Toxoplasmosis is a zoonotic disease caused by Toxoplasma gondii. It is widely parasitized in nucleated cells of humans and animals. The clinical manifestations of the disease are complex, and the signs and symptoms are not specific enough to cause misdiagnosis, mainly affecting the eyes, brain, heart, liver and lymph nodes. Toxoplasma gondii is one of the important pathogens that cause embryonic malformations during intrauterine infection during pregnancy. It is also an important pathogen causing opportunistic infections in immunodeficient patients. Wang Yan, Department of Infectious Diseases, Peking University First Hospital, Wuhan Union Hospital, Jie Shenghua
Pathogenesis]
Toxoplasma gondii is an intracellular parasitic protozoan. The nucleus is located slightly behind the center of the worm body, and it appears mostly in the acute stage of the disease. “The nucleus is located in the central part of the body, and the nucleus is mostly in the acute stage of the disease. Asexual reproduction can often cause systemic infection. The pseudocysts, which are round or oval in shape and 10 to 200 μm in diameter, can survive in tissues for a long time and are usually found in chronic cases, such as brain and muscle. They are usually found in chronic cases, such as brain and muscle tissues. They multiply and accumulate into spherical bodies within the cells, and form elastic cyst walls by themselves. (3) Cleistocytes are found in the intestinal epithelial cells of the terminal host, with a diameter of 12-15 μm, containing 4-20 cleistocytes, with a pointed anterior end and a blunt rounded posterior end. The gametophyte is found in the final host and is divided into two types: large gametophyte and small gametophyte. The oocyst is found in the feces of the final host. The first three stages are asexual and the last two stages are sexual. Toxoplasma gondii can move one to two times its own length in one second with the help of telescopic movements, and can invade cells within 15 to 20 seconds. The resistance of Toxoplasma gondii to the outside world varies at different stages of development, with the free Toxoplasma being the weakest, the encapsulated Toxoplasma being the most resistant, and the oocyst being the most resistant.
The life history of Toxoplasma gondii can be divided into two stages: asexual reproduction (development in intermediate hosts including birds, mammals and humans) and sexual reproduction (both asexual and sexual reproduction in final hosts, cats and felines)
After entering the digestive tract, Toxoplasma gondii quickly reaches various tissues and organs via lymph and blood, actively invades nucleated cells, or is engulfed by phagocytes and develops and multiplies into tachyzoites in their cells. After the host cells rupture, the tachyzoites enter new cells and continue to develop and proliferate. When some tachyzoites invade the host brain, eye, skeletal muscle and other tissue cells, they become slow-growing retarded proliferators and secrete some substances to form a vesicle wall, which becomes an independent capsule after bursting the host cell. The capsule can exist in the intermediate host for months, years, or even for life. When the immune function of the host is reduced, toxoplasmosis can appear again.
2. The developmental stages of oocysts, encysts and pseudocysts in the end-host are swallowed by felines and release ascospores, tachyzoites and retarded ascospores, which reproduce asexually in the feline body. The oocysts develop and proliferate in the epithelial cells of the intestinal mucosa of the final host small intestine, forming a cleavage body. After cell rupture, the lysosomes escape, invade nearby cells, and continue to proliferate. After several generations of proliferation, some of them develop into male and female gametophytes, which proliferate as gametes, and the male and female gametophytes unite to form conidia, which finally develop into oocysts. After maturation, the oocysts are removed from the host intestinal epithelium and fall into the intestinal lumen, where they are excreted in the feces. The oocysts mature at a suitable temperature (24°C) and humidity in about 2-4 days and contain 2 sporangia, each with 4 ascospores, which are infectious and resistant and can survive for more than 1 year.
Epidemiology
Toxoplasmosis is a global epidemic. China is a low-infection area, with an infection rate of 0.09% to 34%, but shows an increasing trend year by year. According to the survey, the existence of this disease has been confirmed in almost all provinces, cities and autonomous regions in China. The infection rate of normal population is less than 10%; the infection rate of special population such as tumor patients, psychiatric patients, infants and children with congenital defects, immunosuppressed or immunodeficient patients is higher.
Toxoplasmosis is a zoonotic protozoan disease. Among domestic animals, it is the most harmful to pigs and sheep, especially pigs, and can cause epidemic outbreaks.
According to the pathogenic survey, 141 species of mammals are confirmed to have Toxoplasma gondii, but for humans, livestock and poultry are important sources of toxoplasmosis, especially cats and felines infected with Toxoplasma gondii, which are important in the transmission of the disease.
The former means that the disease develops when the host is immunocompromised and can be transmitted to the fetus via the placenta in the mother’s womb; the latter means that the infection is mainly oral after birth and can be acquired by eating uncooked meat, eggs, milk, etc. containing Toxoplasma gondii. The latter is mainly transmitted by mouth after birth and can be acquired by ingesting uncooked meat, eggs and milk. In addition, contact with soil and water contaminated by oocysts is also an important route. Blood transfusion and organ transplantation are important routes of medical transmission. Arthropods carrying oocysts also have some transmission significance.
3. Population susceptibility Humans are generally susceptible to Toxoplasma gondii. Especially fetuses, infants and children, tumors and AIDS patients. Long-term use of immunosuppressants and immunodeficient people may rekindle the occult infection and develop symptoms. Occupation, lifestyle, economic level, dietary habits, hygiene, and cultural quality are closely related to Toxoplasma gondii infection.
The disease has certain occupational distribution characteristics, animal breeders, slaughterers, meat processing workers and toxoplasmosis laboratory researchers are all susceptible; in addition, the disease also has certain ethnic distribution characteristics, ethnic minorities are more seriously affected by toxoplasmosis than Han Chinese, which may be related to certain living and eating habits and hygiene conditions of ethnic minorities.
Pathogenesis and pathological changes
Toxoplasma gondii infection can be either dominant or recessive, and is closely related to the immune status of the host. People with normal immune function are mostly asymptomatic after infection, but those with impaired or defective immune function and those with congenital infection often have severe symptoms. Infection in pregnant women can cause miscarriage, premature birth and even stillbirth. AIDS patients can often lead to serious complications and even death. Previous studies have suggested that T lymphocytes play a key role in fighting infection. Recent studies have found that B lymphocytes also play a role that cannot be ignored. Therefore, it is important to enhance the immunity of susceptible individuals.
Toxoplasma gondii, unlike most other intracellular parasitic pathogens, can infect almost all types of cells. Toxoplasma gondii enters the bloodstream from the invasion site and then spreads throughout the body and rapidly enters monocytes-macrophages as well as various organs or tissue cells of the host to multiply until the cells swell up and the escaped tachyzoites can invade neighboring cells, and so on repeatedly, resulting in focal necrosis of local tissues and inflammatory reaction of surrounding tissues, which is the basic lesion in the acute stage. If the patient’s immune function is normal, specific immunity can be generated rapidly to clear Toxoplasma gondii and form a hidden infection; the protozoa can also form a capsule in the body and incubate for a long time, once the body’s immune function is reduced, the tachyzoa in the capsule will break the capsule and escape, causing recurrence. If the immune function of the patient is deficient, the worms will multiply and cause systemic disseminated damage. Toxoplasma gondii can also act as an antigen, causing allergic reactions and granuloma-like lesions. In addition, focal damage caused by Toxoplasma gondii can lead to severe secondary lesions, such as small thrombosis, local tissue infarction surrounded by hemorrhagic and inflammatory cells, and the formation of cavities or calcifications over time.
Toxoplasma gondii can attack a variety of organs or tissues, with the most common sites of lesions being the central nervous system, eyes, lymph nodes, heart, lungs, liver and muscles.
Histopathological examination often shows typical follicular hyperplasia in the lymph nodes, focal damage with mononuclear cell infiltration and irregular concentrations of cytoplasmically eosinophilic, dense tissue phagocytes. Granulocytic infiltration and abscess formation are rarely seen.
Clinical manifestations
There are two types of infections: congenital and acquired, both with occult infection. Clinical symptoms are mostly caused by recent acute infection or activation of underlying lesions.
(A) Congenital toxoplasmosis can be transmitted to the fetus through the placenta when a pregnant woman is infected with Toxoplasma gondii without treatment. The incidence and severity of congenital infection are related to the timing of infection in pregnant women: early gestational infection results in a low rate of congenital infection in the fetus, but the condition is severe. The incidence of congenital Toxoplasma gondii infection in late pregnancy is high, but the disease is mild. The clinical manifestations of congenital toxoplasmosis are complex and varied. Premature birth, miscarriage or stillbirth may occur during pregnancy. After birth, a variety of congenital malformations may occur, including hydrocephalus, microcephaly, spina bifida, microphthalmia, anophthalmia, cleft harelip and palate, etc. Psychomotor disorders due to toxoplasma encephalopathy may include mental retardation, epilepsy, myotonia, spasticity and paralysis; ocular lesions are more common, including chorioretinitis, ocular muscle paralysis, iridocyclitis, cataract, optic neuritis and optic nerve atrophy, etc. In addition, after birth, children with toxoplasmosis may have Fever, rash, pneumonia, hepatosplenomegaly, jaundice, etc. Pregnant women with Toxoplasma gondii infection may also have increased pregnancy complications, such as weak contractions, excessive postpartum bleeding, incomplete uterine regeneration, and endometritis. If infected pregnant women are treated, the incidence of congenital infection can be reduced by about 60%.
(ii) Acquired toxoplasmosis is more complex, with varying severity, ranging from subclinical to fulminant infection, and is related to the soundness of immune function.
Several patients have enlarged nodes, and in addition to enlarged superficial lymph nodes, they can also. The present is more complex, whether soundness related, hepatosplenomegaly, jaundice, etc. And atrophy and other spasms and paralysis; eye lesions are mostly seen as hydrocephalus, microcephaly, spina bifida, microphthalmia, anophthalmia, cleft harelip and palate, etc.
1. 80% to 90% of acquired toxoplasmosis with normal immune function are occult infections or enlarged cervical lymph nodes. 10% to 20% of patients have clinical symptoms, manifested as chills, fever, headache, myalgia, pharyngitis, rash, enlarged liver and spleen, and enlarged lymph nodes throughout the body. in addition to superficial lymph node enlargement, mediastinal, retroperitoneal or mesenteric lymph nodes may also be involved, and abdominal pain may be present in the case of enlarged abdominal lymph nodes. Chorioretinitis may also occur.
The course of the disease is benign and self-limiting in most patients, usually weeks to months and rarely more than a year. Most lymphadenopathy resolves spontaneously, with a few patients becoming chronic. Very few cases may develop pneumonia, acute respiratory distress syndrome, myocarditis, pericarditis, polymyositis, hepatitis and encephalitis.
2. Immunodeficient acquired toxoplasmosis in immunodeficient patients such as AIDS, organ transplantation, Hodgkin’s disease, lymphoma and other patients infected with Toxoplasma gondii or relapse of latent infection may have significant systemic symptoms such as high fever, maculopapular rash, myalgia, arthralgia, headache, vomiting, delirium, etc. K may occur with disseminated and severe multi-organ infection.
(1) Toxoplasma gondii infection of the central nervous system
1) Focal encephalopathy: manifests as occupying lesions in the brain, such as headache, hemiparesis, epilepsy, visual impairment, and confusion.
2) Diffuse encephalopathy: Less common, but rapid onset and progression. There is delirium with signs of meningeal irritation and other meningoencephalitis.
3) Myelitis: seen in AIDS patients with Toxoplasma gondii infection. There may be motor and sensory deficits in one or more limbs.
(2) Pulmonary toxoplasmosis: Most often seen in patients with advanced AIDS. There is prolonged fever, cough and dyspnea.
(3) Ocular toxoplasmosis: The main manifestation is chorioretinitis. There is vision loss, visual distortion, etc.
(4) Other toxoplasmosis: hypopituitarism, uremia; abdominal pain, diarrhea, ascites and acute liver failure, etc.
[Laboratory tests].
Total peripheral blood leukocyte count is usually within normal range or mildly increased. Lymphocytes can be increased, but the percentage of increase usually does not exceed 10%, and abnormal lymphocytes can be seen; the percentage of eosinophils can also be increased. In Toxoplasma gondii encephalopathy, the typical cerebrospinal fluid shows an increased total leukocyte count, with predominantly monocytes; increased protein, normal sugar, and decreased chloride. Tachyzoites are sometimes visible in cerebrospinal fluid by centrifugal Jimsa staining.
(A) Pathogenic tests are less commonly used in clinical practice because of their complexity, low detection rate, and invasive nature. Direct microscopic examination of blood, bone marrow, cerebrospinal fluid, lymph nodes, muscle, liver and spleen, placenta and other tissues inside and outside the cells can find tachyzoites, pseudocapsules or slow colonization can be diagnosed, but the positive rate is not high. Animal inoculation or tissue culture can be used for the identification of Toxoplasma gondii. Currently, polymerase reaction (PCR) and real-time quantitative PCR methods can be used to diagnose this disease with high specificity and sensitivity.
(B) Immunological tests are simple and rapid, with high sensitivity and specificity, and are therefore most widely used in clinical practice.
1.Serum specific antibody detection of Toxoplasma gondii infection, IgM antibodies can appear in the 5th to 7th day, IgM positive or IgG has more than 4 times increase in 2 weeks, which can diagnose the present infection early. Commonly used detection methods include Sabin-Feldman staining test (Sabin-Feldman, SFDT), indirect fluorescent antibody test (IFA), indirect hemagglutination test (IHA), enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA) and so on. Among them, ELISA has high sensitivity and specificity, and is widely used in clinical applications.
2.Serum circulating antigen test is commonly used to detect Toxoplasma gondii circulating antigen in serum by ELISA, which has high sensitivity and specificity and can be used as a reliable method for early diagnosis and confirmation.
3.Intradermal test is performed on the peritoneal fluid of infected mice or chicken embryo fluid. It is generally positive only 4~18 months after infection and can only be used for epidemiological investigation.
Diagnosis
1, congenital toxoplasmosis This disease has complex clinical manifestations and is difficult to diagnose. If the clinical appearance of chorioretinitis, hydrocephalus, microcephaly, intracranial calcification, etc. should be considered the possibility of the disease. Definitive diagnosis depends on pathogenetic examination. Serological examination is the most commonly used diagnostic method. In the acute phase, IgM can be positive within a week. If the initial test is positive for IgM and negative for IgG, a repeat test 2 weeks later is positive for both IgM and IgG, this diagnosis is supported. Because direct contact with felines is not required for Toxoplasma gondii infection, it is important to emphasize that a history of cat contact is not necessary. However, the diagnosis of toxoplasmosis cannot depend on any one test due to sensitivity and specificity issues. High-risk groups (e.g., pregnant women, immunocompromised individuals) require multiple serological testing methods for further diagnosis.
2. Toxoplasma gondii lymphadenitis can be diagnosed in immunocompetent hosts with acute lymphadenopathy, if the serological ELISA test is positive for IgM and positive for both IgM and IgG after 2 weeks; negative for both IgM and IgG can exclude this diagnosis. If the serological ELISA results are suspicious, other serological tests (e.g. staining tests) or PCR for Toxoplasma gondii DNA may be performed to confirm the diagnosis. If ocular lesions are clinically present, Toxoplasma gondii antibodies from relevant intraocular samples will be required to confirm the diagnosis.
Most AIDS patients with Toxoplasma gondii may present with multiple, dense lesions in the brain parenchyma with edema. CT or MRI should be performed if there are clinical symptoms such as headache and neck stiffness, and MRI is more sensitive than CT. If necessary, craniotomy or stereotactic brain biopsy can be performed.
Since Toxoplasma gondii in AIDS patients is a recurrence of latent infection, patients already have IgG antibodies in their bodies, but not IgM antibodies, and less than 1/3 of patients have elevated antibody titers. Therefore, once a patient with AIDS has the following 3 points of performance: CD4+ cell count <0.1×109/L, positive IgG in serological examination, and typical manifestations in brain imaging, it can be considered as a suspected diagnosis and receive empirical treatment. If the 3 diagnostic points cannot be met simultaneously, brain biopsy or other diagnostic tests are required.
Differential diagnosis
Congenital toxoplasmosis should be differentiated from other diseases in the TORCH syndrome (rubella, other congenital anomalies, cytomegalovirus infection, herpes simplex, and toxoplasmosis). It should also be differentiated from congenital syphilis, for example.
Toxoplasma gondii lymphadenitis should be differentiated from lymph node tuberculosis, bacterial lymphadenitis, and lymphoma.
Acute toxoplasmosis with systemic symptoms should be differentiated from EBV or cytomegalovirus infection, sepsis, cat scratch fever, rabbit fever, brucellosis, etc.
Toxoplasmosis of the central seeding system should be differentiated from viral, bacterial, tuberculous and fungal meningitis, encephalitis and meningoencephalitis, etc.
Treatment
I. Target of anti-Toxoplasma treatment
(a) Immunocompetent patients with severe symptoms and important organ involvement, such as cerebral toxoplasmosis and ocular toxoplasmosis;
(ii) Immunocompetent patients with dominant and recessive Toxoplasma gondii infection.
(iii) Children with congenital toxoplasmosis.
(iv) Pregnant women with recent Toxoplasma gondii infection whose serological test has changed from negative to positive.
Anti-Toxoplasma treatment drugs and methods are reliable for trophozoites, but there is no effective drug for encystment, so the recent treatment is effective but easy to relapse. Combined with the Fourth National Symposium on Toxoplasmosis in 2001, we recommend the following treatment plan.
1. The first-line treatment regimen for acute toxoplasmosis with normal immune function is etanercept 50 mg/d given in 2 doses, doubling the first dose, and combined with sulfadoxine-pyrimethamine 80 mg/(kg.d), given orally in 4 doses, doubling the first dose. Or compound sulfamethoxazole 2 tablets/d twice daily, doubling the first dose. Duration of treatment: 15 days. Sulfasalazine allergy or intolerance can be changed to ethamethoxazole combined with clindamycin. Clindamycin 10-30mg/(kg.d) in 3 oral doses for 10-15 days. Because ethamethazine can cause folic acid deficiency, calcium folinic acid needs to be added. The second-line regimen is ethidiazine combined with azithromycin 5mg/(kg.d) once daily, doubling the first dose for 10 days; or ethidiazine combined with atovaquone, atovaquone 750mg per oral dose 4 times daily for 4 weeks. The above treatment regimen should be repeated for 1~2 courses of treatment after an interval of 5~7 days according to the condition.
2. Pregnant women should not use ethidium (to prevent teratogenicity) and sulfonamide during pregnancy treatment. For toxoplasmosis in early pregnancy, treatment with spiramycin is recommended. The dose is 3~4g/d, divided into 3 oral doses. 20 days is a course of treatment. Or azithromycin at a dose of 5mg/(kg.d) once daily, doubling the first dose, two courses of treatment are recommended for early pregnancy. In late pregnancy, one course of treatment is available.
3.Treatment of neonatal infection The recommended treatment regimen for neonatal manifest toxoplasmosis abroad is: ethidiazine 2mg/(kg.d) for 2 days, then 1mg/(kg.d) for 2 to 6 months, then three times a week for 6 months; sulfadiazine 100mg/(kg/d) in two doses, and calcium folinic acid 5~10mg/d for three times a week. three times. Treatment of neonates with asymptomatic congenital toxoplasmosis with etanercept and sulfadiazine may improve neurological symptoms and development. In China, spiramycin combined with sulfadiazine or ethacridine combined with sulfadiazine or azithromycin is recommended.
4. Immunodeficient toxoplasmosis treatment for immunocompromised individuals is at least 1 times longer than the above treatment regimen; at least 2 courses of treatment. The first-line treatment regimen is: etanercept 50mg/d combined with sulfadiazine 6-8g/d, with the addition of calcium folinic acid. The total course of treatment should be at least 6 months.
(1) Cerebral toxoplasmosis etanercept combined with sulfadiazine. Ethacil 100mg/d in two doses for 2 days of treatment, followed by 50mg/d, and sulfadiazine 100mg/(kg.d) in two doses for 2 days of treatment, followed by 75mg/(kg.d) in two doses. Patients who respond well to treatment are treated with the standard dose for a typical course of 6 weeks. In chronic cases, the dose can be reduced for the second course: sulfadiazine 2-4g/d in 2-4 doses, combined with etanercept 25-50mg/d and calcium folinic acid 10-25mg/d. In intracranial lesions, adrenal glucocorticoids can be used for the first 48 hours of the course. Dexamethasone, 4mg/6h, is usually used, while other opportunistic infections are closely monitored and antibiotics are added to prevent secondary bacterial infections. Imaging and neurological examination can be used as indicators to observe the efficacy of treatment.
Other treatment options:Clindamycin 600mg/8h combined with etanercept 25-50mg/d and calcium folinic acid 10-25mg/d. Atovaquone 750mg, orally 2-4 times/d alone or combined with oral etanercept 25mg/d and calcium folinic acid 10mg/d.
Abroad, according to the CDC/NIH/HIVMA (HIVmedicineassociationoftheinfectiousdiseasessocietyofAmerica) guidelines, it is recommended to discontinue primary Toxoplasma gondii treatment in AIDS patients if their CD4+ cell count exceeds 200/ml or more and is maintained for at least 3 months. Treatment for chronic cerebral toxoplasmosis may be discontinued in AIDS patients with CD4+ cell counts above 200/ml and maintained for at least 6 months. Once the CD4+ cell count drops below 200/ml, standard therapy is restarted.
(2) Ocular toxoplasmosis etanercept 75 mg/d given in two divided doses and sulfadiazine 2 g/d given in two divided doses for more than 4 weeks. Clindamycin can also be used, each oral dose of 300mg, 4 times a day, the course of treatment for more than 3 weeks.
Prognosis
The prognosis depends on the immune status of the host and the involved tissues and organs. The prognosis of severe congenital infection is poor. The prognosis of untreated congenital toxoplasmosis is poor, and long-term survival is related to the degree of central nervous system involvement. Chorioretinitis can then lead to corneal damage and eventually blindness. After treatment, the prognosis for Toxoplasma gondii is good, but some children develop late onset keratopathy years after birth and may have recurrent episodes. Treatment is also effective for intracranial calcification. In adults with immune deficiency, such as AIDS, malignancy and organ transplantation, Toxoplasma gondii tends to be systemically disseminated and has a poor prognosis. Simple lymph node enlargement has a good prognosis. Adult ocular toxoplasmosis is also often recurrent.
Prevention
Toxoplasmosis is widely prevalent and both humans and animals are susceptible. Active measures should be taken for its transmission and immunoprophylaxis.
1. Pay attention to dietary hygiene, fully cook meat and separate raw from cooked.
2. Cats should be domesticated to avoid infection and transmission from the digestive tract through contaminated food.
3, pay attention to daily hygiene, pet owners, wash hands carefully after contact with animal excrement.
4. Pregnant women should avoid contact with cats and their feces during pregnancy. Monitor closely for Toxoplasma IgM and IgG, and if necessary, take amniotic fluid for immunological examination. If there is evidence of acute infection, consider whether to terminate the pregnancy.
5. Regularly monitor Toxoplasma gondii infection in key high-risk groups such as AIDS patients; practice good hygiene and dietary habits, do not eat raw food, undercooked meat, eggs and milk, and do not drink raw water.
6. Training on prevention should be strengthened for agricultural and livestock producers, fur processors, slaughterers, meat processors, laboratory animal breeders and users.
Toxoplasma gondii vaccine is under research and has not been used for immunization prevention.