animals has been very successful, wild animals such as skunks and raccoons now constitute the main threat for spread to humans.
species of vampire bat (Desmodontinae) are found in Southern Texas, Mexico, Central America, South America as far south as northern Argentina and northern Chile, and some Caribbean islands, such as Trinidad and
Although antibody induced by European tissue culture rabies vaccines and commercial immune globulin neutralize European bat Lyssavirus, results of challenge experiments in mice vary, but some show poor protection by virus strains used in vaccines available in Europe.
It is possible that infection with rabies-related viruses, such as Kotonkan virus in domestic herbivores in Nigeria and Mokola virus in cats and dogs in Zimbabwe, may confer some protection against rabies.
Incidence of Human Rabies
The true global incidence of human rabies has been obscured by underreporting. Recently, a figure of 50,000 human deaths per year in India alone was suggested. Other countries reporting a high incidence of human rabies include Pakistan, Bangladesh, Sri Lanka, the Philippines, Thailand, Indonesia, Brazil, Colombia, El Salvador, Peru, Ecuador, Mexico, and China. In the United States there were more than 25 human deaths per year in the 1940s, but since 1960 the maximum annual incidence has been 5 (in 1979), and the total number of cases was 50 in 28 years, of which 17 were infected outside the United States. In continental Europe few rabies deaths are now reported.
Intact skin is an adequate barrier to the infection, but broken skin and intact mucosa can admit the virus. Human infections usually result from inoculation of virus-laden saliva through the skin by the bite of a rabid dog or other mammal. Scratches, abrasions, and other wounds can be contaminated with infected saliva. The following are very unusual routes of human infection:
1. Inhalation. This has been reported in caves densely populated with insectivorous bats, which can create an aerosol of rabies virus from infected nasal secretions and possibly urine. In the United States there have been two laboratory accidents involving the inhalation of fixed virus during vaccine preparation.
2. Vaccine-induced rabies (rage de laboratoire).
In the worst incident, 18 people developed paralytic rabies in
3. Comeal transplant grafts. Seven cases have been reported in France, the United States, Thailand, Morocco, and India in which infected comeae were transplanted from donors who had died of unsuspected rabies. Six of the recipients developed rabies and died.
4. Transplacental infection. This has been observed in animals but until recently had not been reported in humans, whereas a number of women who developed rabies encephalitis in late pregnancy were delivered of healthy babies. Transmission of rabies by breast milk is well documented in animals and has been suspected in at least one human case.
Animals can be infected through the gastrointestinal tract (per os and per rectum). In the previrologic era, there were claims that eating infected meat and sexual intercourse could transmit rabies to humans, but these routes remain unproven.
In experimental animals, injected rabies virus replicates locally in striated muscle but is soon detectable at neuromuscular junctions and neuromuscular and neurotendinal spindles. Direct invasion of nerve cells may also occur without prior infection of muscle. Various possible cell surface receptors for attachment of the rabies virus have been suggested, such as phosphatidylserine, carbohydrates, phospholipids, and sialylated gangliosides. At neuromuscular junctions and in the CNS, the postsynaptic nicotinic acetylcholine receptor is an important attachment site for the virus. Binding at these sites is competitive with cholinergic ligands, including the snake venom neurotoxin, alphabungarotoxin, which shows sequence homology with rabies virus glycoprotein.
Once inside peripheral nerves, the virus is carried centripetally by the flow of axoplasm to the dorsal root ganglia where there is further replication, explaining perhaps the characteristic prodromal symptom of paresthesia at the site of the inoculation. Spread along peripheral nerves can be blocked experimentally by local anesthetics, metabolic inhibitors, and section of the nerves. Spread is rapid through the spinal cord and brain, and there is massive viral replication on membranes of neurons and glial cells and direct transmission of virus from neuron to neuron via the synapses. Virus also exists free and spreads within extracellular spaces such as the CSF. In the early stages of the encephalomyelitis, there is selective infection of certain neuronal populations. Finally, there is a phase of passive centrifugal spread of virus from the nervous system in the axoplasm of many efferent nerves, including those of the autonomic nervous system.
Virus has been found in many tissues including skeletal and cardiac muscle, intestine, kidney, liver, pancreas, and brown fat. Extraneural viral replication has been observed in salivary glands, brown fat, and cornea. Virus is shed from salivary and lacrimal glands, taste buds, respiratory tract, and rarely in urine and milk. Viremia has rarely been detected in animals and is not thought to be involved in pathogenesis or spread.
Response to Vaccination
Antibody induced by rabies vaccines has been measured by a variety of methods including the immunofluorescent antibody test, mouse neutralization, rapid immunofluorescent focus inhibition (a tissue culture neutralization test), enzyme immunoassays, and hemagglutination inhibition. The host's immune system is stimulated by a vast array of antigenic determinants on viral proteins and nonviral vaccine constituents. Each serologic test detects a different selection of these antibodies, and so the results of one cannot be compared with those of another. Neutralization tests are the best available indicator of protection from rabies deaths, but the correlation is far from perfect.
Neutralizing antibody is directed solely against the glycoprotein spikes on the viral coat, and so glycoprotein extracts have been used as subunit vaccines. The nueleoprotein molecule was considered irrelevant in the induction of protective immunity until work on influenza virus showed that immunization with purified nueleoprotein was beneficial in mice, not through prevention of infection but by aiding recovery. Dietzschold's group have shown that rabies ribonucleoprotein can induce protective immunity under some experimental conditions that may involve both humoral and cellular arms of immunity. The use of selected, broadly cross-reacting nueleoprotein epitopes in the construction of future vaccines is being investigated.
The amount of antibody produced by vaccine is partly determined by the host. Kuwert observed that in a population of vaccines, 80 % produced high antibody levels more rapidly than the 20 % who had poor, relatively delayed antibody induction. In mice, responsiveness to vaccine was genetically determined. Tissue typing in humans shows some minor differences between the groups of responders.
Vaccine-induced neutralizing antibody is not detectable for 7 to 10 days after starting primary vaccination. During that time passive protection can be provided by specific human or equine immune globulin.
Clinical Features of Rabies Animals
Judged by the median lethal dose of street rabies virus, there is a wide range of susceptibility to rabies infection among mammals and birds. Foxes are the most susceptible, cats and dogs have intermediate susceptibility, and opossums are relatively resistant.
In domestic dogs, the incubation period ranges from 5 days to 14 months. It is less than 4 months in 80 percent of cases; hence the compulsory quarantine of 6 months imposed on dogs imported to the United Kingdom. Prodromal symptoms include change in temperament, fever, and, as in many humans, intense irritation at the site of the infecting bite. The familiar picture of a "mad dog" with furious rabies is seen in only 25 % of infected animals. The more common paralytic or dumb presentation is less dramatic and more dangerous, as it may not be recognized. The clinical features of furious canine rabies include irritability, convulsions, dysphagia, laryngeal paralysis causing an altered bark, hyper-salivation, and extreme restlessness causing the animal to wander miles from home. Dogs with furious rabies attack inanimate objects, often breaking their teeth and injuring their mouths in the process. Before the discovery of Negri bodies, canine rabies was confirmed by examining the stomach contents, which often consisted of earth and stones resulting from pica. Dogs with paralytic rabies may be reclusive and exhibit paralysis of the jaw, neck, and hind limbs, and dysphagia and drooling of saliva, which may make the owner suspect and attempt to remove a bone imagined to be stuck in the throat. Virus may be excreted in the saliva as early as 3 days before the appearance of symptoms, and the animal usually dies within the next 7 days. This is the basis for the traditional 10-day observation period for dogs that have bitten humans.
Clinical features of rabies in humans
The incubation period is between 20 and 90 days and more than two-thirds of cases, with an extreme range of 4 days to more than 20 years. In some animals, latent infections can be reactivated by corticosteroids and stress, providing a possible explanation for the rare authentic reports of very long incubation periods in humans. Facial and severe multiple bites, transmission by corneal transplant, and accidental inoculation of live virus (rage de laboratoire) are associated with relatively short incubation periods. A few days of prodromal symptoms may precede the development of definite signs of rabies encephalomyelitis. These may consist of fever, changes of mood, and nonspecific "flulike" symptoms, but in more than one-third of cases itching, neuritic pain, or paresthesia at the site of the healed bite wound suggests impending rabies. The existence of two distinct clinical patterns of rabies, furious (agitated) and paralytic ("dumb," "rage mue," or "rage muette"), depends on whether the brain or spinal cord is predominantly infected and may reflect differences in the infecting strain of rabies virus or in the host's immune response.
Furious rabies, the more common presentation in humans except those infected by vampire bats, is characterized by hydrophobia, aerophobia, and episodic generalized arousal interspersed with lucid intervals of normal cerebration. Hydrophobia is a reflex series of forceful jerky inspiratory muscle spasms provoked by attempts to drink water and associated with an inexplicable terror. A draft of air on the skin produces a similar reflex response, "aerophobia." Initially, the spasms affect the diaphragm, sternomastoids, and other accessory muscles of inspiration, but a generalized extension response may be produced ending in opisthotonos and generalized convulsions with cardiac or respiratory arrest. Without supportive care, about one-third of patients with furious rabies die during a hydrophobic spasm in the first few days of their illness. There is hyperesthesia and periods of generalized excitation during which the patient becomes hallucinated, wild, and sometimes aggressive. These grotesque symptoms are explained by a selective encephalitis involving the brain stem and limbic system. In rabies, unlike most other encephalitides, patients may remain intermittently conscious and rational. Hypersalivation, lacrimation, sweating, and fluctuating blood pressure and body temperature result from disturbances of hypothalamic or autonomic nervous system function (Fig.9). Conventional neurologic examination may fail to disclose any abnormality unless a hydrophobic spasm is observed. Physical findings include meningism, cranial nerve and upper motor neuron lesions, muscle fasciculation, and involuntary movements. Increased libido, priapism, and frequent spontaneous orgasms may be the presenting symptom in some patients, suggesting involvement of the amygdaloid nuclei. Furious rabies naturally progresses to coma and death within a week, but some patients have been kept alive for several months in intensive care units.
Fig.9. Clinical features of rabies
Paralytic rabies is apparently much less common than the furious form in humans but is frequently undiagnosed. All reported cases of rabies transmitted by vampire bats in Latin America and the Caribbean are of this type. The paralytic form of rabies was also seen in patients with postvaccinal rabies and in the two patients who inhaled fixed virus. It seems more likely to develop in patients who have received antirabies vaccine. After the prodromal symptoms (see above), paralysis, fasciculation, pain, and paresthesia start in the bitten limb and ascend symmetrically or asymmetrically. There is progression to paraplegia with sphincter involvement, quadriparesis, and finally paralysis ofbulbar and respiratory muscles (Fig.10). Hydrophobia is usually absent. Patients with paralytic rabies may survive for several weeks even without intensive care.
Fig.10. Paralytic rabies
In the rabies endemic area, the diagnosis is easy in a patient with hydrophobic spasms who remembers being bitten by a dog in the previous few months.
The spasms of pharyngeal tetanus may resemble hydrophobia, and this disease can also complicate an animal bite. Severe tetanus is distinguished by its shorter incubation period, the presence oftrismus, the persistence of muscular rigidity between spasms, the absence of pleocytosis, and a better prognosis. The rare encephalopathy complicating serum sickness and anaphylactic reactions to Hymenoptera venoms are said to resemble rabies encephalitis. Rabies phobia is an hysterical response to the fear of rabies. It differs from true rabies in its shorter incubation period, often a few hours after the bite, by the emphasis on aggressive and dramatic symptoms, and by its excellent prognosis. Few hysterics could accurately simulate a hydrophobic spasm.
Paralytic rabies should be considered in patients with rapidly ascending flaccid paralysis, suspected Guillain-Barre syndrome, and transverse myelitis. In tropical developing countries that are still dependent on Semple-type and suckling mouse brain rabies vaccines, the most important differential diagnosis is postvaccinal encephalomyelitis. This usually develops within 2 weeks of the first dose of vaccine but has no clinical or laboratory features that reliably distinguish it from rabies while the patient is still alive, except for the absence of demonstrable rabies antigen in skin biopsies (see below). In poliomyelitis there are no sensory abnormalities. Herpes simiae (B virus) encephalomyelitis, which is transmitted by monkey bites, has a shorter incubation period than rabies (3 to 4 days). Vesicles may be found in the monkey's mouth and at the site of the bite. The diagnosis can be confirmed virologically and the patient treated with acyclovir.
Rabies is an acute nonsuppurative meningoencephalomyelitis. By the time the patient dies, ganglion cell degeneration, perineural and perivascular mononuclear cell infiltration, neuronophagia, and glial nodules may be widespread throughout the brain, spinal cord, and peripheral nerves. However, considering the clinical severity, changes are often surprisingly mild. Inflammatory changes are most marked in the midbrain and medulla in furious rabies and in the spinal cord in paralytic rabies. The diagnostic intracytoplasmic inclusion bodies (Negri bodies)(Fig.11) contain viral ribonucleoprotein and probably fragments of cellular organelles such as ribosomes, giving the essential internal structure. They are found in up to 80 % of human cases and are most numerous in the pyramidal cells of Ammon's horn in the hippocampus, in cerebellar Purkinje cells, and in the medulla and ganglia. Apart from these inclusion bodies there are no histologic features that distinguish rabies from poliomyelitis or other forms of viral encephalitis. The brain stem, limbic system, and hypothalamus appear to be most severely affected. A spongiform encephalopathy has been demonstrated in skunks and foxes. It probably represents an immunologic effect of infection. Extraneural changes include focal degeneration of salivary and lacrimal glands, pancreas, adrenal medulla, and lymph nodes. An interstitial myocarditis with round cell infiltration has been described. This may be associated with cardiac arrhythmias. The brain of a fatal human case of Mokola virus encephalitis showed perivascular cuffing with lymphocytes and lymphoblastoid cells. Neurons contain large numbers of homogeneous cytoplasmic inclusion bodies, which were quite different in size and appearance from Negri bodies.
Fig.11. Negri bodies (intracytoplasmic inclusion bodies)
In the mammal responsible/or the bite, rabies can be confirmed within a few hours by immunofluorescence of acetone-fixed brain or spinal cord impression smears, a technique that has replaced the classic Seller's stain for Negri bodies which is notoriously difficult to interpret (Fig.12). A simple ELISA test can be used if fluorescence microscopy is not available, and a sensitive avidin-biotin peroxidase method has recently been developed for use with formalin-fixed histologic sections.
Fig.12. Negri bodies in neurons cytoplasm
Rapid examination of CNS tissue in animals suspected of being rabid is now preferred to observing them in captivity for 10 days. In patients, rabies can be confirmed during life by immunofluorescence of skin, and brain biopsies, but the comeal impression smear technique is falsely negative too often to be useful. Early in the illness, rabies virus can be isolated from saliva, brain, CSF, and even spun urine but not blood. Virus isolation in neuroblastoma cell cultures can produce a result in 2 to 4 days instead of the 2 to 3 weeks required for the traditional intracerebral inoculation of mice. In patients who have not been vaccinated or given rabies immune globulin, rabies antibody in serum and especially in the CSF is diagnostic of rabies encephalitis. Rabies-neutralizing antibody leaks across the blood-CSF barrier in patients with postvaccinal encephalomyelitis, but a very high filer suggests a diagnosis of rabies. The only reliable method for distinguishing rabies from postvaccinal encephalomyelitis during life is by the immunofluorescence of skin biopsies. In rabies, lymphocyte pleocytosis rarely exceeds a few hundred cells per microliter. A neutrophil leukocytosis is commonly found in the blood.
Treatment of Human Rabies Encephalomyelitis
Human rabies remains virtually incurable. Intensive care offers the only hope of prolonging life and, perhaps in a very few cases of paralytic rabies or infection with attenuated virus, of survival. Problems arising during intensive care include a variety of respiratory complications such as aspiration pneumonia, pneumothorax, and respiratory arrest; cardiac arrhythmias, hypertension, pulmonary edema, and effects of myocarditis including congestive cardiac failure; generalized convulsions, cerebral edema, inappropriate secretion of an-tidiuretic hormone or diabetes insipidus, polyneuropathy, hyper- and hypothermia; and hematemesis associated with ulceration or tears in the mucosa of the upper gastrointestinal tract. Heavy sedation and analgesia should be given to relieve the agonizing symptoms. Immunosuppressant agents, including corticosleroids, rabies hyperimmune serum (which may have accelerated death), antiviral agents such as ribavirin, and alpha-interferon have not proved useful. Studies of intrathecal live attenuated vaccines in animals suggest the possibility of applying the treatment in human cases.
Prevention and Control of Rabies Pre-exposure Prophylaxis
In rabies endemic areas, those at high risk of exposure to rabid animals should be given pre-exposure vaccination. These include veterinarians, health care personnel, laboratory workers, and dog catchers. In areas where animal rabies is highly prevalent, especially among domestic dogs, there may even be a case for including rabies vaccine in the expanded programs of immunization for children. In nonendemic areas those who come into contact with imported mammals in quarantine, who work with rabies virus in laboratories, or who intend to travel to rabies endemic areas should be vaccinated.
Travelers at particular risk of exposure to rabies are zoologists and other field workers, foresters, cave explorers, and those whose work involves walking and cycling in urban and rural areas of India, Southeast Asia, and Latin America.
Only tissue culture vaccines are safe enough to use for pre-exposure prophylaxis. Three doses are given on days 0, 7, and 28, either ¯Ì into the deltoid (not into the gluteal region) or 0.1 ml intradennally. A single booster given 1 year later produced sustained immunity for 5 to 8 years.
Alternatively, a booster dose can be given every 2 years if the neutralizing antibody level falls and continued protection is needed. Those working with rabies virus in laboratories should have their antibody titer checked every 6 months as a guide to the need for further booster injections. A failure of pre-exposure vaccination by the intradermal route was found in American Peace Corps workers who were immunized in the tropics while taking chloroquine for malaria prophylaxis. This reduces the neutralizing antibody response, but other unidentified factors contribute to the immunosuppression. The intradermal course should therefore be completed before starting chloroquine, or the vaccine should be given IM.
Cleaning the wound as soon as possible after a bite or other contact with a rabid animal is essential first aid and is particularly effective for superficial wounds. The wound should be scrubbed with soap or detergent and generously rinsed under a running tap for at least 5 minutes. Foreign material and dead tissue should be removed under anesthesia. The wound should be irrigated with a viricidal agent such as soap solution, povidone iodine, 0.1 % aqueous iodine, or 40 to 70 % alcohol. Quaternary ammonium compounds, hydrogen peroxide, and mercurochrome are not recommended. Suturing may inoculate virus deeper into the tissues and so should be avoided or delayed when possible. The risk of other viral, bacterial, fungal, and protozoal infections must be considered after bites by animals and humans. Pathogens commonly associated with mammal bites include Pasteurella multocida, Clostridiwn tetani, orf virus, cat scratch disease bacillus, Leptospira species. Spirillum minor, Streptobacillus moniliformis, and the fungus Blastomyces dermatitidis. Tetanus prophylaxis and antimicrobials may be required. Most of the bacteria are sensitive to benzyl penicillin, amoxicillin, or cefoxitin.
Nervous tissue vaccines, initially introduced by Pasteur in the nineteenth century and developed by Semple, Fermi, Hempt, and Fuenzalida, are still the most widely used throughout the tropical rabies endemic area. In India, about 500,000 postexposure courses of Semple vaccine are given each year. Many of these vaccines have to be given in protracted courses. Their potency is variable, and they may be associated with severe neuroparalytic reactions. In Western countries, tissue culture vaccines are used almost exclusively.
culture vaccines are now in large-scale production, including the long
established human diploid cell strain vaccine (HDCSV) (Institut Merieux), the
more recent and less expensive purified vero cell rabies vaccine (PVRV)
(Institut Merieux), purified chicken embryo cell vaccine (PCEC) (Behringwerke),
and a primary hamster kidney cell vaccine produced in the
The initial dose should be doubled and given at several different sites if there has been a delay of more than 48 hours in starting postexposure prophylaxis, if passive immunization (hyperimmune serum) was given 24 hours or more before active immunization, in elderly patients, in those with chronic diseases such as hepatic cirrhosis, in those likely to be immunodeficient, immunosuppressed, or severely malnourished, and if hyperimmune serum is not available.
An abbreviated regimen consists of two 1-ml injections at different sites on day 0, followed by single 1-ml injections on days 7 and 21. The most economical regimen with proven efficacy consists of intradermal injections of 0.1 ml given at eight sites (deltoids, suprascapular area, abdomen, and thighs) on day 0; four sites on day 7; and single sites on days 28 and 90.
Tissue culture vaccines cause mild local symptoms in about 15 percent ofvaccinees, but intradermal injections cause local irritation in 35 percent. Transient systemic symptoms such as headache, fever, and a flulike illness occur in approximately 7 percent of vaccinees. In the United States, 10 percent of booster injections have been associated with mild immune complex disease 3 to 13 days later.
Hyperimmune equine antirabies serum (EARS) has proved to be effective in neutralizing rabies virus during the first week after initial vaccination, before endogenous neutralizing antibody has appeared. This has been demonstrated in a number of natural experiments when rabid wolves attacked groups of people in remote areas of Iran, USSR, and China. The dose is 40 IU per kilogram of body weight. Intradermal or other test doses do not reliably predict serum reactions and should not be used. The incidence of serum reactions to refined preparations of equine antirabies globulin is less than 5 percent. Human rabies immune globulin (HRIG) has now replaced EARS in all countries that can produce it or afford to import it. The dose is 20 IU per kilogram of body weight. Hyperimmune serum should be given at the same time as the first dose of vaccine but at a different site. Approximately half the dose is infiltrated around the bite wound (unless it is on a digit) and the rest is given IM, preferably not in the gluteal region since absorption from adipose tissue might be delayed. Passive immunization may cause partial suppression of the response to vaccines, so the recommended dose should not be exceeded.
Tetanus is a disease of the nervous system characterized by persistent tonic spasm, with violent brief exacerbations. The spasm almost always commences in the muscles of the neck and jaw. causing closure of the jaws (trismus, lockjaw) and involves the muscles of trunk more than those of the limbs. It is always acute in onset, and a very large proportion of those affected die.
Nicolaier isolated a strychnine-like toxin from anaerobic soil bacteria in 1884; 6 years later. Behring and Kitasato described active immunization with tetanus toxoid. This latter discovery should have reduced tetanus to a historical curiosity, but we still fail to fulfill this promise.
The global incidence of tetanus is thought to be about one million cases annually, or about 18 per 100,000 population. The U.S. Centers for Disease Control and Prevention (CDC) receive reports of about 70 domestic cases per year; this represents underreporting of about 60 %. Most reported cases are in patients over the age of 60: this is one of several indicators that waning immunity is an important risk factor. This may be a particularly serious problem in older women. In developing countries, mortality rates are as high as 28 per 100,000.
Neonatal tetanus accounts for about half of the tetanus deaths in developing nations. In a study of neonatal mortality in Bangladesh 112 of 330 deaths were attributed to tetanus. Up to one-third of neonatal tetanus cases are in children born to mothers of a previously afflicted child, highlighting failure to immunize as a major cause of tetanus. Immunization programs clearly decrease neonatal tetanus deaths.
Acute injuries account for about 70 % of cases, evenly divided between punctures and lacerations. Other identifiable conditions are noted in 23 %, leaving about 7 % of cases without an apparent source. Other studies cite rates of cryptogenic tetanus as high as 23 %.
Fig.13. Clostridium tetani
Tetanospasmin is synthesized as a single 151-kD chain that is cleaved extracellularly by a bacterial protease into a 100-kD heavy chain and a 50-kD light chain (fragment A), which remain connected by a disulfide bridge. The heavy chain can be further divided into fragments Â and Ñ by pepsin. The heavy chain appears to mediate binding to cell surface receptors and transport proteins, whereas the light chain produces the presynaptic inhibition of transmitter release, which produces clinical tetanus. The nature of the receptor to which tetanospasmin binds, previously thought to be a ganglioside, remains debated. The toxin enters the nervous system primarily via the presynaptic terminals of lower motor neurons, where it can produce local failure of neuromuscular transmission. Tetanospasmin appears to act by selective cleavage of a protein component of synaptic vesicles, synaptobrevin II. It then exploits the retrograde axonal transport system, and is carried to the cell bodies of these neurons in the brain stem and spinal cord, where it expresses its major pathogenic action.
Once the toxin enters the central nervous system, it diffuses to the terminals of inhibitory cells, including both local glycinergic interneurons and descending GABAergic neurons from the brain stem. By preventing transmitter release from these cells, tetanospasmin leaves the motor neurons without inhibition. This produces muscular rigidity by raising the resting firing rate of motor neurons, and also generates spasms by failing to limit reflex responses to afferent stimuli. Excitatory transmitter release in the spinal cord can also be impaired, but the toxin appears to have greater affinity for the inhibitory systems. The autonomic nervous system is affected as well: this is predominantly manifested as a hypersympathetic state induced by failure to inhibit adrenal release of catecholamines.
Tetanus is classically divided into four clinical types: generalized, localized, cephalic, and neonatal. These are valuable diagnostic and prognostic distinctions, but reflect host factors and the site of inoculation rather than differences in toxin action. Terms describing the initial stages of tetanus include the incubation period (time from inoculation to the first symptom) and the period of onset (time from the first symptom to the generalized spasm). The shorter these periods, the worse the prognosis. Various rating scales are available. Certain portals of entry (e.g., compound fractures) are associated with poorer prognoses. Tetanus may be particularly severe in narcotic addicts, for unknown reasons.
Generalized tetanus is the most commonly recognized form, and often begins with trismus ("lockjaw", masseter rigidity)(Fig.14) and a risus sardonicus (increased tone in the orbicularis oris)(Fig.15). Abdominal rigidity may also be present. The generalized spasm resembles decorticate posturing, and consists of opisthotonic posturing with flexion of the arms and extension of the legs. The patient does not lose consciousness, and experiences severe pain during each spasm, which are often triggered by sensory stimuli. During the spasm, the upper airway can be obstructed, or the diaphragm may participate in the general muscular contraction. Either of these compromise respiration, and even the first such spasm may be fatal. In the modern era of intensive care, however, the respiratory problems are easily managed, and autonomic dysfunction, usually occurring after several days of symptoms, has emerged as the leading cause of death.
Fig.14. Examination of chewing muscles reflex
The illness can progress for about 2 weeks, reflecting the time required to complete the transport of toxin, which is already intra-axonal when antitoxin treatment is given. The severity of illness may be decreased by partial immunity. Recovery takes an additional month, and is complete unless complications supervene. Lower motor neuron dysfunction may not be apparent until spasms remit, and recovery from this deficit in neuromuscular transmission may take additional weeks. Recurrent tetanus may occur if the patient does not receive active immunization, because the amount of toxin produced is inadequate to induce immunity.
Fig.15. Risus sardonicus
Localized tetanus involves rigidity of the muscles associated with the site of spore inoculation. This may be mild and persistent, and often resolves spontaneously. Lower motor neuron dysfunction (weakness and diminished muscle tone) is often present in the most involved muscle. This chronic form of the disease probably reflects partial immunity to tetanospasmin. However, localized tetanus is more commonly a prodrome of generalized tetanus, which occurs when enough toxin gains access to the central nervous system.
Cephalic tetanus is a special form of localized disease affecting the cranial nerve musculature. Although earlier reports linked cephalic tetanus to a poor prognosis, more recent studies have revealed many milder cases. A lower motor neuron lesion, frequently producing facial nerve weakness, if often apparent. Extraocular muscle involvement is occasionally noted.
Neonatal tetanus follows infection of the umbilical stump, most commonly due to a failure of aseptic technique where mothers are inadequately immunized. Cultural practices may also contribute. The condition usually presents with generalized weakness and failure to nurse; rigidity and spasms occur later. The mortality rate exceeds 90%, and developmental delays are common among survivors. Poor prognostic factors include age less than 10 days, symptoms for fewer than 5 days before presentation to hospital, and the presence of risus sardonicus, fever, opistotonus (Fig.16).
Fig.16. Opistotonus in new born
Tetanus is diagnosed by clinical observation, and has a limited differential diagnosis. Laboratory testing cannot confirm or exclude the condition, and is primarily useful for excluding intoxications that may mimic tetanus. Electromyographic studies are occasionally useful in questionable cases. Such testing becomes more important when no portal of entry is apparent. Antitetanus antibodies are undetectable in most tetanus patients, but many reports document the disease in patients with antibody levels above the commonly cited "protective" concentration of 0.01 IU/liter. Rare patients apparently develop antibodies that are not protective.
Attempts to culture C. tetuni from wounds are not useful in diagnosis, because (1) even carefully performed anaerobic cultures are frequently negative; (2) a positive culture does not indicate whether the organism contains the toxin-producing plasmid; and (3) a positive culture may be present without disease in patients with adequate immunity.
Strychnine poisoning, in which glycine is antagonized, is the only condition that truly mimics tetanus; toxicologic studies of serum and urine should be performed when tetanus is suspected, and tetanus should be considered even if strychnine poisoning appears likely. Because the initial treatment of tetanus and strychnine intoxication are similar, therapy is instituted before the assay results are available. Dystonic reactions to neuroleptic drugs or other central dopamine antagonists may be confused with the neck stiffness of tetanus, but the posture of patients with dystonic reactions almost always involves lateral head turning, which is rare in tetanus. Treatment with anticholinergic agents (benztropine or diphenhydramine) is rapidly effective against dystonic reactions. Dental infections may produce trismus, and should be sought, but do not cause the other manifestations of tetanus.
The patient with tetanus requires simultaneous attention to several concerns. Attention to the airway and to ventilation is paramount at the time of presentation, but the other aspects of care, especially passive immunization, must be pursued as soon as the respiratory system is secure.
Tetanic spasms sometimes demand that the airway be secured before other lines of therapy are possible. An orotracheal tube can be passed under sedation and neuromuscular junction blockade; a feeding tube should be placed at the same time. Because the endotracheal tube may stimulate spasms, an early tracheostomy may be beneficial.
Benzodiazepines have emerged as the mainstay of symptomatic therapy for tetanus. These drugs are GÀÂÀ agonists, and thereby indirectly antagonize the effect of the toxin. They do not restore glycinergic inhibition. The patient should be kept free of spasms, and may benefit from the amnestic effects of the drugs as well. Diazepam has been studied most intensively, but lorazepam or midazolam appear equally effective. Tetanus patients have unusually high tolerance for the sedating effect of these agents, and commonly remain alert at doses normally expected to produce anesthesia.
Intravenous midazolam (5-15 mg/h or more) is effective and does not contain propylene glycol, but must be given as a continuous infusion because of its brief half-life. Propofol infusion is also effective, but is currently very expensive, and the amount necessary to control symptoms may exceed the patient's tolerance of the lipid vehicle. When the symptoms of tetanus subside, these agents must be tapered over at least 2 weeks to prevent withdrawal. Intrathecal baclofen is also effective in controlling tetanus, but has no clear advantage over benzodiazepines. Neuroleptic agents and barbiturates, previously used for tetanus, are inferior for this indication and should not be used.
Most tetanus patients will still have the portal of entry apparent when they present. If the wound itself requires surgical attention may be performed after spasms are controlled. However, the course of tetanus is not affected by wound de-bridement.
Passive immunization with human tetanus immunoglobulin (HTIG) shortens the course of tetanus and may lessen its severity. A dose of 500 units appears as effective as larger doses. There is no apparent advantage to intrathecal HTIG administration. Intrathecal HTIG has also been shown ineffective in neonatal tetanus. Pooled intravenous immunoglobulin has been proposed as an alternative to HTIG. Active immunization must also be initiated.
The role of antimicrobial therapy in tetanus remains debated. The in vitro susceptibilities of C. tetani include metronidazole, penicillins, cephalosporins, imipenem. macrolides, and tetracy-cline. A study comparing oral metronidazole to intramuscular penicillin showed better survival, shorter hospitalization, and less progression of disease in the metronidazole group. This may reflect a true advantage of metronidazole over penicillin, but it more likely corresponds to a negative effect of penicillin, a known GABA antagonist. Topical antibiotic application to the umbilical stump appears to reduce the risk of neonatal tetanus.
Nutritional support should be started as soon as the patient is stable. The volume of enteral feeding needed to meet the exceptionally high caloric and protein requirements of these patients may exceed the capacity of the gastrointestinal system.
The mortality rate in mild and moderate tetanus is presently about 6 percent; for severe tetanus, it may reach as high as 60%, even in expert centers. Among adults, age has very little effect on mortality, with octogenarians and nonagenarians faring as well as middle-aged patients. Tetanus survivors often have serious psychological problems related to the disease and its treatment that persist after recovery, and that may require psychotherapy.
Tetanus is preventable in almost all patients, leading to its description as the “inexcusable disease.” A series of 3 monthly intramuscular injections of alum-adsorbed tetanus toxoid provides almost complete immunity for at least 5 years. Patients less than 7 years of age should receive combined diphtheria-tetanus-pertussis vaccine, and other patients combined diphtheria-tetanus vaccine. Routine booster injections are indicated every 10 years; more frequent administration may increase the risk of a reaction. Some patients with humoral immune deficiencies may not respond adequately to toxoid injection: such patients should receive passive immunization for tetanus-prone injuries regardless of the period since the last booster. Most young patients with human immunodeficiency virus (HIV) infection appear to retain antitetanus antibody production if their primary immunization series was completed prior to acquiring HIV. Vitamin A deficiency interferes with the response to tetanus toxoid. A recent report documented tetanus in babies of women immunized with toxoid later shown to be devoid of potency; this disconcerting report underscores the need for quality control in toxoid production.
Although any wound may be inoculated with tetanus spores. Some types of injury are more frequently associated with tetanus and are therefore deemed tetanus-prone. These include wounds that are contaminated with dirt, saliva, or feces; puncture wounds, including unsterile injections; missile injuries; burns; frostbite; avulsions; and crush injuries. Patients with these wounds who have not received adequate active immunization in the past 5 years, or in whom immunodeficiency is suspected. should receive passive immunization with HTIG (250-500 IU, intramuscularly) in addition to active immunization.
Mild reactions to tetanus toxoid (e.g.. local tenderness, edema, low-grade fever) are common. More severe reactions are rare; some are actually due to hypersensitivity to the preservative thiomersal.
IV. Convalescent stage: 2-6 weeks