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June 3, 2024
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Rabies

Tetanus

Pseudotuberculosis

 

Definition

An acute infectious disease of mammals, especially carnivores, characterized by central nervous system wrilation followed by paralysis and death.

 

Historic reference

Rabies in dogs and the importance of saliva in its transmission may have been recognized in Pharaonic times and in China at least seven centuries ago. But it now seems doubtful whether much-quoted passages from the Babylonian pre-Mosaic Eshnunna code (around 2300 ВС) and those attributed to the Greek philosopher Democritus (500-400 BC) referred specifically to rabies Aristotle (322 BC) described rabies in animals but seems to deny that humans could be infected or could die from the disease. Celsus in “De medicina” (1st century AD) described hydrophobia in afflicted humans and recognized that the disease was spread by saliva, although his use of the Latin word “virus” did not imply a specifically infective origin. He discussed local treatment for the wound, including cupping, suction and cauterization, and the immersion of the patient in sea water. Other persistent myths that arose at that time were the idea that surgical excision of a dog’s “tongue worm” (frenulum linguae) would protect it from rabies (as pointless and malicious an operation as that for “tongue tie” in children) and the belief that rabies could be generated spontaneously in dogs. In the sixteenth century, Fracastoro strengthened the concept of rabies as a contagious disease.

 A scientific or experimental approach to rabies was delayed until 1793, when John Hunter published his very important paper, “Observations and heads of enquiry on canine madness”. Hunter suggested that the transmission of rabies should be studied by inoculating saliva from rabid animals and humans into dogs and that attempts should be made to inactivate the “poison” in the saliva. These ideas may have inspired the experiments by Zinke (1804) and Magendie and Breschet (1813). Zinke used a paintbrush to introduce saliva from rabid dogs into incisions made in the skin of dogs, cats, rabbits, and chickens, which duly developed signs of rabies. In the same year Magendie and Breschet infected dogs with saliva from human patients with hydrophobia.

Galtier (1879) was responsible for an important technical advance. He found that rabbits could be infected with rabies and were far more convenient experimental animals than dogs. Pasteur adopted the use of rabbits in his studies of rabies beginning in 1880. He was the first to recognize that the major site of infection was the CNS. “Street virus” from a naturally infected dog was passaged through a series of rabbits to produce “fixed virus” with a consistent minimum incubation period of 6 or 7 days. Attenuation of the fixed virus was achieved by desiccation of rabbit spinal cord for up to 14 days. Pasteur was able to protect dogs from challenge by immunizing them with the desiccated material, and in 1885 he used his vaccine for the first time in Joseph Meister, a boy severely bitten by a rabid dog. In 1891 passive immunization, using whole blood from vaccinated dogs and humans, was studied by Babes and Cerchez. Negri (1903) described his diagnostic inclusion body, which allowed the laboratory diagnosis of rabies. The introduction of the more specific and sensitive immunofluorescence method by Goldwasser and Kissling in 1958 has now largely replaced the Seller’s stain for Negri bodies. The nature of the infective agent was further elucidated by Remlinger (1903), who showed that it would pass through a Berkefeld filter. It was not until 1936 that the size of the virus was established by reliable ultrafiltration studies (Galloway and Elford), and it was first seen as a bullet-shaped particle by electron microscopy in 1962 (Almeida and colleagues).

Improvements in Pasteur’s vaccine were achieved by Semple and Fermi, who killed the virus rather than attenuated it, and by Fuenzalida and Palacios, who developed a suckling mouse brain vaccine which carried a lower risk of neuroparalytic complications.

Successful growth of rabies virus in tissue culture was achieved by Kissling in 1958, leading to the development of human diploid cell strain vaccine by Wiktor and his colleagues in 1964 and of other safe and highly potent tissue culture vaccines. The use of passive immunization with equine hyperimmune serum has been vindicated by the famous natural experiment following an attack by a rabid wolf on 29 people in Iran in 1954.

 

Etiology

The rhabdoviruses (Greek rhabdos—rod) are a group of about 140 RNA viruses of plants, arthropods, fish, reptiles, birds, and mammals. Rabies and its five related viruses constitute the genus Lyssavirus. The rabies virion is approximately 180 x 80 nm (Fig.1). The nucleocapsid consists of a single negative strand of helical RNA associated with three structural proteins: a nucleoprotein (N), a phosphoprotein (NS), and an RNA-dependent RNA polymerase (L). This is surrounded by a lipid-containing envelope including a matrix protein (M) and a glycoprotein (G) which forms spiky protuberances on the shaft and rounded end of the virion. This surface glycoprotein is the only molecule that induces neutralizing antibody and was therefore considered the only important constituent of vaccines. However, recent work has shown that the nucleoprotein is also capable of inducing protective immunity, although not by neutralization.

Fig.1. Agent of rabies (RNA-containing virus)

 

Rabies virus is rapidly inactivated by heat: at 56 °С the half-life is less than 1 minute and, experimentally, the titer decreased by 105 infectious doses within 15 minutes. At 37 °С the half-life is prolonged to several hours in moist conditions. The lipid coat of the virion renders it vulnerable to disruption by detergents and simple 1 percent soap solution. Forty-five percent ethanol, iodine solutions (with 1 in 10,000 available iodine), 3 percent sodium hydroxide, 1 in 1,000 ben-zaikonium chloride, chloroform, and acetone all inactivate the virus, but mereurochrome is ineffective.

Repeated intracerebral passage in animals of “street virus” from naturally infected animals results in a “fixed virus”of uniformly shortened incubation period and reduced pathogenicity which is used in vaccine production. Strains of rabies virus can now be identified using panels of monoclonal antibodies. Antigenic patterns show differences between vector species, for example distinguishing virus from North American insectivorous bats from fox, raccoon, and skunk strains occurring in the same area.

 Wild or domestic animals occasionally carry the bat strains, indicating the source of their infection. The vector of rabies transmission to nonenzootic species can therefore be identified. Culture of virus is not essential, as monoclonal antibody typing is performed on the abundant nucleoprotein antigen in fixed brain impression smears. Some strains of rabies virus produce distinctive clinical manifestations, such as the sub-acute paralytic form of rabies in dogs in West Africa and paralytic rabies transmitted to bovines and humans by vampire bats in Latin America and the Caribbean.

Rabies virus can be isolated and cultivated in a number of laboratory animals and continuous cell lines. The conventional method, by intracerebral inoculation of suckling mice, is sensitive but takes 2 to 3 weeks. Many laboratories are now using mouse neuroblastoma cell cultures in which the virus can be identified in 3 to 4 days.

 

 

Epidemiology

Rabies is enzootic in mammal populations in most countries. Rabies-free countries include the British Isles, Norway, Sweden, Iceland, Mediterranean and Atlantic islands, Australia, New Guinea, Borneo, New Zealand, Malaysia, Singapore, Japan, Taiwan, and Antarctica. Rabies is spread among animals by bites, ingestion of infected prey, inhalation of aerosols (in heavily populated bat caves), and communal browsing on thorny bushes (kudu antelopes— Tragelaphus strepsiceros in Namibia). Important reservoirs of sylvatic rabies include skunks, foxes, raccoons, and insectivorous bats in North America; foxes in the Arctic; mongooses in Granada and Puerto Rico; vampire bats in Trinidad, Mexico, and Central and South America; wolves, jackals, and small carnivores in Africa and Asia; and foxes, wolves, raccoon dogs, and insectivorous bats in Europe. Rodents are unlikely to be important. Transmission is mainly by species such as foxes and bats in Europe and foxes, skunks, raccoons, and bats in North America. A separate strain of rabies virus may be peculiar to each mammalian host species.

Domestic dogs, and to a much lesser extent cats, are the main reservoir of urban rabies, which is responsible for more than 90 % of human cases worldwide. However, in countries such as the United States, where control of rabies in domestic animals has been very successful, wild animals such as skunks and raccoons now constitute the main threat for spread to humans.

The three species of vampire bat (Desmodontinae) are found in Southern Texas, Mexico, Central America, South America as far south as northern Argentina and northern Chile, and some Caribbean islands, such as Trinidad and Margarita Island. They feed on the blood of large mammals, particularly cattle, transmitting in the process a form of paralytic rabies known as “derriengue”, which causes the loss of between 1 and 2 million head of cattle each year in Latin America. Vampire bats also transmit Venezuelan equine encephalomyelitis virus and equine and bovine trypanosomiasis. Human cases of paralytic rabies transmitted by vampire bats have been reported from Trinidad and Latin America. A few cases of human rabies have also been attributed to bites by insectivorous and frugivorous bats in North America, India, and Europe. There have been three of bat-transmitted serotype 4 (Duvenhage) virus infection in South Africa, Finland, and Russia.

Although antibody induced by European tissue culture rabies vaccines and commercial immune globulieutralize European bat Lyssavirus, results of challenge experiments in mice vary, but some show poor protection by virus strains used in vaccines available in Europe.

It is possible that infection with rabies-related viruses, such as Kotonkan virus in domestic herbivores in Nigeria and Mokola virus in cats and dogs in Zimbabwe, may confer some protection against rabies.

Incidence of Human Rabies

The true global incidence of human rabies has been obscured by underreporting. Recently, a figure of 50.000 human deaths per year in India alone was suggested. Other countries reporting a high incidence of human rabies include Pakistan, Bangladesh, Sri Lanka, the Philippines, Thailand, Indonesia, Brazil, Colombia, El Salvador, Peru, Ecuador, Mexico, and China. In the United States there were more than 25 human deaths per year in the 1940s, but since 1960 the maximum annual incidence has been 5 (in 1979), and the total number of cases was 50 in 28 years, of which 17 were infected outside the United States. In continental Europe few rabies deaths are now reported.

 

Transmission

Intact skin is an adequate barrier to the infection, but broken skin and intact mucosa can admit the virus. Human infections usually result from inoculation of virus-laden saliva through the skin by the bite of a rabid dog or other mammal. Scratches, abrasions, and other wounds can be contaminated with infected saliva. The following are very unusual routes of human infection:

1. Inhalation. This has been reported in caves densely populated with insectivorous bats, which can create an aerosol of rabies virus from infected nasal secretions and possibly urine. In the United States there have been two laboratory accidents involving the inhalation of fixed virus during vaccine preparation.

2. Vaccine-induced rabies (rage de laboratoire). In the worst incident, 18 people developed paralytic rabies in Fortaleza, Brazil, in 1960. The incubation period was 4 to 13 days after inoculation of a vaccine in which the virus had not been inactivated.

3. Comeal transplant grafts. Seven cases have been reported in France, the United States, Thailand, Morocco, and India in which infected comeae were transplanted from donors who had died of unsuspected rabies. Six of the recipients developed rabies and died.

4. Transplacental infection. This has been observed in animals but until recently had not been reported in humans, whereas a number of women who developed rabies encephalitis in late pregnancy were delivered of healthy babies. Transmission of rabies by breast milk is well documented in animals and has been suspected in at least one human case.

Animals can be infected through the gastrointestinal tract (per os and per rectum). In the previrologic era, there were claims that eating infected meat and sexual intercourse could transmit rabies to humans, but these routes remain unproven.

Pathogenesis

In experimental animals, injected rabies virus replicates locally in striated muscle but is soon detectable at neuromuscular junctions and neuromuscular and neurotendinal spindles. Direct invasion of nerve cells may also occur without prior infection of muscle. Various possible cell surface receptors for attachment of the rabies virus have been suggested, such as phosphatidylserine, carbohydrates, phospholipids, and sialylated gangliosides. At neuromuscular junctions and in the CNS, the postsynaptic nicotinic acetylcholine receptor is an important attachment site for the virus. Binding at these sites is competitive with cholinergic ligands, including the snake venom neurotoxin, alphabungarotoxin, which shows sequence homology with rabies virus glycoprotein.

Once inside peripheral nerves, the virus is carried centripetally by the flow of axoplasm to the dorsal root ganglia where there is further replication, explaining perhaps the characteristic prodromal symptom of paresthesia at the site of the inoculation. Spread along peripheral nerves can be blocked experimentally by local anesthetics, metabolic inhibitors, and section of the nerves. Spread is rapid through the spinal cord and brain, and there is massive viral replication on membranes of neurons and glial cells and direct transmission of virus from neuron to neuron via the synapses. Virus also exists free and spreads within extracellular spaces such as the CSF. In the early stages of the encephalomyelitis, there is selective infection of certaieuronal populations. Finally, there is a phase of passive centrifugal spread of virus from the nervous system in the axoplasm of many efferent nerves, including those of the autonomic nervous system.

 Virus has been found in many tissues including skeletal and cardiac muscle, intestine, kidney, liver, pancreas, and brown fat. Extraneural viral replication has been observed in salivary glands, brown fat, and cornea. Virus is shed from salivary and lacrimal glands, taste buds, respiratory tract, and rarely in urine and milk. Viremia has rarely been detected in animals and is not thought to be involved in pathogenesis or spread.

 

Response to Vaccination

Antibody induced by rabies vaccines has been measured by a variety of methods including the immunofluorescent antibody test, mouse neutralization, rapid immunofluorescent focus inhibition (a tissue culture neutralization test), enzyme immunoassays, and hemagglutination inhibition. The host’s immune system is stimulated by a vast array of antigenic determinants on viral proteins and nonviral vaccine constituents. Each serologic test detects a different selection of these antibodies, and so the results of one cannot be compared with those of another. Neutralization tests are the best available indicator of protection from rabies deaths, but the correlation is far from perfect.

Neutralizing antibody is directed solely against the glycoprotein spikes on the viral coat, and so glycoprotein extracts have been used as subunit vaccines. The nueleoprotein molecule was considered irrelevant in the induction of protective immunity until work on influenza virus showed that immunization with purified nueleoprotein was beneficial in mice, not through prevention of infection but by aiding recovery. Dietzschold’s group have shown that rabies ribonucleoprotein can induce protective immunity under some experimental conditions that may involve both humoral and cellular arms of immunity. The use of selected, broadly cross-reacting nueleoprotein epitopes in the construction of future vaccines is being investigated.

The amount of antibody produced by vaccine is partly determined by the host. Kuwert observed that in a population of vaccines, 80 % produced high antibody levels more rapidly than the 20 % who had poor, relatively delayed antibody induction. In mice, responsiveness to vaccine was genetically determined. Tissue typing in humans shows some minor differences between the groups of responders.

Vaccine-induced neutralizing antibody is not detectable for 7 to 10 days after starting primary vaccination. During that time passive protection can be provided by specific human or equine immune globulin.

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Clinical Features of Rabies Animals

Judged by the median lethal dose of street rabies virus, there is a wide range of susceptibility to rabies infection among mammals and birds. Foxes are the most susceptible, cats and dogs have intermediate susceptibility, and opossums are relatively resistant.

In domestic dogs, the incubation period ranges from 5 days to 14 months. It is less than 4 months in 80 percent of cases; hence the compulsory quarantine of 6 months imposed on dogs imported to the United Kingdom. Prodromal symptoms include change in temperament, fever, and, as in many humans, intense irritation at the site of the infecting bite. The familiar picture of a “mad dog” with furious rabies is seen in only 25 % of infected animals. The more common paralytic or dumb presentation is less dramatic and more dangerous, as it may not be recognized. The clinical features of furious canine rabies include irritability, convulsions, dysphagia, laryngeal paralysis causing an altered bark, hyper-salivation, and extreme restlessness causing the animal to wander miles from home. Dogs with furious rabies attack inanimate objects, often breaking their teeth and injuring their mouths in the process. Before the discovery of Negri bodies, canine rabies was confirmed by examining the stomach contents, which often consisted of earth and stones resulting from pica. Dogs with paralytic rabies may be reclusive and exhibit paralysis of the jaw, neck, and hind limbs, and dysphagia and drooling of saliva, which may make the owner suspect and attempt to remove a bone imagined to be stuck in the throat. Virus may be excreted in the saliva as early as 3 days before the appearance of symptoms, and the animal usually dies within the next 7 days. This is the basis for the traditional 10-day observation period for dogs that have bitten humans.

 

Clinical features of rabies in humans

The incubation period is between 20 and 90 days and more than two-thirds of cases, with an extreme range of 4 days to more than 20 years. In some animals, latent infections can be reactivated by corticosteroids and stress, providing a possible explanation for the rare authentic reports of very long incubation periods in humans. Facial and severe multiple bites, transmission by corneal transplant, and accidental inoculation of live virus (rage de laboratoire) are associated with relatively short incubation periods. A few days of prodromal symptoms may precede the development of definite signs of rabies encephalomyelitis. These may consist of fever, changes of mood, and nonspecific “flulike” symptoms, but in more than one-third of cases itching, neuritic pain, or paresthesia at the site of the healed bite wound suggests impending rabies. The existence of two distinct clinical patterns of rabies, furious (agitated) and paralytic (“dumb”, “rage mue” or “rage muette”), depends on whether the brain or spinal cord is predominantly infected and may reflect differences in the infecting strain of rabies virus or in the host’s immune response.

Furious rabies, the more common presentation in humans except those infected by vampire bats, is characterized by hydrophobia, aerophobia, and episodic generalized arousal interspersed with lucid intervals of normal cerebration. Hydrophobia is a reflex series of forceful jerky inspiratory muscle spasms provoked by attempts to drink water and associated with an inexplicable terror. A draft of air on the skin produces a similar reflex response, “aerophobia”. Initially, the spasms affect the diaphragm, sternomastoids, and other accessory muscles of inspiration, but a generalized extension response may be produced ending in opisthotonos and generalized convulsions with cardiac or respiratory arrest. Without supportive care, about one-third of patients with furious rabies die during a hydrophobic spasm in the first few days of their illness. There is hyperesthesia and periods of generalized excitation during which the patient becomes hallucinated, wild, and sometimes aggressive. These grotesque symptoms are explained by a selective encephalitis involving the brain stem and limbic system. In rabies, unlike most other encephalitides, patients may remain intermittently conscious and rational. Hypersalivation, lacrimation, sweating, and fluctuating blood pressure and body temperature result from disturbances of hypothalamic or autonomic nervous system function (Fig.2). Conventional neurologic examination may fail to disclose any abnormality unless a hydrophobic spasm is observed. Physical findings include meningism, cranial nerve and upper motor neuron lesions, muscle fasciculation, and involuntary movements. Increased libido, priapism, and frequent spontaneous orgasms may be the presenting symptom in some patients, suggesting involvement of the amygdaloid nuclei. Furious rabies naturally progresses to coma and death within a week, but some patients have been kept alive for several months in intensive care units.

 

Fig.2. Clinical features of rabies

 

Paralytic rabies is apparently much less common than the furious form in humans but is frequently undiagnosed. All reported cases of rabies transmitted by vampire bats in Latin America and the Caribbean are of this type. The paralytic form of rabies was also seen in patients with postvaccinal rabies and in the two patients who inhaled fixed virus. It seems more likely to develop in patients who have received antirabies vaccine. After the prodromal symptoms (see above), paralysis, fasciculation, pain, and paresthesia start in the bitten limb and ascend symmetrically or asymmetrically. There is progression to paraplegia with sphincter involvement, quadriparesis, and finally paralysis ofbulbar and respiratory muscles (Fig.3). Hydrophobia is usually absent. Patients with paralytic rabies may survive for several weeks even without intensive care.

Fig.3. Paralytic rabies

Differential diagnosis

In the rabies endemic area, the diagnosis is easy in a patient with hydrophobic spasms who remembers being bitten by a dog in the previous few months.

The spasms of pharyngeal tetanus may resemble hydrophobia, and this disease can also complicate an animal bite. Severe tetanus is distinguished by its shorter incubation period, the presence oftrismus, the persistence of muscular rigidity between spasms, the absence of pleocytosis, and a better prognosis. The rare encephalopathy complicating serum sickness and anaphylactic reactions to Hymenoptera venoms are said to resemble rabies encephalitis. Rabies phobia is an hysterical response to the fear of rabies. It differs from true rabies in its shorter incubation period, often a few hours after the bite, by the emphasis on aggressive and dramatic symptoms, and by its excellent prognosis. Few hysterics could accurately simulate a hydrophobic spasm.

Paralytic rabies should be considered in patients with rapidly ascending flaccid paralysis, suspected Guillain-Barre syndrome, and transverse myelitis. In tropical developing countries that are still dependent on Semple-type and suckling mouse brain rabies vaccines, the most important differential diagnosis is postvaccinal encephalomyelitis. This usually develops within 2 weeks of the first dose of vaccine but has no clinical or laboratory features that reliably distinguish it from rabies while the patient is still alive, except for the absence of demonstrable rabies antigen in skin biopsies (see below). In poliomyelitis there are no sensory abnormalities. Herpes simiae (B virus) encephalomyelitis, which is transmitted by monkey bites, has a shorter incubation period than rabies (3 to 4 days). Vesicles may be found in the monkey’s mouth and at the site of the bite. The diagnosis can be confirmed virologically and the patient treated with acyclovir.

 

Pathology

Rabies is an acute nonsuppurative meningoencephalomyelitis. By the time the patient dies, ganglion cell degeneration, perineural and perivascular mononuclear cell infiltration, neuronophagia, and glial nodules may be widespread throughout the brain, spinal cord, and peripheral nerves. However, considering the clinical severity, changes are often surprisingly mild. Inflammatory changes are most marked in the midbrain and medulla in furious rabies and in the spinal cord in paralytic rabies. The diagnostic intracytoplasmic inclusion bodies (Negri bodies)(Fig.4) contain viral ribonucleoprotein and probably fragments of cellular organelles such as ribosomes, giving the essential internal structure. They are found in up to 80 % of human cases and are most numerous in the pyramidal cells of Ammon’s horn in the hippocampus, in cerebellar Purkinje cells, and in the medulla and ganglia. Apart from these inclusion bodies there are no histologic features that distinguish rabies from poliomyelitis or other forms of viral encephalitis. The brain stem, limbic system, and hypothalamus appear to be most severely affected. A spongiform encephalopathy has been demonstrated in skunks and foxes. It probably represents an immunologic effect of infection. Extraneural changes include focal degeneration of salivary and lacrimal glands, pancreas, adrenal medulla, and lymph nodes. An interstitial myocarditis with round cell infiltration has been described. This may be associated with cardiac arrhythmias. The brain of a fatal human case of Mokola virus encephalitis showed perivascular cuffing with lymphocytes and lymphoblastoid cells. Neurons contain large numbers of homogeneous cytoplasmic inclusion bodies, which were quite different in size and appearance from Negri bodies.

Fig.4. Negri bodies (intracytoplasmic inclusion bodies)

 

Laboratory diagnosis

In the mammal responsible/or the bite, rabies can be confirmed within a few hours by immunofluorescence of acetone-fixed brain or spinal cord impression smears, a technique that has replaced the classic Seller’s stain for Negri bodies which is notoriously difficult to interpret (Fig.5). A simple ELISA test can be used if fluorescence microscopy is not available, and a sensitive avidin-biotin peroxidase method has recently been developed for use with formalin-fixed histologic sections.

 

Fig.5. Negri bodies ieurons cytoplasm

 

Rapid examination of CNS tissue in animals suspected of being rabid is now preferred to observing them in captivity for 10 days. In patients, rabies can be confirmed during life by immunofluorescence of skin, and brain biopsies, but the comeal impression smear technique is falsely negative too often to be useful. Early in the illness, rabies virus can be isolated from saliva, brain, CSF, and even spun urine but not blood. Virus isolation ieuroblastoma cell cultures can produce a result in 2 to 4 days instead of the 2 to 3 weeks required for the traditional intracerebral inoculation of mice. In patients who have not been vaccinated or given rabies immune globulin, rabies antibody in serum and especially in the CSF is diagnostic of rabies encephalitis. Rabies-neutralizing antibody leaks across the blood-CSF barrier in patients with postvaccinal encephalomyelitis, but a very high filer suggests a diagnosis of rabies. The only reliable method for distinguishing rabies from postvaccinal encephalomyelitis during life is by the immunofluorescence of skin biopsies. In rabies, lymphocyte pleocytosis rarely exceeds a few hundred cells per microliter. A neutrophil leukocytosis is commonly found in the blood.

Treatment of Human Rabies Encephalomyelitis

Human rabies remains virtually incurable. Intensive care offers the only hope of prolonging life and, perhaps in a very few cases of paralytic rabies or infection with attenuated virus, of survival. Problems arising during intensive care include a variety of respiratory complications such as aspiration pneumonia, pneumothorax, and respiratory arrest; cardiac arrhythmias, hypertension, pulmonary edema, and effects of myocarditis including congestive cardiac failure; generalized convulsions, cerebral edema, inappropriate secretion of an-tidiuretic hormone or diabetes insipidus, polyneuropathy, hyper- and hypothermia; and hematemesis associated with ulceration or tears in the mucosa of the upper gastrointestinal tract. Heavy sedation and analgesia should be given to relieve the agonizing symptoms. Immunosuppressant agents, including corticosleroids, rabies hyperimmune serum (which may have accelerated death), antiviral agents such as ribavirin, and alpha-interferon have not proved useful. Studies of intrathecal live attenuated vaccines in animals suggest the possibility of applying the treatment in human cases.

 

Prevention and Control of Rabies Pre-exposure Prophylaxis

In rabies endemic areas, those at high risk of exposure to rabid animals should be given pre-exposure vaccination. These include veterinarians, health care personnel, laboratory workers, and dog catchers. In areas where animal rabies is highly prevalent, especially among domestic dogs, there may even be a case for including rabies vaccine in the expanded programs of immunization for children. In nonendemic areas those who come into contact with imported mammals in quarantine, who work with rabies virus in laboratories, or who intend to travel to rabies endemic areas should be vaccinated.

Travelers at particular risk of exposure to rabies are zoologists and other field workers, foresters, cave explorers, and those whose work involves walking and cycling in urban and rural areas of India, Southeast Asia, and Latin America.

Only tissue culture vaccines are safe enough to use for pre-exposure prophylaxis. Three doses are given on days 0, 7, and 28, either ЇМ into the deltoid (not into the gluteal region) or 0.1 ml intradennally. A single booster given 1 year later produced sustained immunity for 5 to 8 years.

Alternatively, a booster dose can be given every 2 years if the neutralizing antibody level falls and continued protection is needed. Those working with rabies virus in laboratories should have their antibody titer checked every 6 months as a guide to the need for further booster injections. A failure of pre-exposure vaccination by the intradermal route was found in American Peace Corps workers who were immunized in the tropics while taking chloroquine for malaria prophylaxis. This reduces the neutralizing antibody response, but other unidentified factors contribute to the immunosuppression. The intradermal course should therefore be completed before starting chloroquine, or the vaccine should be given IM.

Postexposure prophylaxis

Cleaning the wound as soon as possible after a bite or other contact with a rabid animal is essential first aid and is particularly effective for superficial wounds. The wound should be scrubbed with soap or detergent and generously rinsed under a running tap for at least 5 minutes. Foreign material and dead tissue should be removed under anesthesia. The wound should be irrigated with a viricidal agent such as soap solution, povidone iodine, 0.1 % aqueous iodine, or 40 to 70 % alcohol. Quaternary ammonium compounds, hydrogen peroxide, and mercurochrome are not recommended. Suturing may inoculate virus deeper into the tissues and so should be avoided or delayed when possible. The risk of other viral, bacterial, fungal, and protozoal infections must be considered after bites by animals and humans. Pathogens commonly associated with mammal bites include Pasteurella multocida, Clostridiwn tetani, orf virus, cat scratch disease bacillus, Leptospira species. Spirillum minor, Streptobacillus moniliformis, and the fungus Blastomyces dermatitidis. Tetanus prophylaxis and antimicrobials may be required. Most of the bacteria are sensitive to benzyl penicillin, amoxicillin, or cefoxitin.

Nervous tissue vaccines, initially introduced by Pasteur in the nineteenth century and developed by Semple, Fermi, Hempt, and Fuenzalida, are still the most widely used throughout the tropical rabies endemic area. In India, about 500,000 postexposure courses of Semple vaccine are given each year. Many of these vaccines have to be given in protracted courses. Their potency is variable, and they may be associated with severe neuroparalytic reactions. In Western countries, tissue culture vaccines are used almost exclusively.

Several tissue culture vaccines are now in large-scale production, including the long established human diploid cell strain vaccine (HDCSV) (Institut Merieux), the more recent and less expensive purified vero cell rabies vaccine (PVRV) (Institut Merieux), purified chicken embryo cell vaccine (PCEC) (Behringwerke), and a primary hamster kidney cell vaccine produced in the Peoples Republic of China. The recommended course of HDCSV and PCEC is five 1-ml injections, and for PVRV the same number of 0.5-ml injections given IM on days 0, 3, 7, 14, and 30. Vaccine should not be injected into the gluteal region but into the deltoid muscle in adults or into the anterolateral aspect of the thigh in small children.

The initial dose should be doubled and given at several different sites if there has been a delay of more than 48 hours in starting postexposure prophylaxis, if passive immunization (hyperimmune serum) was given 24 hours or more before active immunization, in elderly patients, in those with chronic diseases such as hepatic cirrhosis, in those likely to be immunodeficient, immunosuppressed, or severely malnourished, and if hyperimmune serum is not available.

An abbreviated regimen consists of two 1-ml injections at different sites on day 0, followed by single 1-ml injections on days 7 and 21. The most economical regimen with proven efficacy consists of intradermal injections of 0.1 ml given at eight sites (deltoids, suprascapular area, abdomen, and thighs) on day 0; four sites on day 7; and single sites on days 28 and 90.

Tissue culture vaccines cause mild local symptoms in about 15 percent ofvaccinees, but intradermal injections cause local irritation in 35 percent. Transient systemic symptoms such as headache, fever, and a flulike illness occur in approximately 7 percent of vaccinees. In the United States, 10 percent of booster injections have been associated with mild immune complex disease 3 to 13 days later.

Passive Immunization

Hyperimmune equine antirabies serum (EARS) has proved to be effective ieutralizing rabies virus during the first week after initial vaccination, before endogenous neutralizing antibody has appeared. This has been demonstrated in a number of natural experiments when rabid wolves attacked groups of people in remote areas of Iran, USSR, and China. The dose is 40 IU per kilogram of body weight. Intradermal or other test doses do not reliably predict serum reactions and should not be used. The incidence of serum reactions to refined preparations of equine antirabies globulin is less than 5 percent. Human rabies immune globulin (HRIG) has now replaced EARS in all countries that can produce it or afford to import it. The dose is 20 IU per kilogram of body weight. Hyperimmune serum should be given at the same time as the first dose of vaccine but at a different site. Approximately half the dose is infiltrated around the bite wound (unless it is on a digit) and the rest is given IM, preferably not in the gluteal region since absorption from adipose tissue might be delayed. Passive immunization may cause partial suppression of the response to vaccines, so the recommended dose should not be exceeded.

 

TETANUS

Definition

Tetanus is a disease of the nervous system characterized by persistent tonic spasm, with violent brief exacerbations. The spasm almost always commences in the muscles of the neck and jaw. causing closure of the jaws (trismus, lockjaw) and involves the muscles of trunk more than those of the limbs. It is always acute in onset, and a very large proportion of those affected die.

 

History

Nicolaier isolated a strychnine-like toxin from anaerobic soil bacteria in 1884; 6 years later. Behring and Kitasato described active immunization with tetanus toxoid. This latter discovery should have reduced tetanus to a historical curiosity, but we still fail to fulfill this promise.

 

Epidemiology

The global incidence of tetanus is thought to be about one million cases annually, or about 18 per 100.000 population. The U.S. Centers for Disease Control and Prevention (CDC) receive reports of about 70 domestic cases per year; this represents underreporting of about 60 %. Most reported cases are in patients over the age of 60: this is one of several indicators that waning immunity is an important risk factor. This may be a particularly serious problem in older women. In developing countries, mortality rates are as high as 28 per 100.000.

Neonatal tetanus accounts for about half of the tetanus deaths in developing nations. In a study of neonatal mortality in Bangladesh 112 of 330 deaths were attributed to tetanus. Up to one-third of neonatal tetanus cases are in children born to mothers of a previously afflicted child, highlighting failure to immunize as a major cause of tetanus. Immunization programs clearly decrease neonatal tetanus deaths.

Acute injuries account for about 70 % of  cases, evenly divided between punctures and lacerations. Other identifiable conditions are noted in 23 %, leaving about 7 % of cases without an apparent source. Other studies cite rates of cryptogenic tetanus as high as 23 %.

Etiology

Clostridium tetani is an obligate anaerobic bacillus that is gram-positive in fresh cultures but that may have variable staining in older cultures or tissue samples (Fig.6). During growth, the bacilli possess abundant flagellae and are sluggishly motile. Two toxins, tetanospasmin (commonly called tetanus toxin) and tetanolysin, are produced during this phase. Tetanospasmin is encoded on a plasmid, which is present in all toxigenic strains. Tetanolysin is of uncertain importance in the pathogenesis of tetanus. Mature organisms lose their flagellae and develop a terminal spore, coming to resemble a squash racquet. The spores are extremely stable in the environment, retaining the ability to germinate and cause disease indefinitely. They withstand exposure to ethanol, phenol, or formalin, but can be rendered noninfectious by iodine, glutaraldehyde. hydrogen peroxide, or autoclaving at 121°C and 103 kPa for 15 minutes. Growth in culture is optimal at 37°C under strictly anaerobic conditions, but culture results are of no diagnostic value. Antibiotic sensitivity is discussed below.

 

Pathogenesis

Tetanospasmin is synthesized as a single 151-kD chain that is cleaved extracellularly by a bacterial protease into a 100-kD heavy chain and a 50-kD light chain (fragment A), which remain connected by a disulfide bridge. The heavy chain can be further divided into fragments В and С by pepsin. The heavy chain appears to mediate binding to cell surface receptors and transport proteins, whereas the light chain produces the presynaptic inhibition of transmitter release, which produces clinical tetanus. The nature of the receptor to which tetanospasmin binds, previously thought to be a ganglioside, remains debated. The toxin enters the nervous system primarily via the presynaptic terminals of lower motor neurons, where it can produce local failure of neuromuscular transmission. Tetanospasmin appears to act by selective cleavage of a protein component of synaptic vesicles, synaptobrevin II. It then exploits the retrograde axonal transport system, and is carried to the cell bodies of these neurons in the brain stem and spinal cord, where it expresses its major pathogenic action.

 

Fig.6. Clostridium tetani

 

 

Once the toxin enters the central nervous system, it diffuses to the terminals of inhibitory cells, including both local glycinergic interneurons and descending GABAergic neurons from the brain stem. By preventing transmitter release from these cells, tetanospasmin leaves the motor neurons without inhibition. This produces muscular rigidity by raising the resting firing rate of motor neurons, and also generates spasms by failing to limit reflex responses to afferent stimuli. Excitatory transmitter release in the spinal cord can also be impaired, but the toxin appears to have greater affinity for the inhibitory systems. The autonomic nervous system is affected as well: this is predominantly manifested as a hypersympathetic state induced by failure to inhibit adrenal release of catecholamines.

 

 

 

Clinical manifestations

Tetanus is classically divided into four clinical types: generalized, localized, cephalic, and neonatal. These are valuable diagnostic and prognostic distinctions, but reflect host factors and the site of inoculation rather than differences in toxin action. Terms describing the initial stages of tetanus include the incubation period (time from inoculation to the first symptom) and the period of onset (time from the first symptom to the generalized spasm). The shorter these periods, the worse the prognosis. Various rating scales are available. Certain portals of entry (e.g., compound fractures) are associated with poorer prognoses.

Generalized tetanus is the most commonly recognized form, and often begins with trismus (“lockjaw”, masseter rigidity)(Fig.6) and a risus sardonicus (increased tone in the orbicularis oris)(Fig.7). Abdominal rigidity may also be present. The generalized spasm resembles decorticate posturing, and consists of opisthotonic posturing with flexion of the arms and extension of the legs. The patient does not lose consciousness, and experiences severe pain during each spasm, which are often triggered by sensory stimuli. During the spasm, the upper airway can be obstructed, or the diaphragm may participate in the general muscular contraction. Either of these compromise respiration, and even the first such spasm may be fatal. In the modern era of intensive care, however, the respiratory problems are easily managed, and autonomic dysfunction, usually occurring after several days of symptoms, has emerged as the leading cause of death.

Fig.6. Examination of chewing muscles reflex

 

The illness can progress for about 2 weeks, reflecting the time required to complete the transport of toxin, which is already intra-axonal when antitoxin treatment is given. The severity of illness may be decreased by partial immunity. Recovery takes an additional month, and is complete unless complications supervene. Lower motor neuron dysfunction may not be apparent until spasms remit, and recovery from this deficit ieuromuscular transmission may take additional weeks. Recurrent tetanus may occur if the patient does not receive active immunization, because the amount of toxin produced is inadequate to induce immunity.

 

Fig.7. Risus sardonicus

Localized tetanus involves rigidity of the muscles associated with the site of spore inoculation. This may be mild and persistent, and often resolves spontaneously. Lower motor neuron dysfunction (weakness and diminished muscle tone) is often present in the most involved muscle. This chronic form of the disease probably reflects partial immunity to tetanospasmin. However, localized tetanus is more commonly a prodrome of generalized tetanus, which occurs when enough toxin gains access to the central nervous system.

Cephalic tetanus is a special form of localized disease affecting the cranial nerve musculature. Although earlier reports linked cephalic tetanus to a poor prognosis, more recent studies have revealed many milder cases. A lower motor neuron lesion, frequently producing facial nerve weakness, if often apparent. Extraocular muscle involvement is occasionally noted.

Neonatal tetanus follows infection of the umbilical stump, most commonly due to a failure of aseptic technique where mothers are inadequately immunized. Cultural practices may also contribute. The condition usually presents with generalized weakness and failure to nurse; rigidity and spasms occur later. The mortality rate exceeds 90%, and developmental delays are common among survivors. Poor prognostic factors include age less than 10 days, symptoms for fewer than 5 days before presentation to hospital, and the presence of risus sardonicus, fever, opistotonus (Fig.8).

Fig.8. Opistotonus iew born

Diagnosis

Tetanus is diagnosed by clinical observation, and has a limited differential diagnosis. Laboratory testing cannot confirm or exclude the condition, and is primarily useful for excluding intoxications that may mimic tetanus. Electromyographic studies are occasionally useful in questionable cases. Such testing becomes more important wheo portal of entry is apparent. Antitetanus antibodies are undetectable in most tetanus patients, but many reports document the disease in patients with antibody levels above the commonly cited “protective” concentration of 0.01 IU/liter. Rare patients apparently develop antibodies that are not protective.

Attempts to culture C. tetuni from wounds are not useful in diagnosis, because (1) even carefully performed anaerobic cultures are frequently negative; (2) a positive culture does not indicate whether the organism contains the toxin-producing plasmid; and (3) a positive culture may be present without disease in patients with adequate immunity.

Strychnine poisoning, in which glycine is antagonized, is the only condition that truly mimics tetanus; toxicologic studies of serum and urine should be performed when tetanus is suspected, and tetanus should be considered even if strychnine poisoning appears likely. Because the initial treatment of tetanus and strychnine intoxication are similar, therapy is instituted before the assay results are available. Dystonic reactions to neuroleptic drugs or other central dopamine antagonists may be confused with the neck stiffness of tetanus, but the posture of patients with dystonic reactions almost always involves lateral head turning, which is rare in tetanus. Treatment with anticholinergic agents (benztropine or diphenhydramine) is rapidly effective against dystonic reactions. Dental infections may produce trismus, and should be sought, but do not cause the other manifestations of tetanus.

 

 

 

Treatment

The patient with tetanus requires simultaneous attention to several concerns. Attention to the airway and to ventilation is paramount at the time of presentation, but the other aspects of care, especially passive immunization, must be pursued as soon as the respiratory system is secure.

Tetanic spasms sometimes demand that the airway be secured before other lines of therapy are possible. An orotracheal tube can be passed under sedation and neuromuscular junction blockade; a feeding tube should be placed at the same time. Because the endotracheal tube may stimulate spasms, an early tracheostomy may be beneficial.

Benzodiazepines have emerged as the mainstay of symptomatic therapy for tetanus. These drugs are GАВА agonists, and thereby indirectly antagonize the effect of the toxin. They do not restore glycinergic inhibition. The patient should be kept free of spasms, and may benefit from the amnestic effects of the drugs as well. Diazepam has been studied most intensively, but lorazepam or midazolam appear equally effective. Tetanus patients have unusually high tolerance for the sedating effect of these agents, and commonly remain alert at doses normally expected to produce anesthesia.

Intravenous midazolam (5-15 mg/h or more) is effective and does not contain propylene glycol, but must be given as a continuous infusion because of its brief half-life. Propofol infusion is also effective, but is currently very expensive, and the amount necessary to control symptoms may exceed the patient’s tolerance of the lipid vehicle. When the symptoms of tetanus subside, these agents must be tapered over at least 2 weeks to prevent withdrawal. Intrathecal baclofen is also effective in controlling tetanus, but has no clear advantage over benzodiazepines. Neuroleptic agents and barbiturates, previously used for tetanus, are inferior for this indication and should not be used.

Most tetanus patients will still have the portal of entry apparent when they present. If the wound itself requires surgical attention may be performed after spasms are controlled. However, the course of tetanus is not affected by wound de-bridement.

Passive immunization with human tetanus immunoglobulin (HTIG) shortens the course of tetanus and may lessen its severity. A dose of 500 units appears as effective as larger doses. There is no apparent advantage to intrathecal HTIG administration. Intrathecal HTIG has also been shown ineffective ieonatal tetanus. Pooled intravenous immunoglobulin has been proposed as an alternative to HTIG. Active immunization must also be initiated.

The role of antimicrobial therapy in tetanus remains debated. The in vitro susceptibilities of C. tetani include metronidazole, penicillins, cephalosporins, imipenem. macrolides, and tetracy-cline. A study comparing oral metronidazole to intramuscular penicillin showed better survival, shorter hospitalization, and less progression of disease in the metronidazole group. This may reflect a true advantage of metronidazole over penicillin, but it more likely corresponds to a negative effect of penicillin, a known GABA antagonist. Topical antibiotic application to the umbilical stump appears to reduce the risk of neonatal tetanus.

Nutritional support should be started as soon as the patient is stable. The volume of enteral feeding needed to meet the exceptionally high caloric and protein requirements of these patients may exceed the capacity of the gastrointestinal system.

The mortality rate in mild and moderate tetanus is presently about 6 percent; for severe tetanus, it may reach as high as 60%, even in expert centers. Among adults, age has very little effect on mortality, with octogenarians and nonagenarians faring as well as middle-aged patients. Tetanus survivors often have serious psychological problems related to the disease and its treatment that persist after recovery, and that may require psychotherapy.

 

Prophylaxis

Tetanus is preventable in almost all patients, leading to its description as the “inexcusable disease”. A series of 3 monthly intramuscular injections of alum-adsorbed tetanus toxoid provides almost complete immunity for at least 5 years. Patients less than 7 years of age should receive combined diphtheria-tetanus-pertussis vaccine, and other patients combined diphtheria-tetanus vaccine. Routine booster injections are indicated every 10 years; more frequent administration may increase the risk of a reaction. Some patients with humoral immune deficiencies may not respond adequately to toxoid injection: such patients should receive passive immunization for tetanus-prone injuries regardless of the period since the last booster. Most young patients with human immunodeficiency virus (HIV) infection appear to retain antitetanus antibody production if their primary immunization series was completed prior to acquiring HIV. Vitamin A deficiency interferes with the response to tetanus toxoid. A recent report documented tetanus in babies of women immunized with toxoid later shown to be devoid of potency; this disconcerting report underscores the need for quality control in toxoid production.

Although any wound may be inoculated with tetanus spores. Some types of injury are more frequently associated with tetanus and are therefore deemed tetanus-prone. These include wounds that are contaminated with dirt, saliva, or feces; puncture wounds, including unsterile injections; missile injuries; burns; frostbite; avulsions; and crush injuries. Patients with these wounds who have not received adequate active immunization in the past 5 years, or in whom immunodeficiency is suspected. should receive passive immunization with HTIG (250-500 IU, intramuscularly) in addition to active immunization.

Mild reactions to tetanus toxoid (e.g.. local tenderness, edema, low-grade fever) are common. More severe reactions are rare; some are actually due to hypersensitivity to the preservative thiomersal.

IV. Convalescent stage: 2-6 weeks

 

PSEUDOTUBERCULOSIS

Definition

Pseudotuberculosis is an acute infectious disease characterized by the polymorphism of the clinical manifestations, affection of the alimentary tract, locomotor system, liver and other organs, general intoxication, exanthema and frequently prolonged course with relapses.

History and Geographic Spreading

The French scientists L. Malasser and W. Vignal first reported on the pseudotuberculosis microbe. In 1883 they isolated it from the organs of a guinea pig infected with the suspension of the caseous regenerated lymph node of the child who had died from “tuberculosis” meningitis.

In 1885 C. Eberth introduced the term pseudotuberculosis when he observed spontaneous epizootic in the rabbits, it was accompanied by an abrupt emaciation of the animals. At the post-mortem examination of the dead animals the anatomic pathological changes of the timer organs looked like the tuberculosis ones, but it was impossible to discover the tuberculosis pathogen, and the morphological characteristics of the isolated pathogen were identical to the microbe.

In 1889 Pfeiffer studied the characteristics of this microbe in detail and gave it the name “Bacterium pseudotuberculosis rodentium”, he connected the isolation of this pathogen with a certain clinical picture in animals.

 

Etiology

The pseudotuberculosis microbe is a polymorph bacillus, which does not form spores and often has an ovoid form. It is Gram-negative, well painted by all aniline dyes. The question of a capsule in the pseudotuberculosis bacteria is still under discussion. The pseudotuberculosis bacteria grown at a temperature of 4-30°C are actively mobile, have flagellum, whose length is 3-5 times bigger than the length of the body of the bacterial cell. At a temperature higher than 30°C the flagellum atrophy and the mobility of the bacteria ceases. The pseudotuberculosis microbe is a facultative anaerobe, it is quite undemanding to the nutrition, and that is why it grows well on the common dense nutrient media, it can grow on the media without peptone. This characteristic of the pathogen was used to distinguish the pseudotuberculosis bacteria from the plague pathogen.

The bacteria contain H-antigen and 0-antigen, which determine their variability. The H-antigen is thermolabile and is destroyed at boiling, it is synthesized at a temperature of 2-30 °C best of all. The flagellum antigen does not have a diagnostic value as it has a component “a”, which is common to all serologic variants. The somatic 0-antigen of the pseudotuberculosis microbe serologic variants. The somatic 0-antigen of the pseudotuberculosis microbe determines its antigenic peculiarity. It is thermostable, it is not destroyed at a temperature of 100-120 °C during two hours. With the help of such thermal processing of the pseudotuberculosis microbe culture it is possible to prepare an antigen to receive hyperimmune serums, which are used for the serologic identification of the isolated strains of the pseudotuberculosis microbe.

The second factor of the Yersinia pathogenicity is their invasiveness. The virulence of the yersinia is stipulated by their invasiveness directed at the phagocytosis suppression and the ability of the microorganism to form toxins. Such ferments as neurominidase, hyaluronidase are found nowadays, they are produced by the pathogenic strains of yersinia. The most important factor of           the yersinia pathogenicity is their ability to produce thermostable enterotoxin.

Thus, different biologically active substances, which are necessary to initiate and develop an infectious process, are produced in the process of the yersinia pathogen vital activity. Besides this it is established that the yersiniosis pathogen strains of different pathogenicity circulate in the human population.

 

Epidemiology

Before the 60-s of the XIX century the epidemiology of the human yersiniosis was almost unstudied. It is explained by the fact that the disease appeared in the form of sporadic cases. In such situations it was often impossible to discover the pathogen, find the disease source, discover the mechanism of its spreading. The situation changed when the Far East scarlatiniform fever mainly manifested by massive epidemic outbreaks was brought to light in the Far East.

Yersiniosis mainly embraces the urban population as in the cities there are more opportunities for the development of big outbreaks among the contingents of people united by public feeding. On the other hand, a more active revealing and better diagnostics of the disease as compared with the rural area is of a certain importance. Children fall ill the most often as compared with the other age groups of the population. The epidemic outbreaks are quite often observed in the organized collectives, especially, the preschool ones. First of all such outbreaks depend on the conditions of the fruit and vegetables storage as well as the condition of feeding the population.

Animals are a reservoir of the infection under the natural conditions. The pseudotuberculosis microbe was isolated from the organs and excrement of many kinds of the mammals, birds, reptiles, fish and arthropoda. Such a diverse and spontaneous infection of many kinds of animals by the pseudotuberculosis microbe gives a ground to think that none of them are a specific biological host of this pathogen and it testifies that in case its ubicvator spreading iature all kinds of animals get involved in the general process of the microbe circulation and serve as a more or less long reservoir of the pathogen depending on the species susceptibility to it.

Rodents are the most frequent reservoir of the pseudotuberculosis microbe. It is explained by the fact that on the one hand, rodents are distinguished by a high susceptibility and sensitivity to the pseudotuberculosis microbe and on the other hand, they are considerably widespread on the Earth and the speed of their replication is high.

The infection of humans can occur at a direct contact with domestic and wild animals, birds while skinning them and processing the carcasses. A possible mechanism of the infection of humans is using the food and water contaminated by the discharge of rodents and birds – carriers of the pseudotuberculosis microbe. Besides this there are a number of convincing investigations confirming that soil is a reservoir of the pseudotuberculosis pathogens. The authors think that the pseudotuberculosis microbe cannot exist in the soil for a long time without reproduction as it cannot form spores. It has saprophytic and parasitic characteristics and correspondingly has two natural biospheres of existing – the warm-blooded animals and environment. The pseudotuberculosis pathogen was isolated during the bacteriologic investigation of the soil from the fields where vegetables and edible roots, as well as wash-outs from them (beet-roots, carrots, cabbages, onions, potatoes).

The epidemiological examination of many outbreaks of the disease made it possible to ascertain that among all the food staffs vegetables, edible roots, dry food, some dry products, which are eaten without any thermal processing, are of the most importance in the pathogen transmission. The importance of vegetables and edible roots as a factor of the pathogen transmission was proved by the isolation of the pseudotuberculosis microbe from them during the outbreaks, the microbes were identical by their serologic variant to the cultures isolated from the sick people who had eaten that food. Such outbreaks most often occur when dishes from fresh cabbage are used as food at the public feeding places.

Raw vegetables and eatable roots get infected by the pseudotuberculosis microbe considerably more often and in more foci than different pickings. The dissemination of the vegetables and eatable roots by the pseudotuberculosis microbe can occur in the autumn while loading them into the vegetable storage places if the latter ones have not been disinfected after sorting the contaminated vegetables of the previous year harvest. The findings of the pseudotuberculosis microbe in the washouts from the floor and shelves of the vegetable storage places confirm this.

Besides vegetables and edible roots, the second important factor in the pseudotuberculosis pathogen transmission is dairy products. Such diary products as cottage cheese, cheese, and, perhaps, sour cream are the most important. It is necessary to note that the pasteurization of milk (at a temperature of 65°C for 30 minutes) does not destroy the pathogen.

Water can also be a factor of the pseudotuberculosis microbe transmission under the favorable conditions.

 

Pathogenesis

The pseudotuberculosis pathogenesis  cannot be considered to be thoroughly studied so far. The pathogens mainly penetrate the human organism through the mouth with the infected food and water. A further movement of the microbes to the esophagus and then stomach characterizes this phase. The acid medium of the stomach contents ruins most pathogenic microbes of the intestinal group perhaps including the pseudotuberculosis pathogen. Having overcome the stomach barrier, the pathogen gets into the intestines and an enteral phase develops, it is characterized by the penetration of the microbe into the mucous membrane of the intestines, then it goes to the regional mesenteric lymph nodes along the lymph paths. Here they reproduce and accumulate, later overcoming the lymphatic barrier the bacteria penetrate the blood and cause the reciprocal reaction of the organism to the toxic substances, which get into the blood vessels during the destruction and life of bacteria.

Besides the mentioned above facts, it was ascertained by a series of profound experimental investigations that it is not only the intestines epithelium, but also the epithelium of all the alimentary tract is the entrance gate of the infection, the alimentary tract begins with the throat where develops the first affect in the form of stomatitis, glossitis, tonsillitis, pharyngitis, which go with regional cervical, submaxillary lymphadenitis.

In more rare cases some authors mention an airborne way of infection, even marking out a pulmonary form of this infection. They think that the pseudotuberculosis microbe possesses pneumotropism with the development of pneumonia and even lung abscess. As the clinical picture of pneumonia develops in later terms of the disease in experimental pseudotuberculosis, the lungs may be only an entrance gate for the development of the generalized process. Taking into account all the mentioned above facts, there is a ground to suppose that irrespective of the entrance gate pseudotuberculosis immediately takes a course of a generalized infection.

The mechanism and sequence of the development of separate periods of the infectious process in each person are different. Depending on the condition of a microorganism, the activity of nonspecific defense as well as the dose and degree of the pathogen virulence, the pathological process can stop at any of its phases. The pathogen of the disease can be blocked by the secretory immunoglobulins even on the mucous membranes of the intestines and respiratory  tracts.   While  overcoming  this  barrier  and  Yersinia pseudotuberculosis penetration the regional lymph nodes with the lymph How, different macrophagal elements, immunoglobulins and immunocompetement cells take defensive measures. The infectious process can cease at this stage if the organism resistance is good. In such cases the patients note only unpleasant feelings or a slight pain in the area of the affected lymph nodes. Such erased forms of the disease are observed only at the thorough investigation of the contact persons in the infection focus. The bacteriemia, pseudotuberculosis process generalize and all its clinical symptoms are observed if the defensive factors of the organism are weakened as a result of another disease, supercooling, starving, immune deficiency conditions.

 

Anatomic  pathology

  Only  the  sporadic  cases   of  human pseudotuberculosis in the form of the septic-typhoid form, which was diagnosed during the autopsy and confirmed by the pathogen isolation, had been described before the early 50-s of the XX century. The pathoanatomists found small necrotic or abscess-like grayish-white nodes in the enlarged liver and spleen, as well as in the lungs. Many researchers call these abscesses necrotic granulomas. Such granulomas with the central necrosis are considered to be a characteristic symptom of pseudotuberculosis. Besides this, there is swelling and necrosis of the lymph nodes follicles of the intestines and mesentery, hyperemia of the peritoneum covering them, edema and infiltration of the distal part of the iliac and proximal part of the large intestine, catarrhal-desquamative and ulceric enteritis (ileitis), congestional plethora, brain edema, dystrophy of the parenchymatous organs and hemorrhage in them. In some cases there is a picture of catarrhal, phlegmonous and gangrenous appendicitis. In combination with the mechanism of the disease development it is possible to suppose that the lymph nodes of the mesentery as well as the iliac intestine and vermicular process serve as a depot for the microorganisms for a long time, it is clinically manifested by a pain in the area of the right iliac enteritis.

There are ofteo visible changes in the area of the vermicular process in the patients with the appendicular form of pseudotuberculosis during the surgery. Nevertheless, it was possible to discover cellular-tissue reactions characteristic of the initial stage of the pathologic pseudotuberculosis process development and having differential-diagnostic value.

In pseudotuberculosis acute terminal ileitis the inflammatory infiltration in the intestine wall has a diffusive or focal character, sometimes similar to the granular tissue. The inflammatory changes, which are not of a destructive character, also take the serous membrane. The polymorph cells, among which there are a lot of eosinophils, considerably infiltrate the mucous membrane of the intestine, there are cryptabscesses, clinoid necrosis and ulceration. The micro abscesses were found in the plate mucous membrane itself. At the study of the pathology of the distant mesenteric lymph nodes in the patients with pseudotuberculosis it was ascertained that the cellular-tissue changes in them are of a double character: on the one hand, they reflect the immune morphologic reaction, on the other hand, – testify of an inflammatory reaction developing in response to the bacterial infection.

The granulomas develop in the lymphatic follicles, the vessel reaction increases and the inflammatory infiltrates develop in case of the progressive pathologic process. The morphogenesis of granulomas both in the appendix and in the lymph nodes is principally the same. The destruction in the follicles increases in the form of ‘avalanche’, which is manifested by a peripheric growth of the necrotic focus. The inflammatory process ceasing is accompanied by the decrease of the exudate phenomena and limiting the destruction foci by a connective tissue capsule from the surrounding lymphoid tissue.

In those cases when there were no changes on the part of the vermicular process, the clinical picture was stipulated by an inflammatory reaction in the lymph nodes of the mesenteric, the terminal part of the iliac intestine and the nodes located in the area of the blind gut and the initial part of the ascending part of the large intestine. The nodes increased up to 1-3 cm in a diameter, they were pink-red, red or brown. They were dense in consistence, elastic or mollified with the necrosis foci. Sometimes there were microabscesses in the form of yellowish-whitish dots under the serous membrane. In some patients the lymph nodes merged in the conglomerates with a diameter of 5-6 cm, they looked like tumor-like neoplasm. The inflammation often transferred from the lymph nodes to the surrounding tissues, especially, to the distal part of the small intestine including the vermicular process.

Diffusive ileitis is also a severe complication in pseudotuberculosis, it results in the contraction of the ileum lumen, invagination, comissural ileus and paralytic obstruction, necrosis and perforation of the intestines. The phenomena of peritonitis stipulated by the mesenteric node disintegration have been described.

There are a lot of reports on the involvement of the cardiovascular and nervous system, liver, spleen, kidneys and adrenal glands in the pathological process in pseudotuberculosis.

The pathomorphologic basis of the infection is acute generalized reactive reticulocytosis with the primary affection of the lymphatic apparatus of the intestines, mesenteric lymph nodes, liver, spleen. There are specific of pseudotuberculosis foci – granulomas and micro abscesses in the organs, which are rich in the macrophage elements. The nonspecific changes of a dystrophic type often develop in other organs.

 

 

 

Clinical manifestations

The diversity of the pseudotuberculosis clinical manifestations, the involvement of different organs and systems in the pathologic process are the basis for the suggestions of numerous classifications of this disease. The least cumbersome classification, though it does not lack drawbacks, is the classification by N. U. Zalmower, which is based on the syndrome principle with the following clinical forms:

1.     A scarlatiniform characterized by the general intoxication symptoms, fine-dot rash, fever;

2.     A arthralgic form resulting in the joints affection, it takes a course of arthralgia, less often – arthritis;

3.     An abdominal form with the primary affection of different parts of the alimentary tract, sometimes in the initial period;

4.     A generalized form with the affection of different organs and systems when it is impossible to pick out any main syndrome;

5.     An icteric form, in which the affection of the liver with a jaundice syndrome is the primary symptom.

The clinical manifestations of pseudotuberculosis are characterized by a great polymorphism with the prevalence of the general intoxication, which makes an early diagnostics extremely difficult. As well as other acute diseases pseudotuberculosis has a certain cyclic recurrence. The development of the cycle’s periods with a certain time limitation, which is accompanied by different morphologic, immunologic and clinical changes, results in a characteristic picture of the disease. There are following periods in pseudotuberculosis: an initial period, a high point, a period of acute courses and relapses, convalescence.

Evaluating the descriptions of the clinic given in the literature and observing the patients, it is necessary to note that in each separate case these periods can be manifested in different ways depending on the reactivity of the macroorganism, virulence of the pathogen, the time when the treatment began, the quantity of the daily and course doses of the medications and other factors. All the periods of the disease can be observed in the typical cases in half the patients (especially, in case of the pathogenic therapy and short courses of some antibiotics). In other cases some of them cannot be observed or they can be slightly manifested. There can be only separate symptoms of the initial period without a temperature rise in the deleted forms of the disease.

Judging by the epidemiological history, the incubation period in this infection most often lasts 7-10 days with the fluctuations from to 18 days. In this period the disease does not usually have any clinical manifestations, the people consider themselves to be practically healthy and continue working.

The initial period is the time when the first symptoms of the disease develop till the highest possible development of the clinical picture with the symptoms of the local affection.

In most patients the disease has an acute course with a rapid temperature rise, which is accompanied by chills. The prodromal phenomena in the form of  malaise, slight chills, the development of uncertain pains in the abdomen, which developed 1-2 days before the onset of the disease, were described only in separate cases.

This period is clinically characterized by expressed polymorphism and absence of specific symptoms typical of only this disease. The temperature rise is accompanied by a headache of different intensity with its primary location in the forehead and temple areas, pains in the muscles, joints, waist, general asthenia, weakness and lack of appetite. In a number of cases the sick people complain of the pain in the throat at swallowing. In some cases patients complain of pains in the stomach, diarrhea 2-3 times a day, nausea and single or recurrent vomiting. There is brief fainting in some patients in the first hours of the disease together with general asthenia.  An early toxicosis resulting in a lethal outcome can develop in rare cases, especially, in children during 2-4 days.

While examining the patients it is possible to observe hyperemia of the face and neck, some puffiness of the face, hyperemia of the conjunctiva and an injection of the sclera vessels, there is a pale nose-lip triangle in some patients. There is often herpetic rash on the lips and the nose wings, expressed hyperemia of the throat, which is of different intensity, less often – an enanthema on the soft palate, angina. During the first days of the disease the tongue has a grayish-white patch, which begins to clear and becomes raspberry with expressed papilla on the third day.

There are symptoms of acute catarrh of the upper respiratory tract such as a running nose, cough, and pains in the throat at swallowing in most patients in the initial period of the disease.

Such diversity of symptoms testifies about the involvement of different organs and systems in the pathological process even in the first days of pseudotuberculosis infection, which is often a reason for a false diagnostics in this period. The most part of such patients are treated at home, the smaller part is sent to a hospital with the diagnoses: acute respiratory disease, polyarthritis, gastroenteritis, catarrhal angina, scarlatina and others. These diagnoses often remain the final ones as a doctor examines a patient for a second time only in the period of convalescence and does not pay attention to some important symptoms of the disease (rash, ‘raspberry’ tongue, pain in the ileocecal area, etc.)

 

Fig.9. Rash in case of pseudotuberculosis

 

Rash is one of the most striking symptoms of this period. It develops on the 1-4th day of the disease, sometimes on the 5-6th day. According to its character it is often fine-spotted on the hyperemic background or normal skin (Fig.9). During the first outbreak of the disease in some patients it is fine-spotted, and in combination with angina, the enlargement of the submandibular lymph nodes, “raspberry” tongue, the development of peeling typical of scarlatina in the later period gave a ground to first diagnose “scarlatina” in all patients. Later the rash can be spotty (looking like German measles and measles) and confluent erythematous. The spreading of the rash can be different, if it is spread all over the body, it is mainly located on the symmetrical parts (Fig.10). The rash is not often found on the face and neck. There is often hyperemia and swelling of the skin on the hands and feet – the symptoms of “gloves” and “socks”. The petechial-hemorrhagic elements are mainly localized in the natural folds of the skin and on the side surfaces of the chest. The development of hemorrhages in the form of stripes and changes on the side surfaces of the shoulders and in the area of the armpit line. There are endothelial symptoms of plait, pinch with hemorrhages in the patients with a severe form. The development of rash can be accompanied by the deterioration of the patients’ condition, pulse acceleration, hypotonia and even a collapse condition.

Fig.9. Rash in case of pseudotuberculosis

 

There is scaly laminar peeling on the skin of the chest, abdomen, lobes of the ear and then on the back surface of the hands, feet, palms during the 2-3rd week of the disease. The duration of the initial period is 1-5 days.

The highest point of the pseudotuberculosis infection is manifested by the maximum development of fever and other symptoms of intoxication and expressed signs of the local affection. The highest point of the disease, especially, the first days are characterized by considerable intoxication, which is manifested by the affection of the central nervous system – general asthenia, hypotonia, dizziness, intense headache, tactile hyperesthesia, photophobia, vomiting, insomnia, increased excitability or suppression. In a severe course there are manifestations of meningoencephalitis with the symptoms characteristic of it: a headache, nausea, vomiting, drowsiness, suppression, consciousness disorders, signs of irritation of the meninges and the substance of the brain. There are such meningeal symptoms as rigidity of the neck muscles, Kernig and Brudzinsky symptoms, in the cerebrospinal liquid the cytosis is more than 400 cells, increase of the protein contents. Besides the mentioned symptoms there are characteristic disorders of the vegetative nervous system function. In some patients the affection of the nervous system is similar to the intercostal and nape neuralgia or lumbosacral radiculitis.

The changes on the part of the locomotor system are observed almost in all patients. There is often arthralgia, sometimes with very intense pains in the sacrum, waist, joints and less often – acute polyarthritis, which is characterized by swelling of the tissues around the joints with hyperemia of the skin. The radiocarpal, interphalangeal, knee and ankle joints are most often affected in pseudotuberculosis, less often – shoulder and hip joints. Acute polyarthritis is often confused with the attacks of acute rheumatism in case of the poor knowledge of the pseudotuberculosis clinic. The pain syndrome depends on the severity of the disease and can be weak or strong, hindering independent movement. The joints are swollen, painful, hot.

Most patients complain of myalgia in the acute period of the disease. It prevails in the muscles of the neck, abdomen, and extremities. In some cases myalgia of the abdomen muscles is sharply expressed, which stimulates “acute abdomen”. In such cases it is necessary to pay attention even to slight manifestations of other symptoms of the disease.

The submaxillary, neck and axillary lymph nodes can be enlarged in the acute period of the disease. They are slightly painful, elastic, not united with one another and the surrounding tissue.

The changes on the part of the cardiovascular system at the highest point of the disease are manifested by hypotonia, dullness of the heart sounds, and in some patients there is a systolic murmur over the top and extrasystole. In spite of the fact that in a considerable number of patients the subjective symptoms of the heart affection (pain, heartbeat, arrhythmia, and others) are extremely rare, the electrocardiograms show changes, some of them are considerable. The decrease of the P and T waves voltage is the most frequent of them, less often – the deformation as a result of the toxic-infectious influences on the cardiac muscle. There were sometimes symptoms of its diffusive affection.

The respiratory organs also get involved in the pathological process in pseudotuberculosis. The pains in the throat, hyperemia of the fauces mucous membrane, spotted enanthema on the mucous membrane of the soft palate, rhinitis, cough, dry rale in the lungs testify of their affection. There is dulling of the percussion sound over the pulmonary fields and moist rale in the limited areas in some patients who suffer a severe course of the disease. The x-ray investigations usually demonstrate the intensification of the bronchial-vascular picture, the opacity of the roots, less often – infiltration of the lung tissue.

In a mild case of the disease the affection of the alimentary tract is manifested by complaints of a bad appetite, nausea, less often – vomiting diarrhea. The stool is fluidity or watery 3-5 times a day with admixture of mucous. The pain in the abdomen is observed in half of the patients and is often revealed only at palpation. The tongue furred, it becomes raspberry when it gets cleared.

The changes of the alimentary tract are expressed more strongly and prevail over the rest ones in a more severe course. In this case a pseudotuberculosis abdominal form is diagnosed. It is characterized by a pain in the epigastria area of the abdomen, umbilical or right iliac area, less often -in the right hypochondrium and left iliac area. The abdominal syndrome is clinically revealed primarily in the form of the symptoms of mesenteric lymphadenitis, terminal ileitis, acute appendicitis. Mesenteric adenitis of the pseudotuberculosis etiology without any other manifestations is quite often observed in the countries of Western Europe. The affection of the mesentery lymph nodes can occur in different periods of the infectious process, more often in the initial period and at the high point of the disease. In this case there are pains in the right iliac and para umbilical, the palpation demonstrates an enlarged, painful and “grumbling” cecum and mesenteric lymph nodes. Such patients come to hospital with various diagnoses: “acute appendicitis”, “acute cholecystitis”, etc. These patients can come to both infectious and surgical hospitals, and only the carefully collected history of the disease and the clinical investigation data allow to diagnose pseudotuberculosis.

The intensity of the pains in the ileocecal area can be different. In some patients they are revealed only at palpation, in others they are constant aches, in some patients they are so intense that the patients groan and take a forced position with their knees pulled to the abdomen. The patients cannot remain in the same position for a long time. The pains subside and cease troubling the patients on the 2-3th day from the time of their appearance. However, in 3-4 days they recommence and become more intense,

The local manifestations of mesadenitis are usually accompanied by general symptoms as well. They are a temperature increase, sometimes up to 39 °C, chills, which intensify with the development of pains in the abdomen, diarrhea – 2-3 stools a day without admixture of mucous and blood, nausea, and vomiting in almost half of the patients. Besides the patients complain of headaches, pains in the joints of the upper and lower extremities, body muscles, general asthenia, sore throat.

The skin of the face, neck, chest is often hyperemic in the patients with mesenteric lymphadenitis. In separate cases there is fine-spotted rash, which rise above the skin in the area of the chest, abdomen, groin folds, inner surfaces of the shoulders, forearms and thighs, the rash gets pale at pressing.

There is muscles tension and other symptoms of the peritoneum irritation, which are very similar to the picture of the “acute abdomen” in case of a severe course of the disease. However, in contrast to acute appendicitis in the mesadenitis patients the pains in the abdomen do not increase when the abdominal press is strained. This new symptom was observed in all the cases of pseudotuberculosis mesadenitis.

The clinic of acute appendicitis in pseudotuberculosis has its peculiarities connected with the fact that besides the affection of the vermicular process the patients have the manifestations of the main disease. As a rule, the patients, in whom the appendicular syndrome develops during treatment in the infectious hospitals or who arrived with the diagnosis “pseudotuberculosis” and have an expressed appendicular syndrome are not operated on, and the disease has a favorable outcome after the conservatory treatment. It is natural that such patients should be carefully observed by both an infectious doctor and a surgeon in order not to miss authentic appendicitis, whose pathogen can be pseudotuberculosis along with other microbes. It is known that the pseudotuberculosis microbe is isolated in about 7% cases during the bacteriological investigation of the processes ablated during the appendectomy. The surgical aspects of pseudotuberculosis are of great practical interest and need to be thoroughly studied.

Regional ileitis in the abdominal form of pseudotuberculosis is more often observed in the relapse and remission period of the disease. In this case the pains in the abdomen develop on the background of the seeming convalescence, they are accompanied by a recurring rise of the body temperature up to 38-39 °C and chills. The pains are usually moderate, they are of an attack-like character. In 2-3 days from their appearance they become less intense, in some cases they cease troubling a patient. However, on the 3-4th  day they increase and become very intense.

In some patients pseudotuberculosis begins with the symptoms of regional ileitis. In such cases the pseudotuberculosis symptoms are poorly expressed. This results in the diagnostic mistakes. In case of regional ileitis the pains in the stomach are often accompanied by nausea. In half of the patients there is vomiting, sometimes repeated. The affection of the terminal part of the ileum can be accompanied by watery stool up to 3 times a day without an admixture of mucous and blood. The abdomen is sometimes bloated. The right iliac area is the most painful, there is also muscle tension of the front wall of the abdomen. The similarity of the clinical picture of regional ileitis to that of acute appendicitis is a characteristic feature. In many cases it is extremely difficult to diagnose the case before a surgery.

The patients with the pseudotuberculosis abdominal form often have gastroenteritis. Its development can be observed in all periods of the disease. Gastroenteritis usually has a rapid development. The disease starts with pains in the abdomen, nausea, vomiting, it is usually accompanied by the abdomen inflation, watery or pasty stool up to 2-3 times a day, general asthenia, chills, headache  and  other  pseudotuberculosis  manifestations.  Sometimes gastroenteritis takes a chronic course. In these cases patients complain of the periodic pains in the abdomen, which disturb them, general asthenia, headache, general malaise. The stool in such patients is unstable. There is an expressed asthenia right after the meals. The pains in the abdomen can resemble attacks and do not have a distinct localization. The symptoms of the general intoxication are often expressed.

The affection of the alimentary system is not only limited by the pathologic changes of the gastrointestinal tract. The liver affection is often observed in this or that degree in almost half the patients, actually it is acute parenchymatous hepatitis, its expressiveness depends on the severity of the disease. The affection of the liver is manifested by the enlargement of its size, icteric color of the skin and scleras, the bilirubin increase in the blood, it sometimes resembles the clinic of viral hepatitis.

The thorough comparison of the clinical symptoms with the biochemical investigations shows the involvement of the pancreatic gland in the pathologic process. The patients develop pains in the abdomen, which resemble attacks and are localized in the epigastric area, in the right and left hypochondrium. In some cases they irradiate in the waist or back. The patients complain of nausea, vomiting and general asthenia. There can be watery stool. The amylase level of blood and urine as well as the lipase activity in blood can confirm the diagnosis. Some authors pay much attention to elastase. In 1986 V. A. Ivanis noted that the elastase level depended on the severity of the disease and its indexes normalized in the period of convalescence.

The generalized form of the disease is characterized by the combination of a high temperature, exanthema, and severe intoxication with all the main syndromes of the disease: terminal ileitis, parenchymatous hepatitis, acute polyarthritis, meningeal symptoms and a long relapsing character.

 

Diagnosis

The polymorphism of the clinical manifestations of the initial period and absence of the specific symptoms, which are characteristic of only pseudotuberculosis, hinder its early diagnostics. This obliges a doctor to diagnose pseudotuberculosis on the basis of the epidemiological, clinical and laboratory investigations all together. It is not difficult to recognize the infection during the massive diseases as it is possible to clearly establish different stages of the disease during the simultaneous examination of a number of patients. In case of the sporadic cases the diagnostics is more difficult and demands additional epidemiological data confirmed by the bacteriological investigations.

In the clinical aspect an acute onset, chills, general asthenia, malaise, frequent pains in the throat at swallowing are typical. The hyperemia of the skin of the face, neck, fauces mucous membrane, moderately expressed signs of scleritis and conjunctivitis, in some patients – the yellowness of the scleras are considered to be early symptoms during the external examination of the patients. Sometimes during the first day of the disease there is redness and edema of the palms and soles skin, which is accompanied by itching. Such a rapid development of the disease with intoxication and the above mentioned objective data together with the epidemiological situation allow to suspect pseudotuberculosis.

It is necessary to take into account the major symptoms of the disease during the following days at the highest point of the disease. They are a fever with the alternation of the temperature rise up to 40 °C and the temperature decrease down to the subfebrile indexes, the development of the spotted (scarlatiniform) or fine-spotted, less often – petechial rash, the involvement of the joints in the pathological process, dysfunction of the intestines, enlargement of the liver with the development of the jaundice syndrome, “raspberry tongue”. In the later terms of the disease it is necessary to take into account the development of acute forms and relapses with predomination of the abdominal or arthralgic syndromes in the clinical diagnostics. As a rule, the two mentioned above primary syndromes of pseudotuberculosis develop together with cerebrostenic syndrome.

There are no reliable diagnostic tests on pseudotuberculosis among the nonspecific laboratory signs. In particular the blood clinical analysis is not informative. The changes of the morphological blood contents do not take place in all the patients and they are of a moderate character.

The specific laboratory diagnostics of pseudotuberculosis is very important in its diagnosing. It is of primary importance in the mild and unexpressed forms of the disease, especially, occurring in the form of separate sporadic cases.

The specific laboratory diagnostics of pseudotuberculosis is represented by the bacteriologic and serologic methods of investigation in the medical practice nowadays.

The main material for the bacteriologic investigation is excrement and in a lesser degree – washouts from the fauces, urine and the appendicular processes, which are ablated during the surgery. The pseudotuberculosis patients excrete bacteria with mucous from the fauces, excrement, urine. The duration of their excreting with mucous and urine is not long. The pseudotuberculosis pathogen is found in excrement during all the disease and in the period of relapses. In separate cases it can be excreted with excrement for about 75 days. The excrement inoculations are done on the differential-diagnostic medium №67 where it is easy to distinguish the pseudotuberculosis colonies from other microbes.

The serologic investigations began to be done after the discovery of the Far East scarlatiniform fever. In the beginning the agglutination reaction with alive cultures as an antigen was used, later a reaction of indirect hemagglutination as well as the reaction of the bacterial lysis, method of fluorescent antibodies and others. In spite of the fact that the pseudotuberculosis diagnostics is improving every year, it does not satisfy the practical doctors so far. The percentage of the bacteriologic confirmation of the diagnosis remains low, and the reaction of indirect agglutination, which is used everywhere, is not enough sensitive and specific. The reaction of coagglutination and immune ferment analysis, which make it possible to discover both the antigen and antibodies to it during the first 3-5 days from the disease onset, is considered to be promising.

 

Treatment

 It is impossible to agree with the recommendations of some author about the possibility of treating the pseudotuberculosis patients at home. In spite of some positive results the possibility of sudden acute forms development and relapses obliges to treat the patients only in hospital and to thoroughly follow the regimen and an according nursing.

The patients do not need a special diet. The nutrition is typical of the patients with an acute fever. The food should be easily assimilating and high-calorie, containing a sufficient amount of vitamins. A daily food allowance should contain 3200-3500 big calories. The patients with the predominant liver affection, are prescribed diet №5 containing a sufficient amount of carbohydrates and a limitation of fat, especially, refractory.

The treatment depends on the clinical form, the period and gravity of disease. Among etiotropic agents use Levomycetin, Metacyclin, Tetracyclin, Streptomycin, Gentamicin, Ampicillin in moderate therapeutic doses during not less than 7 days and more. At serious current of disease, the septic form the best results can be gained if simultaneously use 2 – 3 antibiotics and one of them infuse into vein: course of treatment prolong up to 10 – 14 days, and through 6 – 7 days it is replaced by preparations with the account of antibioticosensitivity of allocated yersinias.  Cefazolin (Kefzol), Cefotaxim (Claforan) are effective. As alternative preparation may be Bactrim (Biseptol). Less effective are Nitrofuranes and Sulfanilamid preparations.

With the purpose of desintoxication and Rehydratation of organism indicate 5 %  solution of a glucose, a seralbum, Reopolyglycin, Trisol, Quartasol. Widely use vitamin, antihistamine preparations and agents stimulating regenerative processes – Diprazin, Suprastin, Tavegil, Methyluracil (Methacil), Pentoxyl, Apylac, Natrii nucleinic, Thymalin etc. At gastroenterocolitic form indicate  Enterosorbents (activated microspherical coals, Sillard P, Enterosgel, Smecta), replaceable fermental therapy (Festal, Pancreatin, Pancurmen, Pancitrat), diet № 4 is indicated. Colibacterin, Bificol and other biological preparations are indicated in case of development of dysbacteriosis . At acute tonsillitis indicate gargles. Development of arthritis,  myocarditis, Reiter syndrome is the indication to use Indomethacin, Ibufrofen, Diclofenac-Natrii (Ortophen) and other not steroid preparations.

 All the patients are prescribed vitamin therapy in the form of complex B, vitamins A, C, PP and others.

The therapeutic tactics should be strictly individual in case of every patient who is to be constantly looked after. Only an individual approach and a complex of the treatment measures can bring invariable success and allow to achieve good results.

 

Prophylaxis

In spite of the achieved success in the pseudotuberculosis study, the problems of the specific prophylaxis have not been worked out so far.

A complex of nonspecific measures directed at the source and transmission factors is widely used in the medicine to prevent the pseudotuberculosis spreading.

 

 

 

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