Ehrlichioses

Ehrlichiosis is a group of acute zoonotic, mainly transmissible, infectious diseases characterized by polymorphism of clinical manifestations.

Epidemiology of ehrlichiosis

The maintenance and spread of the pathogens of monocytic and granulocytic ehrlichiosis in nature are associated with ixodid ticks, and the pathogen of sennetsu ehrlichiosis is presumably associated with mollusks and fish.

In the USA, the causative agent of monocytic ehrlichiosis is transmitted by ticks A. americanum, D. variabilis, I. pacificus, in a significant part of Eurasia - I. persulcatus. The main carrier of granulocytic anaplasmosis in the USA is the tick I. scapularis, in Europe - I. ricinus, in the West Siberian region - I. persulcatus. The infection rate of various ixodid ticks with ehrlichia can vary from 4.7 to 50%. In addition, several different microorganisms can coexist in the body of one tick (for example, ehrlichia, borrelia and tick-borne encephalitis virus) and it is possible for a person to be infected with these pathogens simultaneously.

The main reservoir hosts of E. canis are considered to be dogs, and the hosts of E. chaffeensis are deer. Dogs and horses may also be possible reservoirs of E. chaffeensis. Antibodies to E. phagocytophila have been found in several species of wild rodents, but apparently in the USA the main host of these ehrlichia is the white-footed hamster, as well as wood rats, and in Great Britain - roe deer. In Russia and Ukraine - the main host of Anaplasma phagocytophilum is the bank vole.

Ehrlichia enters the human body with the saliva of an infected tick. In the case of sennetsu fever, infection is associated with eating raw fish.

People of any age are susceptible to the disease; men predominate among those who fall ill. In the USA, it has been established that monocytic ehrlichiosis occurs among permanent residents of some states in the South of the country with the same frequency as Rocky Mountain spotted fever, which is endemic to these areas. Hunters, rural residents, and people who frequently visit forests and taiga are more likely to fall ill. Group diseases are also possible.

Ehrlichiosis is currently registered in many countries. In the USA, monocytic ehrlichiosis has been confirmed by serological testing in almost the entire country. Isolated cases of monocytic ehrlichiosis have been registered serologically in Europe (Spain, Belgium, Portugal), as well as in Africa (Mali). Granulocytic anaplasmosis, in addition to the USA, has been registered among people attacked by ixodid ticks in England, Italy, Denmark, Norway, and Sweden.

Monocytic and granulocytic ehrlichiosis have also been detected in Russia. A PCR study of ticks collected in the Perm Territory revealed that I. persulcatus was infected with monocytic ehrlichia, which is classified as E. muris. This type of ehrlichia was described in Japan, but its pathogenicity for humans was unknown. Since 1999-2002, antibodies to E. muris and E. phagocytophila, as well as to A. phagocytophilum, have been detected in patients who have been bitten by a tick. In the Perm Territory of Russia, the share of granulocytic anaplasmosis in the structure of tick-borne infections is 23% and is second only to tick-borne borreliosis; in more than 84% of cases, these diseases occur as mixed infections.

Mortality rates in the United States are 3-5% for monocytic ehrlichiosis and 7-10% for granulocytic anaplasmosis.

The activation of ticks in warmer seasons determines the seasonality of monocytic ehrlichiosis: April-September with a peak in May-July. Granulocytic anaplasmosis is characterized by two-peak incidence: the most significant peak in May-June is associated with the activity of the nymphal stage of the carrier, and the second peak in October (until December) is associated with the predominance of adult ticks at this time.

Emergency specific prophylaxis should be carried out in endemic areas when a tick bite is detected (single dose of 0.1 g doxycycline). Non-specific prophylaxis consists of anti-tick measures before going to an area endemic for ixodid ticks (special closed clothing, treatment with secaricides). After visiting an endemic area, mutual and self-examination is necessary to identify attached ticks.

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What causes ehrlichiosis?

The generic name Ehrlichia was proposed in 1945 by Sh.D. Moshkovsky in honor of Paul Ehrlich. Ehrlichia are non-motile, gram-negative, rickettsiosis-like organisms, obligate intracellular parasites that reproduce by binary fission and do not form spores. According to the modern classification, the tribe Ehrlichia is part of the Rickettsiaceae family of the Rickettsiales order of the α-proteobacteria tribe. In addition to unclassified genera and the genus Ehrlichia itself, the tribe also includes three more genera of bacteria (Anaplasma, Cowdria, Neorickettsia) that cause diseases in mammals. The genus Ehrlichia itself is divided into three genogroups. The canis genogroup unites four species of Ehrlichia: E. canis, E. chaffeensis, E. ewingii, E. muris. The phagocytophila genogroup includes E. bovis, E. equi, E. phagocytophila, E. platus. Several genospecies of Ehrlichia spp. The risticii genogroup includes two species - E. risticii and E. sennetsu. Some Ehrlichia have not yet been classified and are combined into the Ehrlichia spp.

At least four species of these bacteria can cause the disease in humans. Two species of Ehrlichia are considered to be the etiologic agents of monocytic ehrlichiosis: E. chaffeensis and E. muris. Anaplasma phagocytophilum, the causative agent of human granulocytic ehrlichiosis (which has been called granulocytic anaplasmosis since 2004), is also classified as a member of the Ehrlichia tribe (Anaplasma genus). E. sennetsu, the causative agent of sennetsu fever, is highly endemic to a limited area in southern Japan.

Morphologically, all types of Ehrlichia are small pleomorphic coccoid or ovoid microorganisms, which have a dark blue or purple tint when stained according to Romanovsky-Giemsa. They are found in vacuoles - phagosomes of the cytoplasm of affected eukaryotic cells (mainly leukocyte series) in the form of compact clusters of individual particles of the pathogen, called morulae due to their appearance. Cytoplasmic vacuoles usually contain 1-5 Ehrlichia, and the number of such vacuoles can reach 400 or more in one cell. Electron microscopy of Ehrlichia revealed an ultrastructure similar to Rickettsia and the same method of reproduction - simple binary fission. A feature of the cell wall of an individual Ehrlichia is the lagging of the outer membrane from the cytoplasmic membrane and its wavy appearance. The internal membrane maintains a smooth contoured profile.

Based on the distribution of ribosomes and DNA fibrils, Ehrlichia, in particular monocytic Ehrlichiosis, is represented by two types of cells that are morphologically different.

• With uniform distribution throughout the cytoplasm - reticular type cells; they have dimensions of 0.4-0.6x0.7-2.0 µm.
• With the concentration and compaction of the specified components in the center of the cell. This type of cells has dimensions of 0.4-0.8x0.6 µm.

It is assumed that the reticular type cells are an early stage of microbe development, and the second type cells reflect the stationary phase of the life cycle. The exit of Ehrlichia occurs when the membrane of the morula-vacuole ruptures and then the cell wall of the target cell or by exocytosis (squeezing) of Ehrlichia from the morula or exocytosis of the morula entirely from the cell.

In terms of antigen composition, Ehrlichia has no common properties with tick-borne and typhus group rickettsia, as well as with Borrelia. Within the Ehrlichia group itself, there are cross-antigens.

Ehrlichia do not grow on artificial nutrient media. The only available substrate for the accumulation of Ehrlichia in order to study them and prepare specific antigens is macrophage-like (canine macrophage line DN 82) or epithelial-like (human endothelial cell line, VERO, HeLa, LEC cells) transplantable eukaryotic cells. This process is labor-intensive and takes a long time; the accumulation of Ehrlichia in these cells is insignificant. In addition, white mice can be used for the reproduction of E. sennetsu, in which Ehrlichia cause a generalized process with the accumulation of the pathogen in the macrophages of the peritoneal fluid and in the spleen.

Pathogenesis of ehrlichiosis

The pathogenesis and pathomorphology of ehrlichioses have not been sufficiently studied due to the limited availability of autopsy data, but experimental studies on macaques have made it possible to study this disease in more detail at the histomorphological level.

The pathogenesis of monocytic and granulocytic ehrlichiosis in the initial stage is caused by the penetration of the pathogen through the skin and is identical to that of rickettsioses. There are no traces left at the site of tick attachment. The pathogen enters the underlying tissues and spreads hematogenously throughout the body. Just as with rickettsioses, the pathogen penetrates the cells, reproduces in the cytoplasmic vacuole and then exits it. Macrophages of the spleen, liver, lymph nodes and bone marrow are predominantly affected. Focal necrosis and perivascular lymphohistiocytic infiltrates may develop in many organs and the skin. Megakaryocytosis and hemophagocytosis develop in the spleen, liver, lymph nodes and bone marrow, and myeloid hypoplasia forms in response. Polyorgan perivascular infiltration by lymphohistiocytes, hemophagocytosis in organs and bone marrow, impaired vascular permeability and development of hemorrhage in internal organs and skin are especially pronounced in severe cases of the disease. In case of fatal outcome of monocytic ehrlichiosis, total damage of vital organs with irreversible impairment of their function occurs. E. chaffeensis is capable of penetrating into cerebrospinal fluid and causing meningitis. Changes in the cellular composition of blood are described as "hemophagocytosis syndrome". The mechanism of suppression of immune defense in ehrlichiosis is still unknown, but fatal outcome develops more often in patients with clinical signs of secondary lesions of fungal or viral nature. There is experimental data suggesting that ehrlichia may be characterized by the process of L-transformation.

In sennetsu fever, the portal of entry is located in the oral mucosa or pharynx. The infection then spreads through the lymphatic and blood vessels and is accompanied by generalized lymphadenopathy, bone marrow damage, and leukopenia. The capillary endothelium is sometimes involved in the infectious process, as evidenced by the appearance of a petechial or erythematous rash.

In ehrlichiosis, the production of cytokines, regulators of the immune response of various families (TNF-a, IL-6, granulocyte-macrophage cholonestimulating factor), decreases and the production of IL-1beta, IL-8 and IL-10 increases, which contributes to the death of phagocytized bacteria and indicates the participation of immunocompetent cells in local inflammatory reactions.

Symptoms of Ehrlichiosis

Ehrlichioses have an incubation period of 1-21 days, and clinically expressed disease - 2-3 weeks, but sometimes can last up to 6 weeks. Symptoms of ehrlichioses are varied - from asymptomatic to pronounced clinical picture with severe, life-threatening course. Common symptoms of ehrlichioses: sudden development of fever, chills, fatigue, headache, muscle pain, anorexia, nausea and vomiting, as well as other non-specific symptoms of intoxication observed in rickettsial infections. In sennetsu ehrlichiosis, fatal outcomes have not been described, and a rash is rarely observed, while in monocytic and granulocytic ehrlichiosis, mortality reaches 3-10%, and erythematous or petechial rash is recorded in 2-11 (up to 36)% of cases, respectively. The main symptoms of sennetsu fever are an increase in body temperature to 38-39 °C, generalized lymphadenopathy, and an increased content of monocytes in the peripheral blood.

The duration of the febrile period in sennetsu fever does not exceed 2 weeks, in monocytic ehrlichiosis - 23 days, in granulocytic anaplasmosis - 3-11 weeks. Since ehrlichioses do not have clinical pathognomonic signs, patients are most often suspected of having various types of rickettsiosis, sepsis, influenza, upper respiratory tract infections, infectious mononucleosis, etc.

In patients with granulocytic anaplasmosis, the disease began acutely, with a rise in temperature during the first day to 39-40 ° C, which was accompanied by chills. At the same time, severe headache, aching pain in the muscles and large joints appear. As the disease progressed, patients complained of persistent insomnia, restless sleep, drowsiness during the day. None of the patients had neurological disorders. Tachycardia, hypotension, muffled heart sounds were noted; half of the patients had nausea and vomiting in the first two days of the disease. According to the literature, erythematous, papular or petechial rash is detected at an earlier stage in 10% of patients, in the first week of the disease - in 23%, and throughout the entire period of the disease - in 36.2%. The rash spreads over the entire body, excluding the palms and soles. In the Khabarovsk Territory, the rash was registered in 87% of cases; It appeared on the 1st-8th day, more often on the 3rd day of the disease. The rash was predominantly spotted, pale pink, the elements did not merge, the sizes did not exceed 10 mm. The phenomenon of rash was not noted. The rash reversed without residual effects, usually on the 8th-9th day. In some patients, at the site of tick attachment, a dense infiltrate of up to 20 mm was noted, covered in the center with a dark brown crust (this local reaction was only in patients with a long-term, more than 24 hours, tick attachment). No patient had lymphadenopathy. Against the background of high temperature, dry mouth, anorexia, stool retention for several days were noted. Darkening of urine, icterus of the sclera were detected in 20% of patients; an enlarged liver was found in 33% of patients. The most constant laboratory sign in most patients with monocytic and granulocytic ehrlichiosis was an increase in the activity of liver transferases in the blood serum (ALT - 3-4 times, AST - 1.5-2.5 times). Leukopenia, neutropenia (no more than 2.0x10 ⁹ /l), and a pronounced shift in the formula to the left were noted in the hemogram. Moderate thrombocytopenia was registered in 71% of patients, ESR was often increased (on average up to 23 mm / h). Changes in urine were observed in 40% of patients, which were characterized by proteinuria (0.033-0.33 g / l) to moderate leukocyturia (up to 30-40 in the field of vision).

In patients with monocytic ehrlichiosis from the Perm Territory (1999-2000), almost the same symptoms were noted, with the exception of catarrhal phenomena in 1/4 of patients, enlarged submandibular lymph nodes up to 1.5 cm, and the development of meningitis in a number of patients. Some of them had facial nerve damage of the central type. Unlike patients with granulocytic anaplasmosis, patients with monocytic ehrlichiosis did not have a rash. Injection of the vessels of the sclera and conjunctiva was noted in 42%. Hepatomegaly, subicteric sclera, and darkening of the urine with an increase in the bilirubin level and aminotransferase activity are possible. In some patients, a two-wave course of the disease was noted: the second wave had a more severe course, which was manifested by high and prolonged fever, severe intoxication: in some patients, serous meningitis developed at this time. An increase in creatinine levels was also noted, but there were no clinical manifestations of renal failure. Thrombocytopenia, increased ESR (16-46 mm/h): leukopenia (2.9-4.0x10 ⁹ /l) were registered in half of the patients.

Clinical symptoms disappear on the 3rd-5th day after the start of antibiotic therapy. Convalescents retain asthenia for 4-6 weeks after discharge. In severe cases of monocytic and granulocytic ehrlichiosis and the absence of etiotropic therapy, renal dysfunction was most often noted. up to renal failure (9%), the development of DIC syndrome with gastrointestinal, pulmonary or multiple bleeding. In 10% of patients with granulocytic anaplasmosis, the development of pulmonary infiltrates was observed. Some patients experienced seizures at the onset of the disease, and a comatose state developed.

Diagnosis of ehrlichiosis

The main signs that allow a diagnosis of ehrlichiosis are clinical and laboratory data in combination with an epidemiological history: the patient's stay in an area endemic for ehrlichiosis, a tick attack.

Examination of blood smears stained according to Romanovsky-Giemsa gives positive findings (vacuoles in the cytoplasm of neutrophils or monocytes containing clusters of Ehrlichia) rarely, and only in the acute phase of the disease.

Serological diagnostics of ehrlichiosis is performed using RNIF, ELISA, and, less frequently, immunoblotting. Seroconversion occurs during the first week of the disease, and antibodies detected in those who have recovered can persist for 2 years. The minimum diagnostic titer is 1:64-1:80 when examining one serum sample taken during the febrile period or early convalescence, as well as within a period not exceeding one year after the onset of the disease. Maximum antibody titers in monocytic ehrlichiosis in the 3rd-10th week of the disease were 1:640-1:1280. If the results of serological testing are inconclusive, PCR is promising.

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Differential diagnostics of ehrlichiosis

Since there are no pathognomonic symptoms of ehrlichiosis and the disease may progress as a mixed infection, differential diagnostics is difficult. It is quite difficult to suggest a clinical diagnosis, even taking into account changes in the blood picture. Information about a tick attack 1-3 weeks before the disease gives grounds to suspect systemic tick-borne borreliosis (Lyme borreliosis), and in endemic areas - other tick-borne fevers (Colorado, Rocky Mountain spotted fever). Differential diagnostics are also carried out with infectious mononucleosis, typhus and typhoid fever, leptospirosis. The frequently occurring mixed infection (ehrlichiosis with the classical form of tick-borne borreliosis and tick-borne encephalitis) leaves its mark on the picture of the disease and often does not have clear differential signs necessary for clinical diagnosis, however, in granulocytic anaplasmosis, the supporting symptoms may be acute anicteric hepatitis, as well as severe leukopenia, lymphopenia and an increase in the number of band elements at the onset of the disease.

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Indications for consultation with other specialists

Life-threatening complications (severe renal failure, massive bleeding, etc.) require consultation with a resuscitator with subsequent treatment of the patient in the intensive care unit.

Indications for hospitalization

Indications for hospitalization are considered to be a severe course of the disease, development of complications. Hospitalization is required by 50-60%, with about 7% of patients requiring intensive care.

Treatment of ehrlichiosis

Ehrlichia are sensitive to drugs of the tetracycline series (tetracycline, doxycycline), and to a lesser extent to chloramphenicol.

The most effective are tetracycline (0.3-0.4 g four times a day for 5-10 days) or doxycycline (0.1 g twice on the first day, then once): Levomycetin can be used. Treatment of ehrlichiosis should be combined with pathogenetic and symptomatic means (detoxification, control of complications, etc.).

Clinical examination

Medical examination is not regulated. Medical supervision is recommended until the ability to work is restored.

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What is the prognosis for ehrlichiosis?

Ehrlichiosis has a grave prognosis when severe complications develop in the absence of timely comprehensive treatment.