Infectious diseases with nthe dominant involvement of kidneys: leptospirosis, HFKS n(hemorrhagic fevers with kidneys syndrome). Hemorrhagic fevers: yellow fever, nCongo-Crimean fever,
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http://www.cdc.gov/leptospirosis/index.html
Leptospirosis nis an acute generalized infectious disease, characterized by extensive nvasculitis, caused by spirochetes of the genus Leptospira. It is primarily a ndisease of wild and domestic mammals; humans are infected only through direct nor indirect contact with animals.
Historic reference
A. Weil (1886) was the first who described leptospirosis as aindependent disease, four cases with a high temperature, jaundice, hemorrhages nand the renal affection.
R. Virchout (1865) considered the described disease as a kind of typhoid nfever and called it “typhus biliosus” differentiating it from “katarrhalischeicterus“.
In 1888 in the book “Infectious Jaundice” S. P. Botkin’s pupil N.K.Vasiliev informed about twelve cases nof a similar disease but did not paid much attention to the character of the ntemperature, the expressiveness of jaundice, the time when hemorrhages and the nrenal affection appear, he comes to the conclusion that the new disease is ndifferent from typhoid fever and catarrhal jaundice.
For a long ntime leptospirosis was divided into icteric and non-icteric forms. The first ndescription of non-icteric leptospirosis was given by W. A. Bashenin in 1928, nhe suggested naming me disease “water fever”.
Leptospirosis nis registered in many countries.
Etiology
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The leptospirosis pathogen belongs to the genus of Leptospira Nogychi nand can be divided into 2 kinds – parasitic and saprophytic. There are hundreds nof serotypes in each kind. The body of the leptospira consists of a long naxis thread which is covered with a cytoplasmatic spiral that has a three-layer nmembrane (Fig.1). The average length of leptospiras is 10-14 mkm, the nnumber of cons – 10-12. There are no spores or capsules. Leptospiras nhave energetic and complex movements. This explains their high invasive nability. Leptospiras do not get well painted with common aniline dyes. nSome special liquid media containing animal (rabbit) serum are used to ncultivate leptospiras. Leptospiras are unstable in the nenvironment but are adapted to living in water.
Fig.1. nLeptospira
The leptospira nlife time in water oscilates within wide limits – from several days to many months ndepending on pH, the salty composition and the microflora of the reservoirs.
It has beediscovered that leptospiras have hemolysin and also lipases that cahave a cytotoxic influence on the organs and tissues which are rich with nlipids. There is endotoxin in the leptospira cells.
The moderclassification of leptospiras is based on their antigenic structure. nThere have been discovered 200 serovars united in 25 serological groups.
There are two nactive serologic complexes among the antigens of leptospiras each of nthem has a complex set of components. One of them is situated on the cell nsurface and determines its typospecific qualities, the other – in the depth of nthe microbe and characterizes genospecific peculiarities of leptospiras.
The vital ncapacity of leptospiras in the environment depends on many factors. nThere is a considerable discrepancy in the whimsicality of leptospiras n(the necessary conditions of their survival are high humidity, warmth, pH of nthe water and soil (7.0-7.4), the limited amount of salt). In the water of the nrivers, pools, lakes and marshes leptospiras remain viable for 5-10 days nbut in the sea water they die in several hours. Leptospiras nremain viable in the damp soil up to 270 days, in dry soil – not more than 3 ndays. Leptospiras can easily endure low temperatures and remain viable nduring prolonged freezing, however, they quickly die when warmed, dried if nexposed to salt or acid.
Epidemiology
http://www.cdc.gov/leptospirosis/infection/index.html
Leptospirosis is a nzoonotic infection. The source of the infection is animals wild, domestic and ngame animals (pigs, cattle, foxes, white foxes, nutrias and others). They form nanthropurgias foci.
The small mammals who live in the forests, near the reservoirs (volemice) nplay the main role in maintenance the leptospirosis foci. Their infection takes na form of a symptomless chronic process in the kidneys. Leptospiras multiply ithe tubules of the kidneys and go out with urine.
The natural nfoci are situated in low lying areas. They are marshes, flood-lands, nwater-meadows, the marsh-ridden parts of the rivers and irrigation system, novergrown with bushes and abundant grassy vegetation. The infection of people nin the natural foci is of a seasonal character (June-September), it usually noccurs during the agricultural work (mowing the meadows, collecting hay, ngrowing rice, flax, hemp and other abundantly irrigated crops, felling and nduring hunting, fishing, gathering mushrooms, drinking water and washing with nwater from the contaminated shallow reservoirs). The morbidity in the natural nfoci has a sporadic or group character. The development of natural resources, nunorganized rest result in the immediate contact of people with nature and ncreate an opportunity for infecting people with leptospiras. The natural foci nare the source of infection for the domestic animals.
In recent years the gray rat has been playing a more important part ithe epidemiology of leptospirosis, its infectedness has been proved in many ncountries of the world. For a long time leptospirosis was considered a disease nof big cities, mainly ports. However, in the present situation the intensive nprocesses of urbanization, creation of large cattle-breeding complexes, growing nrice and other elements of the economic activity of man gave changed the necology of the gray rat, so the anthropurgias foci of leptospirosis can be both nin the rural areas and in the cities.
The foci which nappear in the cattle-breeding industries as a result of bringing animals that nare leptospira-carriers or infecting the cattle, pigs m the natural foci ithe pastures, watering-places play the most important part in the epidemiology nof the disease. The agricultural animals often have leptospirosis in the nobliterated, symptomless form. That is why the sick animals are not isolated itime, they excrete leptospiras into the environment and infect water, forage, npastures, soil.
In many big ncities, especially ports, there is a high rate of leptospirosis among the gray nrats. This is the reason for the citizens to fall ill with leptospirosis if due nto their occupation they contact sinanthropos rodents or the things ncontaminated by them.
The clinical nsymptoms of leptospirosis among dogs had been described before the pathogen was ndiscovered and the term “leptospirosis” appeared. In 1898 in
The infection is mainly transmitted from animals to humans by water. The ncontact way is considerably less important. The transmission of the infectiothrough food is rare. Humans can be infected while swimming in the reservoirs, ndrinking water from them or using it for economic needs, during different kinds nof the agricultural work in the marsh-ridden places, when fishing. There have nbeen described some cases of leptospirosis infection among the personal of the nslaughter-houses, meat-packaging plants.
The sick rate nrises up in June – September. In other months there are registered some nsporadic cases that are not connected with the infection in the opereservoirs.
Leptospirosis can be referred to the professional diseases. The people who nare involved in the agricultural work in the marsh-ridden places fall ill more noften, they include cattle-breeders, the personal of meat-packaging plants, nminers, dockers, plumbers.
There have been some cases when people fell ill after being bitten by a ncoypu rat, as well as the personal of the laboratories, who work with nleptospiras. The susceptibility of people to leptospirosis is high. A ntypospecific immunity remains for a longtime after having the disease.
Pathogenesis
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The pathogenesis of leptospirosis is characterized by changing several nphases. The first phase includes the pathogen penetration and a short-time nprimary leptospiremia. The leptospiras penetrate the human organism through the nskin of the mucous membranes, travel along the lymph tracts, penetrate the nblood and then various organs – the liver, kidneys, adrenal glands, spleen, lungs nand others. This phase lasts 7-20 days, it corresponds to the incubate period.
The second phase includes secondary leptospiremia, it coincides with the nbeginning of the clinical manifestations of the disease, the generalization of nthe process. The leptospiras penetrate the organs and tissues with the blood nflow again, fix on the cell surface (especially, in the kidneys, liver, adrenal nglands), can overcome the hametoencephalic barrier. The leptospiras do not ncause a destruction and they do not parasites intracutaneously. They stick to nthe cell surface, can stay in the inter-cell space.
The third phase is a phase of toxinemia that is accompanied by aexpressed fever. The most important pathogenic factor of this phase is ncapillary toxicosis. The rupture of the capillary endothelium results in the ndiapedesious hemorrhages into various organs and tissues. It is clinically nmanifested as a hemorrhagic syndrome. Thrombocytopenia plays a part in the norigin of the hemorrhagic syndrome, it is connected with the influence of the nleptospira lipase on the phospholipids of thrombocytes membranes and their ngluing together with the formation of the primary thrombocytous congestion. The nvessels of the liver, kidneys, adrenal glands get affected most of all, there nmay develop Waterhause – Friedrichen syndrome. The degenerative nand partially necrotic changes of the liver parenchyma as well as hemolysis noferythrocytes under the affection of hemolysins are the cause of jaundice nwhich has a mixed character.
The influence nof leptospiras and their metabolites on the cellular wall results in the naffection of the adrenal gland epithelium, all the cortical and subcortical nlayer of the kidney that results in the uropoiesis affection. There is a npossibility of the development of renal insufficiency.
The fifth nphase includes the formation of the sterile immunity. The tense humoral nimmunity is combined with the expressed local organic and cellular immunity. nThen comes a stable recovery.
Pathological anatomy
Leptospirosis is characterized by the affection of the capillary nendothelium of a various organs and tissues. The walls of the vessels are nfragile, their permeability is increased, this is accompanied with numerous nhemorrhages in the kidneys, liver, lungs, endocardium and pericardium, mucous nmembrane of the gastroenteral tract. The liver is enlarged, plethoric and with nsmooth surface.
The histological ninvestigation shows an edema of the interstitial tissue, dystrophy of the nhepatic cells without an expressed cytoptesis of hepatocytes, biliary nthromboses in the central zone of the lobules.
The most considerable changes can be found in the kidneys. The kidneys nare considerably enlarged, there are such typical symptoms as a stroma edema, nnumerous hemorrhages, a sharply expressed granular degeneration of the nconvoluted tubules epithelium up to necrosis. The kidney affection ileptospirosis can be considered as nephrosonephritis.
There are hemorrhages in the adrenal glands, sometimes considerable. The nmuscle affection is also characteristic of leptospirosis, especially the naffection of musculus gastrocnemius and musculus thoracic. There are nhemorrhages of various sizes; an uneven swelling of the fibers, degenerative nchanges in the synapses of the muscular fiber and nerve, sometimes coagulatioecrosis nwhich causes myalgia.
Dystrophy and nlipid dystrophy develops in the heart muscle, sometimes there is interstitial nmyocarditis. There are hemorrhages in the lungs as well as in other organs. nThere is often an edema of the meninx vasculosas.
Clinical manifestations
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The course of leptospirosis can be mild, middle-moderate and severe. The nseverity of the course depends on the microbe virulence, the dose of infection, nthe reactivity of the microorganism.
The main criteria of the severity are follows: the degree of toxicity, nthe expressiveness of the affection of the liver, kidneys, central nervous nsystem, heart, adrenal glands, hemorrhagic manifestations.
There are cycles in the leptospirosis course. There is and incubate nperiod, the beginning, height and convalescence.
The incubation period lasts 2-20 days (more often 7-10 days). The disease nhas an acute onset. The patient can indicate not only to the date but even the nhour of the disease onset. The fever usually has a remitting or constant ncharacter, it lasts 5-9 days then it falls down in the form of accelerated nlysis. There can be another wave (a relapse).
From the first hours the patients complain of intense headaches, pain ithe muscles, especially, musculus gastrocnemius, the muscles of the scalp, nneck, back and abdomen. In 1888 W. P. Vasiliev wrote that there is no such aintensive myalgia in the musculus gastrocnemius in case of any other disease. nThe abdomen pain can be so intense that there is a suggestion about an acute nsurgical pathology.
The symptoms of toxicity increase. The patients are flaccid, adynamic. nThe patients has a characteristic appearance – face is edemic, hyperemic, nvessels 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 % ncases) a polymorphic symmetric rash which stays for several days appears on the nthird – fifth day of the disease.
In some cases there is an enlargement and painfulness of the peripheral nlymph nodes. The liver gets enlarged early, on the second-third day of the ndisease. Jaundice develops in the moderate severe – course as well as in the nsevere course. The liver has a dense consistence, it is painful at palpation. nIn a half of the patients the spleen gets enlarged.
There are considerable changes in the cardiovascular system: dull heart nsounds, sometime relative bradycardia, arrhythmia, extrasystole. In case of aexpressed toxicity the arterial pressure sharply decreases (up to collapse) as na result of a decrease of the precapilary arteries.
The initial period of leptospirosis is characterized by the peculiar nchanges in the central nervous system, in some patients there are such symptoms nas disorders of the consciousness and even unconsciousness, cramps besides aexpressed persistent headache, insomnia, delirium. In 10-40 % cases there are nmeningeal symptoms: rigidity of the occipital muscles, Kernig’s sign, nBrudzinsky’s sign that are distinctly manifested on the fifth-eighth day of the ndisease. In such patients the spinal puncture confirms the diagnosis of serous nleptospirous meningitis – cerebrospinal fluid flows out under an increased npressure, it is transparent. The microscopia of the cerebrospinal fluid shows nleptospiras, during the regular one outside the dark field of vision – moderate nlymphocytic pleocytosis. The amount of protein is increased. Leptospirous meningitis nusually has a nonmalignant character, it usually lasts 8-10 days.
At the end of the first week, and sometimes earlier jaundice develops isome patients (12-20 %). The intensity of jaundice and its duration depends othe severity of the disease and can last several weeks (1-4). A moderate skiitching is quite possible. The urine is dark, the color of the excrements is nnot changed.
With the development of jaundice the condition of the patients usually nworsens. The most severe manifestations of leptospirosis appear at the end of nthe first week – at the beginning of the second week of the disease.
The hemorrhagic syndrome appears on the seventh-tenth day: petechial neruption on skin, hemorrhages under the conjunctive, hemorrhages in the nose, ngums, stomach, intestine, uterus. The hemorrhages can be repeated, massive and nresult in anemia. Many clinicians have observed that the expressiveness of the nhemorrhagic syndrome corresponds the severity of leptospirosis and has a ncertain prognostic significance. The degree of the kidneys affection is evemore significant while evaluating the severity of leptospirosis, the kidneys nare always affected to some degree in leptospirosis.
From the first ndays of the disease there can be oliguria, moderate proteinuria, in the urine nthere are fresh erythrocytes, leukocytes as well as hyaline casts and the cells nof the renal epithelium. The symptom of the kidneys affection become the most nexpressed from the seventh-tenth day of the disease. Oliguria can be followed nby anuria, an acute renal insufficiency may develop, m spite of the development nof an acute renal insufficiency, there is usually no edema and arterial nhypertonia in leptospirosis. Sometimes an acute renal insufficiency develops nvery early, on the fourth day of the disease. It is an acute renal ninsufficiency resulting in uremia that is a frequent cause of the lethal noutcome of the disease. If the therapy is timely and adequate, the kidneys naffection in leptospirosis can be cured. Oliguria is followed by polyuria, and functioof the kidneys gets gradually normalized.
The second week corresponds to the severity of disease. At this time njaundice becomes the most intensive, the hemorrhagic and meningeal syndromes nincrease or appear for the first time. The changes in the cardiovascular system nincrease: the pulse is rapid and weak, a systolic murmur is sounded in the apex ncordis, there can be extrasystolia. The electrocardiogram shows diffusive nchanges of the myocardium.
At this period of the disease the infiltrates connected with the nhemorrhagic foci are sometimes formed in lungs, this is accompanied by the nsanguinolent sputum secretion.
By the end of the second week the condition of the patients improves. The nheadache and myalgia reduce, the jaundice intensity gradually decreases, a ngreat amount of urine begins to excrete. The patients feel weak for a long nperiod. The duration of the disease averages to 3-4 weeks. Some patients (20-60 n%) may have relapses. In 5-7 days after the feverish period the temperature nrises again, headaches and myalgia appear. The relapses and acute forms are not nso severe as the first phase, as a rule. The temperature does not usually rises nvery high, the fever does not last more than 2-3 days. Some patients have 3-4 nacute forms of relapses.
In leptospirosis the hemogram is characterized by the progressive anemia, na low reticulocytes number. In the patients with a hemorrhagic syndrome there nis expressed thrombocytopenia, an increased period of the blood coagulability. nLeukocytosis is a characteristic feature. The number of leukocytes increases up nto 12-25×105 in 1 mkL. In the differential blood count there is nneutrophilia with a shift to the left, expressed lymphopenia. The ESR reaches n40-60 mm/h.
The bilirubiamount in blood increases in case of the icteric form. The level of prothrombimay moderately decrease. The activity of transaminases is either normal or nslightly increased on the tenth-fifteenth day of the disease.
The nasthenovegetative syndrome is a characteristic feature of the convalescence period. nAnemia and proteinuria remain for a long time.
Some npatients have eye affections – uveitis, iritis, iridocvclitis that develop in 2 nweeks and in several months after the onset of the disease. There can be other ncomplications in the acute period – massive hemorrhages, an acute renal and nhepatic insufficiency, uremia, myocarditis, an acute cardiovascular ninsufficiency.
Diagnosis
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It is quite ndifficult to diagnose leptospirosis, especially during the first days of the ndisease. The bacteriological method is of a little practical importance because nleptospiras grow badly and slowly on the artificial media. The correctly takeepidemiological history plays the most important part in diagnosing nleptospirosis. It is necessary to take into account the patient’s occupation, nhis contact with agricultural animals, work in the meadows, swimming in the nrivers and ponds, the existence of rodents in the surroundings. The nepidemiological history not only determines the direction of diagnosis but ngives an opportunity to control the environment. The following peculiarities of nthe clinical symptoms are taken into consideration: jaundice, accompanied by nfever, myalgia, hematuria, hemorrhages. The diagnosis based on the nclinical-epidemiological investigation, is confirmed by the laboratory data.
The materials used for diagnosing leptospirosis are blood, urine, ncerebrospinal fluid.
The following methods of the laboratory diagnosis are used:
1. Bacteriological, bacterioscopic.
2. Serologic.
3. Biologic.
The bacteriologic investigation includes the primary microscopia of the ninitial material and its inoculation of media for acquiring the leptospira nclean culture. The patient’s blood serum, cerebrospinal fluid or urine are ncentrifuged. The fall out is investigated with microscope in a dark floor. nLeptospiras are found as thin sinous mobile threads that look grayish -whitish non the dark background. That is necessary to note that the presence of nleptospiras in blood is undoubtedly indicative of leptospirosis, but the nnegative result does not allow us to exclude the disease. The initial material ninoculation of the water-serum medium consists of the native rabbit serum. The ninoculation 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 nincluding the convalescence period. The reaction of the microscopic nagglutination and lysis, as well as the complement fixation reaction are used nto find antibodies in the serum of the sick people.
The reaction of the microscopic agglutination and lysis are done by a ndrop method with various serums of the patient’s blood and with those nleptospira serotypes which can be found hi this area. The results of the nreaction are taken into account with the help of a microscope with a dark nfloor. In the positive case there are phenomena of sticking together, the nleptospira agglomeration in form of small “spiders” and different degrees of ntheir lysis. The titer is considered to be diagnostic when the serum is diluted n1:50 -1:100.
The specific antibodies are discovered in the patient’s serum at the end nof the first – the beginning of the second week of the disease. The antibodies ncan remain in patients for several years, that is why the investigation of the ntwin serums are of a great diagnostic importance.
Leptospiras nappear in liquor later than in the blood, that is why its investigatio(microscopia and inoculation of the same media as the blood) are done whethere are symptoms of meningitis. Urine can be investigated from the first day nto 3 months from the disease onset.
The guinea-pigs that are nvery sensitive to L. icterochaemorrahaigae are used as a model for the nbiological test. The animals are infected by injecting the infected material n(blood, urine, cerebrospinal fluid taken sterile from the sick person) nintraperitoneally, intracutaneously, intravenously, through the scarified skm nand mucous membranes. The material is taken at the time when the nbacteriological and bacterioscopic investigations are done. The animals die if nthere are leptospiras in the initial material.
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Differential diagnosis
However, in some cases there are diagnostic difficulties because of the npolymorphism of the clinical picture, separate symptoms of which make it ndifficult to diagnose a disease (jaundice, fever, abdomen pain, myalgia, nmeningeal syndrome).
First of all it is required to differentiate the disease from flue, ntyphoid fever, hemorrhagic fever with a renal syndrome (HFRS), virus hepatitis, nmeningitis.
In case of nflue the headache has a distinct location (in the superciliary arch area), nthere is no hepatosplenomegaly, jaundice. There are expressed catarrhal nsymptoms. The hemogram shows leukopenia, neutropenia, the ESR is usually nnormal. The fever last from 2-3 to 5 days.
If there are nsuch symptoms as an acute onset of the disease, a high temperature, intense nheadaches, the appearance of the patients, the liver and spleen enlargement, it nis necessary to differentiate leptospirosis from typhoid fever. However, the nfollowing symptoms are characteristic of the initial period of typhoid fever: nKiari-Avtcin’s sign, Govorov-Godolie’s sign, Rozenberg’s sign, and early nincrease of the spleen. There appears massive roseole-petechial eruption on the nside surfaces of the breast, abdomen, extension surface of the extremities.
In HFRS there are no pains nin the musculus gastrocnemius, there are such characteristic symptoms as loipains, Pastematsky’s positive sign, petechial eruption located in the area of nthe shoulders and armpits. There is prolonged hypoisosthenuria, and in the nurine fall out there are waxy casts, degenerative cells of the renal epithelium nbesides erythrocytes, hyaline casts. There is no jaundice and meningeal nsyndrome. The hemogram shows leukopenia at the increased ESR at the onset of nthe disease.
Virus nhepatitis has a gradual onset, without chills, the temperature rises at the npre-icteric period. Muscle pains, scleritis, conjunctivitis are not ncharacteristic of it. There are no meningeal and renal syndromes. The activity nof transaminases is considerably increased. The hemogram shows leukopenia, low nESR.
If it is necessary nto differentiate leptospirous meningitis form serous meningitis of another netiology, it is necessary to take into account the epidemiological history, npain in the musclus gastrocnemius; the development of the meningeal syndrome i4-6 days after the disease onset, the simultaneous affection of the liver, nkidneys; a hemorrhagic syndrome.
Treatment
Among the most effective etiotropic agent there is combination of nantibiotics and antileptospirosis immunoglobulin if they are indicated in ainitial stage when Leptospires are in blood. Benzylpenicillin, Tetracyclin, nErythromicin and Streptomycin are indicated more often. The daily dose of nBenzylpenicillin can be changed from 3 to 12 millions UN, however, the dose 6 – n8 millions UN is more often indicated per day (in a muscle). It dosage depends non gravity of the disease current. The maximal dose of a preparation is nindicated at development of meningitis. Ampicillin, Oxacillin, Ampiox are neffective semisynthetic Penicillins. Benzylpenicillin or semisyntetic analogue ncan 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, nhowever strengthens a permeability of vascular wall and promotes development of na hemorrhagic syndrome. It is contrindicated at the icteric form of nleptospirosis fever and development of renal failure. Treatment with nantibiotics is carried out during all feverish period and 2-3 days of normal ntemperature. In case of occurrence of relapse a new course of an antibiotic ntherapy must be indicated.
Clinical observations of last years has testified the inefficiency nheterogeneous antileptospirosis immunoglobulin, oppression of immune system nby it. The allogenic donor immunoglobulin which is effective in the first 3-5 ndays of disease are applied in medical practice, has no side-effects. The npreparation prevents development of acute renal failure.
With the purpose of desintoxication and improvements of microcirculatioin a vein there are infused solution of glucose, Reopolyglucin, Rheogluman, nTrisol, Quartasol, and ascorbic acid. Good desintoxication effect have the npreparations that neutralize ammonia: an Ornithine, Ornicetil, Glutargin. At nsevere intoxication Prednisolon and its analogues are indicated. The initial ndose of Prednisolon is 60-120 mg and more, it is used for short course, quickly nreducing dose in process of clinical improvement. Enterosorbtion with using of ngranulated coal SKN, Sillard P, Enterosgel, Polyphepan can be effective. At the nicteric form there should be prescribed diets № 5, 5A, and at pathology of nkidneys – a diet № 7.
At the development of the Disseminated Intravascular Coagulation (DIC) ncarry out a complex of medical actions according to hematological research. At nI stage (hypercoagulation) infuse in a vein Heparin 2500 UN 4 times per day, nReopolyglycin, Dipiridamol (Curantyl), Pentoxyfilin (Trental) Contricali ibottles, ascorbic acid 5 % solution in ampoules 1 mL: 5-10 mL 2 times per nday. At II stages Heparin can be infused under the control of blood clotting ntime, other preparations (Reopolyglycin, Curantyl, Trental) – in the same ndoses, as at I stage of syndrome. At III stage of DIC infusing of Heparin is nnot indicated. At hypocoagulation there is indicated native plasma or nCryoprecipitat of plasma, trombocite mass. At hypofibrinolisis there are giveacid aminocapronic, Contrical, Gordox, at secondary hyperfibrinolysis – nsynthetic antifibrinolitics, inhibitors of proteases – Streptokinasa, nFibrinolysin are indicated.
At the bleeding with a tamponade cold, and infuse Calcii chlorid, nVicasol, aminocapronic acid are used. Infusions of a blood plasma, a red cells nmass, Albumin are indicated at bleeding. If hepatonephric insufficiency ndevelops simultaneously plasma transfusion of blood with infusion of nerythrocytar and trombocytar mass 2-3 times, and are used instead of albuminous npreparations, a mixture of amino acids, for example Alveosin-Neo is nrecommended.
In occurrence of acute renal insufficiency (oliguria, hypoisosthenuria) nthere should be repeated lavages of stomach and an intestine 2-4 % solution of nsodium hydrocarbonate, intravenous infusion of 40 % of glucose solution, nEuphyllin, Mannit. At later infuse Furosemid (Lasix). At development of nmetabolic acidosis indicate Natrii hydrocarbonas and Tris-buffer. If nmedicamental therapy is not effective and oliguria stage lasts more than 3-4 ndays, there is a necessity in Plasmaferesis or Plasmasorbtion or Extracorporal ndialysis by means of artificial kidney.
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Prophylaxis
The deratization and sanitation veterinary measures the essential part of nthe prevention. Deratization is for decreasing of the activity of the natural nfoci (wild rodents control) and the sanitation of the anthropurgias foci (the nsinanthropos rodents control).
One of the directions of leptospirosis prevention is the actions which nbreak the transmission of the disease by water in the natural foci n(mechanization of me agricultural work, the supplying of workers with nwater-proof clothes, a ban to swim in the infected reservoirs and to use nunboiled water). Vaccination is recommended for the people who permanently stay nin the natural foci. The people who belong to a group of high risk infectio(cattle-breeders, veterinary doctors, the meat packing plant personal, nnight-men, deratizators) should be vaccinated with inactivated vaccine.
(FEBRES nHAEMORRHAGICAE)
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Group of acute natural foci diseases ncharacterized by a general intoxication, fever, systemic lesion of small-sized nveins with development of a hemorrhagic syndrome.
There are hemorrhagic fevers with a renal nset of symptoms hemorrhagic fever with renal syndrome, Lassa, Ebоlа and Маrburg nfevers, Yellow fever, caused by viruses of miscellaneous sets and labors.
Etiology
The diseases are caused by RNA-containing nviruses of Bunyaviridae family: from Hantaan kind (HFRS), Togaviridae n- Flavivirus (Yellow fever), Filoviridae – (Ebola fever,
Epidemiology
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http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/vhf.htm
Source of hemorrhagic fever with a renal nsyndrome are mice-like (about 16 kinds), which are excreting the virus with nurine, stool and saliva. Among the gnawers the transmissible way of causative nagent is possible. The contamination of the person descends by air – dust, nnutritional and contact pathes (routes). The transplacental transmission of a nvirus from the pregnant woman is possible. The probability transmission from nthe ill person is not fixed.
In the natural foci the source of an infection – nmultipapillary rat, and ill in the main (basic) visitants. For Ebola fever and nМarburg the source of contamination in the nature is not known yet, probably, nit is primacy. The relevant feature contagious hemorrhagic fever Lass, Ebola nand Мarburg – capability of transmission of a virus from the person. It results nin originating intrahospital flashes, including among employees of hospitals nand secondary diseases in monogynopaediums. The transfer (transmission) of the nhospital causative agent from the person descends by an aerogenic way, and also nat common use by subjects of household activities, at sexual contacts, is more noften – at maintenance for ill, usage of not sterile medical instruments. The ncontamination is possible both in height of illness and in the period of a nreconvalescence.
There are two forms of a yellow fever: a yellow fever of njungle (natural foci – monkey, hedgehogs) and urban yellow fever (source – ill nperson). Both are diffused by mosquitoes Haemagogus and Aedes n(Fig.3). The contamination those at a puncture of the ill person are possible nat the end of an incubation interval or per the maiden 3 days of illness. A nsensibility of the people overall.
Fig.3. Yellow fever mosquitoes
Contagious hemorrhagic fevers Lassa, Ebola and Маrburg are nusual for definite terrains of Africa. The cases of their delivery in countries nof America and Europe by ill primacy and people are described, which one have ncaught 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 nto conventional illnesses, the strife with which one is regulated by (with) ninternational medico sanitary rules.
As the majority of causative agents hemorrhagic fever can be ndiffused with the help of the air drop, they are also potential agents of nbiological weapons.
Pathogenesis
After inoculation of organism of the nperson through an injured skin and mucous of respiratory tract or digestive tract nthe virus propagates lymphatic system, falls in a blood with the subsequent nvirusemia. The antipathy, histic destruction, and responses of an organism by nthe way immunopathologic processes, changes of a curtailing system of a blood, nendocrine disturbance, development of acute renal failure develops. The virus ncauses a serious capillary toxicosis, multiple hemorrhages, hemorrhagic neruption, rising of a permeability of capillary tubes with an output for limits nof a vascular bed of a fluid part of a blood, severe edema of tissues, nviolation of microcirculation, and dystrophic changes of internal organs of ainternals.
Clinic
Hemorrhagic fever with a nrenal syndrome. An incubation interval on the average 10-15 day (duratiofrom 8 about 35 day).
The illness starts is acute with extremely nstrong chills. Temperature of a body is increased till 39-40 °С. The visual ndisturbances, decrease of visual acuity, “mist” before eyes) complain on a nsharp headache, backache, muscles of extremities, photophobia. Arise nausea and nvomiting. At inspection ill mark paleness nasolabial triangle, hyperemia of a nface, necks, upper half of trunk. The palpebral fissures are narrowed down, nscleratis. A mucosa of an oral cavity and pharynx are bright red with nhaemorrhages. The Kerning’s signs, Brudzinsky sign can be determined and stiff nneck. Fever 7-9 days is prolonged.
On 3-5th day of illness on a neck, lateral nareas of a thoracic cell, in axillaries fossas, above clavicles occurs npetechial eruption. It is sporadic the members small-sized, have the shape of nsprockets and are assorted by the way of red or violet strias the eruptiopresent during all feverish season (Fig.4). Then there are nasal, intestinal, npulmonary bleedings.
Fig.4. Petechial eruption
Cardiac sounds are dull; the initial ntachycardia is replaced by a bradycardia, hypotonia. The phenomena of nbronchitis are possible. Almost for all ill the signs of a lesion of the nalimentary canal are watched: dryness of tongue, nausea, vomiting, inflatioand abdominal pain without definite localization. For 25 % of patients enlarged na liver and spleen and the icterus are possible.
Leading is the renal syndrome patient nshows the sharp back pain, positive sign Pasternatsky from both sides, development nof an oliguria, and in sever cases – anuria and uremia. In height of illness nfind a proteinuria reaching 40 gm/l and higher, hematuria, hyaline and nfibrinous barrels, augmentation of number of cells of a renal epithelium. In a nblood is sharply raised the level of a filtrate nitrogen, urea, creatinine. Ia hemogram: the moderate hypochromia anemia, leukocytosis with a neutrocytosis, nthrombocytopenia, increased ESR.
Flow of illness is predominantly severe, nlethality up to 6-8 %. There are also moderate, mild and deleted forms .
Congo-Crimean hemorrhagic nfever. The incubation interval lasts 3-7 day. The illness starts with nchills, hyperthermia till 39-40 °С. There are pains in a head, joints and muscles, extremities nand spin, gaste, repeated vomiting. Vessels of scleras and conjunctivas ninjected are provoked, their face, and neck, top of a chest hyperemic (Fig.5, n6). The mucosa of an oral cavity bloodshots with punctulate exanthema, the soft npalate is hydropic.
The fever stays 7-8 days, for the majority nan ill temperature curve double-peak, the decrease of temperature of a body nwith occurrence (appearance) of a hemorrhagic set of symptoms is ncharacteristic.
Fig. 5. Skleritis
Fig.6. Conjunctivitis
On 2-4th the day of illness on a skin of a lateral area of a ntrunk, inguinal and axillary areas, on a gaste and extremities petechias and neruption occurs. The eruptions are of the round or oval shape with legible ncontours of dark – cherry colour, peter on 5-8th day. Simultaneously with aeruption there are odontorrhagias, nose, mild, alimentary canal, and icterus. nThe condition ill is sharply degraded. The hyperemia of a face is replaced by npaleness and одутловатостью. It is marked sleepiness, adynamia, sometimes stiff nneck, and Kernig’s sign. The liver enlarged, the icterus is possible n(probable). The Pasternatsky sign is positive. Develop an oliguria, nmicrohematuria, and proteinuria. In a peripheral blood: a leukopenia with a nneutrocytosis, thrombocytopenia, augmentation ESR, on 2nd week of illness – nrelative lymphocytosis.
The illness can be mild, moderate and sever degree. The nlethality reaches 40 %, predominantly owing to an infectious-toxic shock, nmassive bleedings, and hepatonephric failure.
http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/cchf.htm
Lassa fever. Incubatioperiod lasts 3-17 day. The disease starts with a minor fever, malaise, muscle naches, and conjunctivitis. Step-by-step temperature reaches 39-40 °С and develops nrepresentative pharingitis, more often ulcerative-necrotic. The ulcers have nyellowish center with bright erythematic borders, are localized on a soft npalate, tonsils and mucosa of a pharynx. In height of illness the meningeal nsigns is marked a strong headache, giddiness, sleepiness, at a normal structure nof liquor, violation (disturbance) of consciousness. Are watched nausea, a nvomiting, diarrhea, deaquation, abdominal pain and chests, tussis, the dysuric nphenomena generalized lymphadenopathy, specially enlarged cervical nlymphonoduses. It are marked a relative bradycardia, sometimes dicrotism of nsphygmus. The liver enlarged. In the analysis of a blood – leukopenia with nshift of the formula to the left, the thrombocytopenia, ESR is step-by-step nincreased till 40-80 mm/hour. In moderate and severe cases – moderate bleedings nof miscellaneous localization and petechias an eruption on a skin and mucosa, nless often – roseola, papule, and spot. In very sever cases develops an edema nof a face and neck, exudates (pleural, pericardial, peritoneal). Considerably ncomplicate flow of illness pneumonia, fluid lungs, uremia, and infectious-toxic nshock. Lethality is up to 30-67 of %. In the period of a reconvalescence the npalindromias, deterioration of hearing, baldness are seen an asthenia, nsometimes. http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/lassaf.htm
Incubation period of Ebola fever n7-14 day, Marburg fever – 4-9 days a beginning is acute, precursory nsymptoms serve conjunctivitis and exanthemas. Per the maiden days of illness nthere are a strong pain of a head, chills, fever till 39-40 °С, dorsodynias, muscles, njoints, the nausea, vomiting, often watery chair, that can result in a nconsiderable deaquation of an organism. The маculo-papular eruptiodistributing to a neck and a face, upper extremities, breech is representative, nfurther there is an eruption on palms and base surfaces. Is watched enantema oa mucosa of a mild and firm palate, ulcer. Dermatitis of a scrotum quite oftedevelops. Enough often on the maiden week of illness the lymphadenitis ioccipital, cervical, axillary areas is marked. The lymph nodules enlarged up to nthe pea size, mild, are a little morbid. From the 5-7-th of day of illness the nhemorrhagic set of symptoms more expressed is affixed than at Lassa fever; for nthe women – parent bleedings, spontaneous abortions. The psychics, nhyperesthesia, cramp is sometimes upset. Complications – bronchopneumonia, norchitis, panreatitis, uveitis. After petering fevers is long the external tags nof illness – deeply sunk down of an eye, cachexia labored gait are saved. In a nblood at first leukopenia, then leukocytosis with a left-shift, nthrombocytopenia. Immediate causes of death – infectous-toxic shock, heart nfailure, cerebral distresses. Lethality – 30-90 %.
http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/ebola.htm
http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/marburg.htm
Yellow fever. Aincubation period is 3-6 days. Distinguish two stages of illness. First stage nis characterized by the sudden beginning with strong chills, fever repeated nvomiting. Ill has pains in a head, back, lower back, bones. It are marked a nsharp hyperemia and edema of a face and neck, eye injected by a blood. A mucosa nof a or pharynx and tongue of bright red colour. The photophobia develops. nPatients are irritable and are provoked. Pulse is fast. From the 3-rd day of nillness there are yellow colouring of a skin and sclera, dot hemorrhages on a nskin, are enlarged a liver and spleen. Then there comes a remission continuing n1-2 days. Temperature of a body is reduced up to the norm, the state of health nis improved.
From the 5-th day of illness the condition of patient is nsharply degraded (stage of venous stasis). Temperature of a body up to 40 °С and above is agaiincreased, there can be a delirium. The icterus rises. The face becomes pale nyellow with cyanotic tint. Strengtheausea and vomiting. Emesis masses are of ndark brown or black colour. A feces are dark (melena). On a skin of a trunk nboth extremities there are petechias and ecchymomas. The copious nasal and nparent bleedings, bleeding gums are observed. The nephroses – oliguria or nanuria, blood and barrels in urine, azotamia are struck.
The tachycardia is replaced by a bradycardia n(Faget’s sign). The arterial pressure is reduced. In the analysis of a blood a nleukopenia – up to 1,5-2,0-10 /l, neutropenia. Encreased ESR. Are ncharacteristic a hyperbilirubinemia (at the expense of both fractions of a npigment), enhancement of activity aminotransferase, in urine – bilirubin, nurobilin, it is a lot of albumin, erythrocytes, leucocytes, barrels.
The fever stage lasts 8-9 days. The death ncan occure due to bleedings, shock, hepato–renal failure. The lethality makes n5-10 %, in the season of epidemics – up to 60 % and higher.
The abortive forms of illness without aicterus and hemorrhagic set of symptoms are possible mild, deleted.
Diagnosis
The diagnostic hemorrhagic fever is carried out with nallowance for of epidemiological anamnesis (seasonal prevalence, connectiowith the causative agent, contact with ticks, rodens and exotic animal) and nrepresentative clinical developments acute onset, fever, hemorrhagic syndromes. nThe diagnosis confirms virology and serological methods of research. Causative nagent of Lassa fever, Ebola and Маrburg – on culture of cells Vero or oguinea pigs epidemic parotitises. “The Gold standard” – detection of RNA of nthe originator. For serodiagnosis will use RCC, RN, RIA, RIIF, IFA with double nserums of patients, immunosorbent methods. With material of sick persons work nonly in the specially equipped labs, adhering to strick safety measures n(Fig.7).
Fig.7. Specially equipped department for ntreatment
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The differential diagnosis
As against hemorrhagic fever, for an ill flu the hemorrhagic ndevelopments are very seldom. The high contagiousness, more short feverish nseason(term), availability катарального of a set of symptoms, Morozkin sign is ncharacteristic for him(it). In outwashes with a slimy nasopharynx by a method nfind antigens of a virus of a flu.
The virus hepatitises often start step-by-step, with npreicteric of the period, the flow which one is accompanied ncatarrhal,dyspeptic, asteno-vegetative syndromes. In height of illness are not nwatched a hyperemia and одутловатость of a face, горячка, озноб, lesion of nnephroses. The hemorrhagic set of symptoms arises only at a very serious degree nof illness.
The тyphoid-paratyphoid diseases have a gradual beginning, nstepwise temperature rise, reference predominantly roseola eruption. Easy ndiagnostic confirming epidemiological anamnesis, research of a hemoculture, nserological tests.
At a canicola fever the strong muscle pains, specially iикроножных muscles are characteristic; a liver, often icteric forms(shapes) of nillness with the sharply expressed hyperbilirubinemia practically always nenlarged; in a blood on all stretch(extent) of illness – hyperleukocytosis with na neutrocytosis, shift of the formula to the left, very high ESR. The diagnosis nconfirms by the laboratory data – detection of the originator at a dark field nmethod of a blood and urine, serological tests RMA with leptospira.
For a hemorrhagic vasculitis are characteristic long-lived nrecurrent flow, lesion of joints, and localization of an eruption on extensor nsurfaces of top and bottom extremities.
At Q fever are struck mild with development of a pneumonia, nare enlarged a liver and lien.
For a malaria pathognomic representative attacks of a fever nwith definite periodicity. At examination find a splenomegaly, in a blood – nmalarial plasmodium.
The meningococcal infection contamination starts is acute, nbut in a clinical picture of the generalized form (shape) on the foreground nmore often the meningitis or sepsis with a copious hemorrhagic eruption acts, nit is a lot of members of the star-shaped form (shape) with a necrosis of aepithelium. In the analysis of a blood a hyperleukocytosis with shift of the nformula to the left, enlarged ESR. The diagnosis confirms by detectioменингококка in sowings from a nasopharynx, blood and liquor.
Treatment
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All sick are subject to mandatory nhospitalization. The basis of treatment make desintoxication (i.v. 5-10 % nglucose, polyionic solutions, 5 % donor Albuminum), glucocorticoids, strife nwith a hemorrhagic set of symptoms (Ascorutinum, Vicasolum, Dicynonum, nEtamsylatum, calcium Dobesilat, Adroxonum, Acidum aminocapronicum; blood). Icase of renal failure (for decreasing of remic intoxication a gastric lavage nand intestine with 2 % sodium of Sodium hydrogenum solutions; at increasing of nacute renal failure and infectious-toxic shock – extra corporal haemodialysis). nAntiviral drugs per the maiden days of illness assign virolex, ribavirin, ninducers of endogenic interferonogenesis (cycloferon, groprinosin), specific nimmunoglobulin or plasma. The antibiotics in case of bedding of a bacterial ninfection contamination.
Prophylaxis and measures in the locus
At hemorrhagic fever with a renal nsyndrome the preventive measures are directed on strife with the gnawers. Are noffered inactivated cultural and cerebral vaccines (China, Russia, Japan), recombinant of a vaccine (USA, China), which one have appeared effective in endemial nterrains. With this purpose carry out a disinfestation in the natural locuses, nputtings, and also collect of tongs with animal and poultries. For a ndisinfestation will use gexachloran. In a burn-time in a field and on timber nloggings it is recommended to use a special protective clothing and repellents.
Medical observation in the focus for 10 ndays. Conduct mandatory final disinfection with 3 % Chloraminum solution and nchlorofos. For contact persons or one who was bitten by tongs in endemial ndistricts enter a specific immunoglobulin i.m. in doses 5-7.5 ml for adult, n2.5-3.5 ml – for children. Apply a vaccine, inactivated by formalinum for nspecific prophylaxis of Congo-Crimean hemorrhagic fever.
Primary antiepidemic measures after ndetection of sick with contagious hemorrhagic fevers Lassa, Ebola and
The specific prophylaxis contagious nhemorrhagic fever. The quarantine for arriving from epidemic areas lasts 17 nday. In endemial districts of yellow fever vaccination of the population by aalive “
Rabies
Definition
Aacute infectious disease of mammals, especially carnivores, characterized by ncentral nervous system wrilation followed by paralysis and death.
Historic nreference
Rabies in dogs nand the importance of saliva in its transmission may have been recognized iPharaonic times and in China at least seven centuries ago. But it now seems ndoubtful whether much-quoted passages from the Babylonian pre-Mosaic Eshnunna ncode (around 2300 ВС) and those attributed to the Greek philosopher Democritus n(500-400 BC) referred specifically to rabies Aristotle (322 BC) described nrabies in animals but seems to deny that humans could be infected or could die nfrom the disease. Celsus in “De medicina” (1st century AD) described hydrophobia in afflicted nhumans and recognized that the disease was spread by saliva, although his use nof the Latin word “virus” did not imply a specifically infective norigin. He discussed local treatment for the wound, including cupping, suctioand cauterization, and the immersion of the patient in sea water. Other npersistent myths that arose at that time were the idea that surgical excisioof a dog’s “tongue worm” (frenulum linguae) would protect it from rabies n(as pointless and malicious an operation as that for “tongue tie” ichildren) and the belief that rabies could be generated spontaneously in dogs. nIn the sixteenth century, Fracastoro strengthened the concept of rabies as a ncontagious disease.
A scientific or experimental approach to rabies was delayed until 1793, nwhen John Hunter published his very important paper, “Observations and nheads of enquiry on canine madness.” Hunter suggested that the ntransmission of rabies should be studied by inoculating saliva from rabid nanimals and humans into dogs and that attempts should be made to inactivate the n”poison” in the saliva. These ideas may have inspired the experiments nby Zinke (1804) and Magendie and Breschet (1813). Zinke used a paintbrush to nintroduce saliva from rabid dogs into incisions made in the skin of dogs, cats, nrabbits, and chickens, which duly developed signs of rabies. In the same year nMagendie and Breschet infected dogs with saliva from human patients with nhydrophobia.
Galtier (1879) nwas responsible for an important technical advance. He found that rabbits could nbe infected with rabies and were far more convenient experimental animals thadogs. Pasteur adopted the use of rabbits in his studies of rabies beginning i1880. He was the first to recognize that the major site of infection was the nCNS. “Street virus” from a naturally infected dog was passaged nthrough a series of rabbits to produce “fixed virus” with a nconsistent minimum incubation period of 6 or 7 days. Attenuation of the fixed nvirus was achieved by desiccation of rabbit spinal cord for up to 14 days. nPasteur was able to protect dogs from challenge by immunizing them with the ndesiccated material, and in 1885 he used his vaccine for the first time iJoseph Meister, a boy severely bitten by a rabid dog. In 1891 passive nimmunization, using whole blood from vaccinated dogs and humans, was studied by nBabes and Cerchez. Negri (1903) described his diagnostic inclusion body, which nallowed the laboratory diagnosis of rabies. The introduction of the more nspecific and sensitive immunofluorescence method by Goldwasser and Kissling i1958 has now largely replaced the Seller’s stain for Negri bodies. The nature nof the infective agent was further elucidated by Remlinger (1903), who showed nthat it would pass through a Berkefeld filter. It was not until 1936 that the nsize of the virus was established by reliable ultrafiltration studies (Galloway nand Elford), and it was first seen as a bullet-shaped particle by electromicroscopy in 1962 (Almeida and colleagues).
Improvements in Pasteur’s vaccine were achieved by Semple and Fermi, who nkilled the virus rather than attenuated it, and by Fuenzalida and Palacios, who ndeveloped a suckling mouse brain vaccine which carried a lower risk of nneuroparalytic complications.
Successful growth of rabies virus in tissue culture was achieved by nKissling in 1958, leading to the development of human diploid cell straivaccine by Wiktor and his colleagues in 1964 and of other safe and highly npotent tissue culture vaccines. The use of passive immunization with equine nhyperimmune serum has been vindicated by the famous natural experiment nfollowing an attack by a rabid wolf on 29 people in Iran in 1954.
http://emedicine.medscape.com/article/220967-overview
Etiology
The rhabdoviruses (Greek rhabdos—rod) are a group of about n140 RNA viruses of plants, arthropods, fish, reptiles, birds, and mammals. nRabies and its five related viruses constitute the genus Lyssavirus. The nrabies virion is approximately 180 x 80 nm (Fig.8). The nucleocapsid consists nof a single negative strand of helical RNA associated with three structural nproteins: a nucleoprotein (N), a phosphoprotein (NS), and an RNA-dependent RNA npolymerase (L). This is surrounded by a lipid-containing envelope including a nmatrix protein (M) and a glycoprotein (G) which forms spiky protuberances othe shaft and rounded end of the virion. This surface glycoprotein is the only nmolecule that induces neutralizing antibody and was therefore considered the nonly important constituent of vaccines. However, recent work has shown that the nnucleoprotein is also capable of inducing protective immunity, although not by nneutralization.
Fig.8. Agent of rabies (RNA-containing nvirus)
Rabies virus is rapidly inactivated by heat: at 56 °С the half-life is nless than 1 minute and, experimentally, the titer decreased by 105 ninfectious doses within 15 minutes. At 37 °С the half-life is prolonged to nseveral hours in moist conditions. The lipid coat of the virion renders it nvulnerable to disruption by detergents and simple 1 percent soap solution. nForty-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” nfrom naturally infected animals results in a “fixed virus” of nuniformly shortened incubation period and reduced pathogenicity which is used nin vaccine production. Strains of rabies virus caow be identified using npanels of monoclonal antibodies. Antigenic patterns show differences betweevector species, for example distinguishing virus from North American insectivorous nbats from fox, raccoon, and skunk strains occurring in the same area.
Wild or ndomestic animals occasionally carry the bat strains, indicating the source of ntheir infection. The vector of rabies transmission to nonenzootic species catherefore be identified. Culture of virus is not essential, as monoclonal nantibody typing is performed on the abundant nucleoprotein antigen in fixed nbrain impression smears. Some strains of rabies virus produce distinctive nclinical manifestations, such as the sub-acute paralytic form of rabies in dogs nin West Africa (oulou fato) and paralytic rabies transmitted to bovines and nhumans by vampire bats in Latin America and the Caribbean.
Rabies virus ncan be isolated and cultivated in a number of laboratory animals and continuous ncell lines. The conventional method, by intracerebral inoculation of suckling nmice, is sensitive but takes 2 to 3 weeks. Many laboratories are now using nmouse neuroblastoma cell cultures in which the virus can be identified in 3 to n4 days.
Epidemiology
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Rabies is enzootic in mammal populations in most countries. nRabies-free countries include the British Isles, Norway, Sweden, Iceland, Mediterranean and Atlantic islands, Australia, New Guinea,
Domestic dogs, nand to a much lesser extent cats, are the main reservoir of urban rabies, which nis responsible for more than 90 % of human cases worldwide. However, icountries such as the United States, where control of rabies in domestic nanimals has been very successful, wild animals such as skunks and raccoons now nconstitute the main threat for spread to humans.
The three nspecies 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 ninduced by European tissue culture rabies vaccines and commercial immune nglobulieutralize European bat Lyssavirus, results of challenge nexperiments in mice vary, but some show poor protection by virus strains used nin vaccines available in Europe.
It is possible nthat infection with rabies-related viruses, such as Kotonkan virus in domestic nherbivores 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 nunderreporting. Recently, a figure of 50,000 human deaths per year in India alone was suggested. Other countries reporting a high incidence of human rabies ninclude 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 nsince 1960 the maximum annual incidence has been 5 (in 1979), and the total nnumber of cases was 50 in 28 years, of which 17 were infected outside the nUnited States. In continental Europe few rabies deaths are now reported.
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Transmission
Intact skin is an adequate barrier to the infection, but broken skin and nintact mucosa can admit the virus. Human infections usually result from ninoculation of virus-laden saliva through the skin by the bite of a rabid dog nor other mammal. Scratches, abrasions, and other wounds can be contaminated nwith infected saliva. The following are very unusual routes of human infection:
1. Inhalation. This has been reported in caves ndensely populated with insectivorous bats, which can create an aerosol of nrabies virus from infected nasal secretions and possibly urine. In the United States there have been two laboratory accidents involving the inhalation of fixed nvirus during vaccine preparation.
2. Vaccine-induced rabies (rage de laboratoire). nIn the worst incident, 18 people developed paralytic rabies in
3. Comeal transplant grafts. Seven cases have nbeen reported in France, the United States, Thailand, Morocco, and India in which infected comeae were transplanted from donors who had died of nunsuspected rabies. Six of the recipients developed rabies and died.
4. Transplacental infection. This has beeobserved in animals but until recently had not been reported in humans, whereas na number of women who developed rabies encephalitis in late pregnancy were ndelivered of healthy babies. Transmission of rabies by breast milk is well ndocumented in animals and has been suspected in at least one human case.
Animals can be ninfected through the gastrointestinal tract (per os and per rectum). nIn the previrologic era, there were claims that eating infected meat and sexual nintercourse could transmit rabies to humans, but these routes remain unproven.
Pathogenesis
In experimental animals, injected rabies virus replicates locally istriated muscle but is soon detectable at neuromuscular junctions and nneuromuscular and neurotendinal spindles. Direct invasion of nerve cells may nalso occur without prior infection of muscle. Various possible cell surface nreceptors for attachment of the rabies virus have been suggested, such as nphosphatidylserine, carbohydrates, phospholipids, and sialylated gangliosides. nAt neuromuscular junctions and in the CNS, the postsynaptic nicotinic nacetylcholine receptor is an important attachment site for the virus. Binding nat these sites is competitive with cholinergic ligands, including the snake nvenom neurotoxin, alphabungarotoxin, which shows sequence homology with rabies nvirus glycoprotein.
Once ninside peripheral nerves, the virus is carried centripetally by the flow of naxoplasm to the dorsal root ganglia where there is further replication, nexplaining perhaps the characteristic prodromal symptom of paresthesia at the nsite of the inoculation. Spread along peripheral nerves can be blocked nexperimentally by local anesthetics, metabolic inhibitors, and section of the nnerves. Spread is rapid through the spinal cord and brain, and there is massive nviral replication on membranes of neurons and glial cells and direct ntransmission of virus from neuron to neuron via the synapses. Virus also exists nfree and spreads within extracellular spaces such as the CSF. In the early nstages of the encephalomyelitis, there is selective infection of certaineuronal populations. Finally, there is a phase of passive centrifugal spread nof virus from the nervous system in the axoplasm of many efferent nerves, nincluding those of the autonomic nervous system.
Virus has been found in many tissues including skeletal and cardiac nmuscle, intestine, kidney, liver, pancreas, and brown fat. Extraneural viral nreplication has been observed in salivary glands, brown fat, and cornea. Virus nis shed from salivary and lacrimal glands, taste buds, respiratory tract, and nrarely in urine and milk. Viremia has rarely been detected in animals and is nnot thought to be involved in pathogenesis or spread.
Response to Vaccination
Antibody induced by rabies vaccines has been measured by a variety of nmethods including the immunofluorescent antibody test, mouse neutralization, nrapid immunofluorescent focus inhibition (a tissue culture neutralizatiotest), enzyme immunoassays, and hemagglutination inhibition. The host’s immune nsystem is stimulated by a vast array of antigenic determinants on viral nproteins and nonviral vaccine constituents. Each serologic test detects a ndifferent selection of these antibodies, and so the results of one cannot be ncompared with those of another. Neutralization tests are the best available nindicator of protection from rabies deaths, but the correlation is far from nperfect.
Neutralizing nantibody is directed solely against the glycoprotein spikes on the viral coat, nand so glycoprotein extracts have been used as subunit vaccines. The nnueleoprotein molecule was considered irrelevant in the induction of protective nimmunity until work on influenza virus showed that immunization with purified nnueleoprotein was beneficial in mice, not through prevention of infection but nby aiding recovery. Dietzschold’s group have shown that rabies nribonucleoprotein can induce protective immunity under some experimental nconditions that may involve both humoral and cellular arms of immunity. The use nof selected, broadly cross-reacting nueleoprotein epitopes in the constructioof future vaccines is being investigated.
The amount of antibody produced by vaccine is partly determined by the nhost. Kuwert observed that in a population of vaccines, 80 % produced high nantibody levels more rapidly than the 20 % who had poor, relatively delayed nantibody induction. In mice, responsiveness to vaccine was genetically ndetermined. Tissue typing in humans shows some minor differences between the ngroups of responders.
Vaccine-induced nneutralizing antibody is not detectable for 7 to 10 days after starting primary nvaccination. During that time passive protection can be provided by specific nhuman or equine immune globulin.
Clinical nFeatures of Rabies Animals
Judged by the nmedian lethal dose of street rabies virus, there is a wide range of nsusceptibility to rabies infection among mammals and birds. Foxes are the most nsusceptible, cats and dogs have intermediate susceptibility, and opossums are nrelatively resistant.
In domestic ndogs, the incubation period ranges from 5 days to 14 months. It is less than 4 nmonths in 80 percent of cases; hence the compulsory quarantine of 6 months nimposed on dogs imported to the United Kingdom. Prodromal symptoms include nchange in temperament, fever, and, as in many humans, intense irritation at the nsite of the infecting bite. The familiar picture of a “mad dog” with nfurious rabies is seen in only 25 % of infected animals. The more commoparalytic or dumb presentation is less dramatic and more dangerous, as it may nnot be recognized. The clinical features of furious canine rabies include nirritability, convulsions, dysphagia, laryngeal paralysis causing an altered nbark, hyper-salivation, and extreme restlessness causing the animal to wander nmiles from home. Dogs with furious rabies attack inanimate objects, oftebreaking their teeth and injuring their mouths in the process. Before the ndiscovery of Negri bodies, canine rabies was confirmed by examining the stomach ncontents, which often consisted of earth and stones resulting from pica. Dogs nwith paralytic rabies may be reclusive and exhibit paralysis of the jaw, neck, nand hind limbs, and dysphagia and drooling of saliva, which may make the owner nsuspect and attempt to remove a bone imagined to be stuck in the throat. Virus nmay be excreted in the saliva as early as 3 days before the appearance of nsymptoms, and the animal usually dies within the next 7 days. This is the basis nfor 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, nwith an extreme range of 4 days to more than 20 years. In some animals, latent ninfections can be reactivated by corticosteroids and stress, providing a npossible explanation for the rare authentic reports of very long incubatioperiods in humans. Facial and severe multiple bites, transmission by corneal ntransplant, and accidental inoculation of live virus (rage de laboratoire) are nassociated with relatively short incubation periods. A few days of prodromal nsymptoms may precede the development of definite signs of rabies nencephalomyelitis. These may consist of fever, changes of mood, and nonspecific n”flulike” symptoms, but in more than one-third of cases itching, nneuritic pain, or paresthesia at the site of the healed bite wound suggests nimpending rabies. The existence of two distinct clinical patterns of rabies, nfurious (agitated) and paralytic (“dumb,” “rage mue,” or n”rage muette”), depends on whether the brain or spinal cord is npredominantly infected and may reflect differences in the infecting strain of nrabies virus or in the host’s immune response.
Furious rabies, the more common presentation in humans except those ninfected by vampire bats, is characterized by hydrophobia, aerophobia, and nepisodic generalized arousal interspersed with lucid intervals of normal ncerebration. Hydrophobia is a reflex series of forceful jerky inspiratory muscle nspasms provoked by attempts to drink water and associated with an inexplicable nterror. A draft of air on the skin produces a similar reflex response, n”aerophobia.” Initially, the spasms affect the diaphragm, nsternomastoids, and other accessory muscles of inspiration, but a generalized nextension response may be produced ending in opisthotonos and generalized nconvulsions with cardiac or respiratory arrest. Without supportive care, about none-third of patients with furious rabies die during a hydrophobic spasm in the nfirst few days of their illness. There is hyperesthesia and periods of ngeneralized excitation during which the patient becomes hallucinated, wild, and nsometimes aggressive. These grotesque symptoms are explained by a selective nencephalitis involving the brain stem and limbic system. In rabies, unlike most nother encephalitides, patients may remain intermittently conscious and nrational. Hypersalivation, lacrimation, sweating, and fluctuating blood npressure and body temperature result from disturbances of hypothalamic or nautonomic nervous system function (Fig.9). Conventional neurologic examinatiomay fail to disclose any abnormality unless a hydrophobic spasm is observed. nPhysical findings include meningism, cranial nerve and upper motor neuron lesions, nmuscle fasciculation, and involuntary movements. Increased libido, priapism, nand frequent spontaneous orgasms may be the presenting symptom in some npatients, suggesting involvement of the amygdaloid nuclei. Furious rabies nnaturally progresses to coma and death within a week, but some patients have nbeen 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 ihumans but is frequently undiagnosed. All reported cases of rabies transmitted nby vampire bats in Latin America and the Caribbean are of this type. The nparalytic form of rabies was also seen in patients with postvaccinal rabies and nin the two patients who inhaled fixed virus. It seems more likely to develop ipatients who have received antirabies vaccine. After the prodromal symptoms n(see above), paralysis, fasciculation, pain, and paresthesia start in the nbitten limb and ascend symmetrically or asymmetrically. There is progression to nparaplegia with sphincter involvement, quadriparesis, and finally paralysis nofbulbar and respiratory muscles (Fig.10). Hydrophobia is usually absent. nPatients with paralytic rabies may survive for several weeks even without nintensive care.
Fig.10. nParalytic rabies
Differential diagnosis
In the rabies endemic area, the diagnosis is easy in a patient with nhydrophobic spasms who remembers being bitten by a dog in the previous few nmonths.
The spasms of npharyngeal tetanus may resemble hydrophobia, and this disease can also ncomplicate an animal bite. Severe tetanus is distinguished by its shorter nincubation period, the presence oftrismus, the persistence of muscular rigidity nbetween spasms, the absence of pleocytosis, and a better prognosis. The rare nencephalopathy complicating serum sickness and anaphylactic reactions to nHymenoptera venoms are said to resemble rabies encephalitis. Rabies phobia is nan hysterical response to the fear of rabies. It differs from true rabies iits shorter incubation period, often a few hours after the bite, by the nemphasis on aggressive and dramatic symptoms, and by its excellent prognosis. nFew hysterics could accurately simulate a hydrophobic spasm.
Paralytic nrabies should be considered in patients with rapidly ascending flaccid nparalysis, suspected Guillain-Barre syndrome, and transverse myelitis. Itropical developing countries that are still dependent on Semple-type and nsuckling mouse brain rabies vaccines, the most important differential diagnosis nis postvaccinal encephalomyelitis. This usually develops within 2 weeks of the nfirst dose of vaccine but has no clinical or laboratory features that reliably ndistinguish it from rabies while the patient is still alive, except for the nabsence of demonstrable rabies antigen in skin biopsies (see below). Ipoliomyelitis there are no sensory abnormalities. Herpes simiae (B virus) nencephalomyelitis, which is transmitted by monkey bites, has a shorter nincubation period than rabies (3 to 4 days). Vesicles may be found in the monkey’s nmouth and at the site of the bite. The diagnosis can be confirmed virologically nand the patient treated with acyclovir.
Pathology
Rabies is an acute nonsuppurative meningoencephalomyelitis. By the ntime the patient dies, ganglion cell degeneration, perineural and perivascular nmononuclear cell infiltration, neuronophagia, and glial nodules may be nwidespread throughout the brain, spinal cord, and peripheral nerves. However, nconsidering the clinical severity, changes are often surprisingly mild. Inflammatory nchanges are most marked in the midbrain and medulla in furious rabies and ithe spinal cord in paralytic rabies. The diagnostic intracytoplasmic inclusiobodies (Negri bodies)(Fig.11) contain viral ribonucleoprotein and probably nfragments of cellular organelles such as ribosomes, giving the essential ninternal structure. They are found in up to 80 % of human cases and are most nnumerous in the pyramidal cells of Ammon’s horn in the hippocampus, icerebellar Purkinje cells, and in the medulla and ganglia. Apart from these ninclusion bodies there are no histologic features that distinguish rabies from npoliomyelitis or other forms of viral encephalitis. The brain stem, limbic nsystem, and hypothalamus appear to be most severely affected. A spongiform nencephalopathy has been demonstrated in skunks and foxes. It probably nrepresents an immunologic effect of infection. Extraneural changes include nfocal degeneration of salivary and lacrimal glands, pancreas, adrenal medulla, nand lymph nodes. An interstitial myocarditis with round cell infiltration has nbeen described. This may be associated with cardiac arrhythmias. The brain of a nfatal human case of Mokola virus encephalitis showed perivascular cuffing with nlymphocytes and lymphoblastoid cells. Neurons contain large numbers of nhomogeneous cytoplasmic inclusion bodies, which were quite different in size nand appearance from Negri bodies.
Fig.11. nNegri bodies (intracytoplasmic inclusion bodies)
Laboratory diagnosis
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In the mammal responsible/or the bite, rabies can be confirmed nwithin a few hours by immunofluorescence of acetone-fixed brain or spinal cord nimpression smears, a technique that has replaced the classic Seller’s stain for nNegri bodies which is notoriously difficult to interpret (Fig.12). A simple nELISA test can be used if fluorescence microscopy is not available, and a nsensitive avidin-biotin peroxidase method has recently been developed for use nwith formalin-fixed histologic sections.
Fig.12. Negri bodies ineurons cytoplasm
Rapid nexamination of CNS tissue in animals suspected of being rabid is now preferred nto observing them in captivity for 10 days. In patients, rabies can be nconfirmed during life by immunofluorescence of skin, and brain biopsies, but nthe comeal impression smear technique is falsely negative too often to be nuseful. Early in the illness, rabies virus can be isolated from saliva, brain, nCSF, and even spun urine but not blood. Virus isolation ieuroblastoma cell ncultures can produce a result in 2 to 4 days instead of the 2 to 3 weeks nrequired for the traditional intracerebral inoculation of mice. In patients who nhave not been vaccinated or given rabies immune globulin, rabies antibody iserum and especially in the CSF is diagnostic of rabies encephalitis. nRabies-neutralizing antibody leaks across the blood-CSF barrier in patients nwith postvaccinal encephalomyelitis, but a very high filer suggests a diagnosis nof rabies. The only reliable method for distinguishing rabies from postvaccinal nencephalomyelitis during life is by the immunofluorescence of skin biopsies. Irabies, lymphocyte pleocytosis rarely exceeds a few hundred cells per nmicroliter. A neutrophil leukocytosis is commonly found in the blood.
Treatment of Human Rabies nEncephalomyelitis
Human rabies remains virtually incurable. Intensive care offers the nonly hope of prolonging life and, perhaps in a very few cases of paralytic nrabies or infection with attenuated virus, of survival. Problems arising during nintensive care include a variety of respiratory complications such as naspiration pneumonia, pneumothorax, and respiratory arrest; cardiac narrhythmias, hypertension, pulmonary edema, and effects of myocarditis nincluding congestive cardiac failure; generalized convulsions, cerebral edema, ninappropriate secretion of an-tidiuretic hormone or diabetes insipidus, npolyneuropathy, hyper- and hypothermia; and hematemesis associated with nulceration or tears in the mucosa of the upper gastrointestinal tract. Heavy nsedation and analgesia should be given to relieve the agonizing symptoms. nImmunosuppressant agents, including corticosleroids, rabies hyperimmune serum n(which may have accelerated death), antiviral agents such as ribavirin, and nalpha-interferon have not proved useful. Studies of intrathecal live attenuated nvaccines in animals suggest the possibility of applying the treatment in humacases.
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Prevention and Control of Rabies Pre-exposure Prophylaxis
In rabies endemic areas, those at high risk of exposure to rabid animals nshould be given pre-exposure vaccination. These include veterinarians, health ncare personnel, laboratory workers, and dog catchers. In areas where animal nrabies is highly prevalent, especially among domestic dogs, there may even be a ncase for including rabies vaccine in the expanded programs of immunization for nchildren. Ionendemic areas those who come into contact with imported mammals nin quarantine, who work with rabies virus in laboratories, or who intend to ntravel to rabies endemic areas should be vaccinated.
Travelers at nparticular risk of exposure to rabies are zoologists and other field workers, nforesters, cave explorers, and those whose work involves walking and cycling iurban and rural areas of India, Southeast Asia, and Latin America.
Only tissue culture vaccines are safe enough to use for pre-exposure nprophylaxis. Three doses are given on days 0, 7, and 28, either ЇМ into the ndeltoid (not into the gluteal region) or 0.1 ml intradennally. A single booster ngiven 1 year later produced sustained immunity for 5 to 8 years.
Alternatively, na booster dose can be given every 2 years if the neutralizing antibody level nfalls and continued protection is needed. Those working with rabies virus ilaboratories should have their antibody titer checked every 6 months as a guide nto the need for further booster injections. A failure of pre-exposure nvaccination by the intradermal route was found in American Peace Corps workers nwho were immunized in the tropics while taking chloroquine for malaria nprophylaxis. This reduces the neutralizing antibody response, but other nunidentified factors contribute to the immunosuppression. The intradermal ncourse should therefore be completed before starting chloroquine, or the vaccine nshould be given IM.
Postexposure prophylaxis
Cleaning the wound as soon as possible after a bite or other contact with na rabid animal is essential first aid and is particularly effective for nsuperficial wounds. The wound should be scrubbed with soap or detergent and ngenerously rinsed under a running tap for at least 5 minutes. Foreign material nand dead tissue should be removed under anesthesia. The wound should be nirrigated with a viricidal agent such as soap solution, povidone iodine, 0.1 % naqueous iodine, or 40 to 70 % alcohol. Quaternary ammonium compounds, hydrogeperoxide, and mercurochrome are not recommended. Suturing may inoculate virus ndeeper into the tissues and so should be avoided or delayed when possible. The nrisk of other viral, bacterial, fungal, and protozoal infections must be nconsidered after bites by animals and humans. Pathogens commonly associated nwith mammal bites include Pasteurella multocida, Clostridiwn tetani, orf nvirus, cat scratch disease bacillus, Leptospira species. Spirillum nminor, Streptobacillus moniliformis, and the fungus Blastomyces ndermatitidis. Tetanus prophylaxis and antimicrobials may be required. Most nof the bacteria are sensitive to benzyl penicillin, amoxicillin, or cefoxitin.
Nervous tissue vaccines, initially introduced by Pasteur in the nnineteenth century and developed by Semple, Fermi, Hempt, and Fuenzalida, are nstill 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 nthese vaccines have to be given in protracted courses. Their potency is nvariable, and they may be associated with severe neuroparalytic reactions. IWestern countries, tissue culture vaccines are used almost exclusively.
Several tissue nculture vaccines are now in large-scale production, including the long nestablished human diploid cell strain vaccine (HDCSV) (Institut Merieux), the nmore recent and less expensive purified vero cell rabies vaccine (PVRV) n(Institut Merieux), purified chicken embryo cell vaccine (PCEC) (Behringwerke), nand a primary hamster kidney cell vaccine produced in the
The initial ndose should be doubled and given at several different sites if there has been a ndelay of more than 48 hours in starting postexposure prophylaxis, if passive nimmunization (hyperimmune serum) was given 24 hours or more before active nimmunization, in elderly patients, in those with chronic diseases such as nhepatic cirrhosis, in those likely to be immunodeficient, immunosuppressed, or nseverely malnourished, and if hyperimmune serum is not available.
An abbreviated nregimen consists of two 1-ml injections at different sites on day 0, followed nby single 1-ml injections on days 7 and 21. The most economical regimen with nproven efficacy consists of intradermal injections of 0.1 ml given at eight nsites (deltoids, suprascapular area, abdomen, and thighs) on day 0; four sites non day 7; and single sites on days 28 and 90.
Tissue culture nvaccines cause mild local symptoms in about 15 percent ofvaccinees, but nintradermal injections cause local irritation in 35 percent. Transient systemic nsymptoms such as headache, fever, and a flulike illness occur in approximately n7 percent of vaccinees. In the United States, 10 percent of booster injections nhave been associated with mild immune complex disease 3 to 13 days later.
Passive Immunization
Hyperimmune equine antirabies serum (EARS) has proved to be effective ineutralizing rabies virus during the first week after initial vaccination, nbefore endogenous neutralizing antibody has appeared. This has beedemonstrated in a number of natural experiments when rabid wolves attacked ngroups of people in remote areas of Iran, USSR, and China. The dose is 40 IU nper kilogram of body weight. Intradermal or other test doses do not reliably npredict serum reactions and should not be used. The incidence of serum nreactions to refined preparations of equine antirabies globulin is less than 5 npercent. Human rabies immune globulin (HRIG) has now replaced EARS in all ncountries that can produce it or afford to import it. The dose is 20 IU per nkilogram of body weight. Hyperimmune serum should be given at the same time as nthe first dose of vaccine but at a different site. Approximately half the dose nis infiltrated around the bite wound (unless it is on a digit) and the rest is ngiven IM, preferably not in the gluteal region since absorption from adipose ntissue might be delayed. Passive immunization may cause partial suppression of nthe response to vaccines, so the recommended dose should not be exceeded.
TETANUS
Definition
Tetanus is a disease of the nervous system characterized by persistent ntonic spasm, with violent brief exacerbations. The spasm almost always ncommences in the muscles of the neck and jaw. causing closure of the jaws (trismus, nlockjaw) and involves the muscles of trunk more than those of the limbs. It nis always acute in onset, and a very large proportion of those affected die.
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History
Nicolaier isolated a strychnine-like toxin from anaerobic soil bacteria nin 1884; 6 years later. Behring and Kitasato described active immunization with ntetanus toxoid. This latter discovery should have reduced tetanus to a nhistorical curiosity, but we still fail to fulfill this promise.
Epidemiology
The global incidence of tetanus is thought to be about one million cases nannually, or about 18 per 100,000 population. The U.S. Centers for Disease nControl and Prevention (CDC) receive reports of about 70 domestic cases per nyear; this represents underreporting of about 60 %. Most reported cases are ipatients over the age of 60: this is one of several indicators that waning nimmunity is an important risk factor. This may be a particularly serious nproblem in older women. In developing countries, mortality rates are as high as n28 per 100,000.
Neonatal ntetanus accounts for about half of the tetanus deaths in developing nations. Ia study of neonatal mortality in Bangladesh 112 of 330 deaths were attributed nto tetanus. Up to one-third of neonatal tetanus cases are in children born to nmothers of a previously afflicted child, highlighting failure to immunize as a nmajor cause of tetanus. Immunization programs clearly decrease neonatal tetanus ndeaths.
Acute injuries naccount for about 70 % of cases, evenly divided between punctures and nlacerations. Other identifiable conditions are noted in 23 %, leaving about 7 % nof cases without an apparent source. Other studies cite rates of cryptogenic ntetanus as high as 23 %.
Etiology
Clostridium tetani is an obligate nanaerobic bacillus that is gram-positive in fresh cultures but that may have nvariable staining in older cultures or tissue samples (Fig.13). During growth, nthe bacilli possess abundant flagellae and are sluggishly motile. Two toxins, ntetanospasmin (commonly called tetanus toxin) and tetanolysin, are produced nduring this phase. Tetanospasmin is encoded on a plasmid, which is present iall toxigenic strains. Tetanolysin is of uncertain importance in the npathogenesis of tetanus. Mature organisms lose their flagellae and develop a terminal nspore, coming to resemble a squash racquet. The spores are extremely stable ithe environment, retaining the ability to germinate and cause disease nindefinitely. They withstand exposure to ethanol, phenol, or formalin, but cabe rendered noninfectious by iodine, glutaraldehyde. hydrogen peroxide, or nautoclaving at 121°C and 103 kPa for 15 minutes. Growth in culture is optimal nat 37°C under strictly anaerobic conditions, but culture results are of no ndiagnostic value. Antibiotic sensitivity is discussed below.
Fig.13. Clostridium ntetani
Pathogenesis
Tetanospasmin is synthesized as a single 151-kD chain that is cleaved nextracellularly by a bacterial protease into a 100-kD heavy chain and a 50-kD nlight chain (fragment A), which remain connected by a disulfide bridge. The nheavy chain can be further divided into fragments В and С by pepsin. The heavy nchain appears to mediate binding to cell surface receptors and transport proteins, nwhereas the light chain produces the presynaptic inhibition of transmitter nrelease, which produces clinical tetanus. The nature of the receptor to which ntetanospasmin binds, previously thought to be a ganglioside, remains debated. nThe toxin enters the nervous system primarily via the presynaptic terminals of nlower motor neurons, where it can produce local failure of neuromuscular ntransmission. Tetanospasmin appears to act by selective cleavage of a proteicomponent of synaptic vesicles, synaptobrevin II. It then exploits the nretrograde axonal transport system, and is carried to the cell bodies of these nneurons in the brain stem and spinal cord, where it expresses its major npathogenic action.
Once the toxienters the central nervous system, it diffuses to the terminals of inhibitory ncells, including both local glycinergic interneurons and descending GABAergic nneurons from the brain stem. By preventing transmitter release from these ncells, tetanospasmin leaves the motor neurons without inhibition. This produces nmuscular rigidity by raising the resting firing rate of motor neurons, and also ngenerates spasms by failing to limit reflex responses to afferent stimuli. nExcitatory transmitter release in the spinal cord can also be impaired, but the ntoxin appears to have greater affinity for the inhibitory systems. The nautonomic nervous system is affected as well: this is predominantly manifested nas a hypersympathetic state induced by failure to inhibit adrenal release of ncatecholamines.
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Clinical manifestations
Tetanus is classically divided into four clinical types: generalized, nlocalized, cephalic, and neonatal. These are valuable diagnostic and prognostic ndistinctions, but reflect host factors and the site of inoculation rather thadifferences in toxin action. Terms describing the initial stages of tetanus ninclude the incubation period (time from inoculation to the first symptom) and nthe period of onset (time from the first symptom to the generalized spasm). The nshorter these periods, the worse the prognosis. Various rating nscales are available. Certain portals of entry (e.g., compound fractures) are nassociated with poorer prognoses. Tetanus may be particularly severe inarcotic addicts, for unknown reasons.
Generalized tetanus is the most commonly recognized form, and oftebegins with trismus (“lockjaw”, masseter rigidity)(Fig.14) and a nrisus sardonicus (increased tone in the orbicularis oris)(Fig.15). Abdominal nrigidity may also be present. The generalized spasm resembles decorticate nposturing, and consists of opisthotonic posturing with flexion of the arms and nextension of the legs. The patient does not lose consciousness, and experiences nsevere pain during each spasm, which are often triggered by sensory stimuli. nDuring the spasm, the upper airway can be obstructed, or the diaphragm may nparticipate in the general muscular contraction. Either of these compromise nrespiration, and even the first such spasm may be fatal. In the modern era of nintensive care, however, the respiratory problems are easily managed, and nautonomic dysfunction, usually occurring after several days of symptoms, has nemerged as the leading cause of death.
Fig.14. nExamination of chewing muscles reflex
The illness can progress for about 2 weeks, reflecting nthe time required to complete the transport of toxin, which is already nintra-axonal when antitoxin treatment is given. The severity of illness may be ndecreased by partial immunity. Recovery takes an additional month, and is ncomplete unless complications supervene. Lower motor neuron dysfunction may not nbe apparent until spasms remit, and recovery from this deficit ieuromuscular ntransmission may take additional weeks. Recurrent tetanus may occur if the patient ndoes not receive active immunization, because the amount of toxin produced is ninadequate to induce immunity.
Fig.15. nRisus sardonicus
Localized tetanus involves rigidity of the muscles associated with the nsite of spore inoculation. This may be mild and persistent, and often resolves nspontaneously. Lower motor neuron dysfunction (weakness and diminished muscle ntone) is often present in the most involved muscle. This chronic form of the ndisease probably reflects partial immunity to tetanospasmin. However, nlocalized tetanus is more commonly a prodrome of generalized tetanus, which noccurs when enough toxin gains access to the central nervous system.
Cephalic tetanus is a special form of localized disease affecting the ncranial nerve musculature. Although earlier reports linked cephalic tetanus to na poor prognosis, more recent studies have revealed many milder cases. A lower nmotor neuron lesion, frequently producing facial nerve weakness, if ofteapparent. Extraocular muscle involvement is occasionally noted.
Neonatal tetanus follows infection of the umbilical stump, most commonly ndue to a failure of aseptic technique where mothers are inadequately immunized. nCultural practices may also contribute. The condition usually presents with ngeneralized weakness and failure to nurse; rigidity and spasms occur later. The nmortality rate exceeds 90%, and developmental delays are common among nsurvivors. Poor prognostic factors include age less than 10 days, symptoms for nfewer than 5 days before presentation to hospital, and the presence of risus nsardonicus, fever, opistotonus (Fig.16).
Fig.16. nOpistotonus iew born
Diagnosis
Tetanus is diagnosed by clinical observation, and has a limited ndifferential diagnosis. Laboratory testing cannot confirm or exclude the ncondition, and is primarily useful for excluding intoxications that may mimic ntetanus. Electromyographic studies are occasionally useful in questionable cases. nSuch testing becomes more important wheo portal of entry is apparent. nAntitetanus antibodies are undetectable in most tetanus patients, but many nreports document the disease in patients with antibody levels above the ncommonly cited “protective” concentration of 0.01 IU/liter. Rare npatients apparently develop antibodies that are not protective.
Attempts to culture C. tetuni from wounds are not useful idiagnosis, because (1) even carefully performed anaerobic cultures are nfrequently negative; (2) a positive culture does not indicate whether nthe organism contains the toxin-producing plasmid; and (3) a positive nculture may be present without disease in patients with adequate immunity.
Strychnine npoisoning, in which glycine is antagonized, is the only condition that truly nmimics tetanus; toxicologic studies of serum and urine should be performed whetetanus is suspected, and tetanus should be considered even if strychnine npoisoning appears likely. Because the initial treatment of tetanus and nstrychnine intoxication are similar, therapy is instituted before the assay nresults are available. Dystonic reactions to neuroleptic drugs or other central ndopamine antagonists may be confused with the neck stiffness of tetanus, but nthe posture of patients with dystonic reactions almost always involves lateral nhead turning, which is rare in tetanus. Treatment with anticholinergic agents n(benztropine or diphenhydramine) is rapidly effective against dystonic nreactions. Dental infections may produce trismus, and should be sought, but do nnot cause the other manifestations of tetanus.
Treatment
The patient with tetanus requires simultaneous attention to several nconcerns. Attention to the airway and to ventilation is paramount at the time nof presentation, but the other aspects of care, especially passive nimmunization, must be pursued as soon as the respiratory system is secure.
Tetanic spasms sometimes demand that the airway be secured before other nlines of therapy are possible. An orotracheal tube can be passed under sedatioand neuromuscular junction blockade; a feeding tube should be placed at the nsame time. Because the endotracheal tube may stimulate spasms, an early ntracheostomy may be beneficial.
Benzodiazepines nhave emerged as the mainstay of symptomatic therapy for tetanus. These drugs nare GАВА agonists, and thereby indirectly antagonize the effect of the toxin. nThey do not restore glycinergic inhibition. The patient should be kept free of nspasms, and may benefit from the amnestic effects of the drugs as well. Diazepam nhas been studied most intensively, but lorazepam or midazolam appear equally neffective. Tetanus patients have unusually high tolerance for the sedating neffect of these agents, and commonly remain alert at doses normally expected to nproduce anesthesia.
Intravenous midazolam (5-15 mg/h or more) is effective and does not ncontain propylene glycol, but must be given as a continuous infusion because of nits brief half-life. Propofol infusion is also effective, but is currently very nexpensive, and the amount necessary to control symptoms may exceed the npatient’s tolerance of the lipid vehicle. When the symptoms of tetanus subside, nthese agents must be tapered over at least 2 weeks to prevent withdrawal. nIntrathecal baclofen is also effective in controlling tetanus, but has no clear nadvantage over benzodiazepines. Neuroleptic agents and barbiturates, previously nused for tetanus, are inferior for this indication and should not be used.
Most tetanus patients will still have the portal of entry apparent whethey present. If the wound itself requires surgical attention may be performed nafter spasms are controlled. However, the course of tetanus is not affected by nwound de-bridement.
Passive immunization with human tetanus immunoglobulin (HTIG) shortens nthe course of tetanus and may lessen its severity. A dose of 500 units appears nas effective as larger doses. There is no apparent advantage to nintrathecal HTIG administration. Intrathecal HTIG has also been showineffective ieonatal tetanus. Pooled intravenous immunoglobulin has beeproposed as an alternative to HTIG. Active immunization must also be initiated.
The role of antimicrobial therapy in tetanus remains debated. The ivitro susceptibilities of C. tetani include metronidazole, penicillins, ncephalosporins, imipenem. macrolides, and tetracy-cline. A study comparing oral nmetronidazole to intramuscular penicillin showed better survival, shorter nhospitalization, and less progression of disease in the metronidazole group. nThis may reflect a true advantage of metronidazole over penicillin, but it more nlikely corresponds to a negative effect of penicillin, a known GABA antagonist. nTopical antibiotic application to the umbilical stump appears to reduce the nrisk of neonatal tetanus.
Nutritional support should be started as soon as the patient is stable. nThe volume of enteral feeding needed to meet the exceptionally high caloric and nprotein requirements of these patients may exceed the capacity of the ngastrointestinal system.
The mortality nrate in mild and moderate tetanus is presently about 6 percent; for severe ntetanus, it may reach as high as 60%, even in expert centers. Among adults, age nhas very little effect on mortality, with octogenarians and nonagenarians nfaring as well as middle-aged patients. Tetanus survivors often have serious npsychological problems related to the disease and its treatment that persist nafter recovery, and that may require psychotherapy.
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Prophylaxis
Tetanus is preventable in almost all patients, leading to its descriptioas the “inexcusable disease.” A series of 3 monthly intramuscular injections of nalum-adsorbed tetanus toxoid provides almost complete immunity for at least 5 nyears. Patients less than 7 years of age should receive combined ndiphtheria-tetanus-pertussis vaccine, and other patients combined ndiphtheria-tetanus vaccine. Routine booster injections are indicated every 10 nyears; more frequent administration may increase the risk of a reaction. Some npatients with humoral immune deficiencies may not respond adequately to toxoid ninjection: such patients should receive passive immunization for tetanus-prone ninjuries regardless of the period since the last booster. Most young patients nwith human immunodeficiency virus (HIV) infection appear to retain antitetanus nantibody production if their primary immunization series was completed prior to nacquiring HIV. Vitamin A deficiency interferes with the response to tetanus ntoxoid. A recent report documented tetanus in babies of women immunized with ntoxoid later shown to be devoid of potency; this disconcerting report nunderscores the need for quality control in toxoid production.
Although any wound may be inoculated with tetanus spores. Some types of ninjury are more frequently associated with tetanus and are therefore deemed ntetanus-prone. These include wounds that are contaminated with dirt, saliva, or nfeces; puncture wounds, including unsterile injections; missile injuries; nburns; frostbite; avulsions; and crush injuries. Patients with these wounds who nhave not received adequate active immunization in the past 5 years, or in whom nimmunodeficiency is suspected. should receive passive immunization with HTIG (250-500 nIU, intramuscularly) in addition to active immunization.
Mild reactions to tetanus toxoid (e.g.. local tenderness, edema, nlow-grade fever) are common. More severe reactions are rare; some are actually ndue to hypersensitivity to the preservative thiomersal.
IV. nConvalescent stage: 2-6 weeks
