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Toxoplasmosis during pregnancy wide spread phobia Dr Roli Gautam MS Assistant Professor MedicityInstitute of Medical Sciences Hyderabad,A.P., India, Prof. Dr. Veena Agrawal MS, MICOG, WHO Fellow U.S.A. Prof. Obst.& Gynae G. R. Medical College, Gwalior MP India History • Toxoplasma gondii is an obligate intracellular protozoan . • It derives its name from a North African rodent the gondi, from which it was first isolated in 1908 . • First case of a congenitally infected human baby was reported in 1923 • Until 1969, life cycle of parasite was fully elucidate with the discovery of its definitive host, cats and other felines. Toxoplasma gondii Toxoplasmosis is the result of infection by Toxoplasma gondii, an obligate intracellular protozoan parasite in the phylum Apicomplexa. The major forms of the parasite are: • Oocysts (containing sporozoites), which are shed in the feces. • Tachyzoites, rapidly multiplying organisms found in the tissues. • Bradyzoites, slowly multiplying organisms found in the tissues. • Tissue cysts: walled structures, often found in the muscles and central nervous system (CNS), containing dormant T. gondii bradyzoites. Oocyst • Oocyst are formed as a results of fertilization between male and female gametocytes and are found in the epithelial cells of the intestines of definitive host • They are oval and 10-12 m in diameter • Oocysts are excreted in the faeces of the cat, contamination with which results in human infection. Trophozoites • Trophozoites crescent shaped with one pointed end and the other rounded end, and measure approximately 3-7m • released from the ingested oocysts, invade epithelial cells of the intestinal tract of the host • Disseminate via blood and lymph to most of the organs. • Invade all mammalian cells except nonnucleated erythrocytes and are found extracellulary as well as intracellularly in various organs. • multiply in a host cell by a process known as endodyogeny or internal budding. • The rapidly proliferating trophozoites, as known as techyzoites. • The trophozoites are either eliminated by the immune system of the host or by a drug or they are transformed into cysts. Tissue cysts • Tissue cysts are 10-100 in diameter and contain thousands of slowly multiplying forms of the parasite, aptly known as bradyzoites. • Formed within the host cells are early as 7 days after the entry of trophozoites. • Predominantly found in heart and skeletal muscles and central nervous system. • Known to persist within the tissue for the entire life span of the host and are responsible for the recrudescence of the infection, specially in immuno-compromised hosts. PARASITOLOGIC CONSIDERATIONS • • • • T. gondii has two of hosts: a definitive host - like cats and other felines an intermediate host - man and other . It multiplies by sexual reproduction in the definitive hosts, and by asexual multiplication in definitive as well as intermediate hosts. • Oocysts are highly resistant to environmental conditions and can remain infectious for as long 18 months in water or warm, moist soils. They do not survive well in arid, cool climates. • Tissue cysts can remain infectious for weeks in body fluids at room temperature, and in meat for as long as the meat is edible and uncooked. • Tachyzoites aremore fragile and can survive in body fluids for up to a day and in whole blood for as longas 50 days at 4°C. Source of infection • Domestic cats • Rodents (Rats) • Contaminated soil (persist in environment if moist) • Farm animal (Cow, goat, sheep, rabbits) Transmission of the infection • Occur as a result of ingestion of occysts excreted in the faeces of cats or by ingestion of udercooked meat harbouring tissue cysts. • Approximately 5-35% of pork, 9-60% of lamb and 0-9% of beef contain T. gondii. • Trans-placental transmission ot foetus from a mother infected during pregnancy is also a common occurrence. • In days of modern medicine, the odes of transmission have attained a new perspective, like blood transfusion, leucocyte transfusion and organ transplantation. TRANSMISSION A Diagram showing how infection is transmitted to Non-Immune Individuals Immunity to Toxoplasma gondii • • • • • • Active infection normally occur once The risk is only from an infection caught for the first time during pregnancy, or 2-3 months before conception. Acquired immunity is life long. Parasite remains in body as latent infection in the form of cyst in skeletal muscle, cardiac muscle and brain. Usually inactive and harmless. Reactivation occurs only in immunocomproised patients- Chemotherapy, Corticosteroid therapy, Congenital immunodeficiendy deficiency, HIV/AIDS, Patient having organ transplant Disinfection • oocysts are resistant to most disinfectants but can be inactivated by iodine, formalin and ammonia. • Can be destroyed within 10 minutes by temperatures greater than 66°C (150°F), and can be killed with boiling water. • Tachyzoites and tissue cysts are susceptible to most disinfectants, including l% sodium hypochlorite and 70% ethanol. • Tachyzoites are also inactivated at pH < 4.0. • Freezing at –15°C for more than three days or –20°C for more than 2days destroys a high percentage of the cysts. Geographic Distribution • Toxoplasmosis is found worldwide. • Infections are particularly common in warm,humid climates and at lower altitudes. • Acc. to one estimate, over 500 million humans around the world are infected with T. gondii. App 90% of the population in France, 20 to 70% in the in the USA and 30% in the U K, 1.4% - 27% in India are infected • Studies shown that 30% of 30-yr-olds and 50% of 70-yearolds have had a toxoplasmosis infection It is estimated that only 15% of women booking in for antenatal care are already immune. This leaves 85% of pregnant women still at risk of contracting the infection - Tommy's, the baby charity Incubation Period • 10 to 23 days after ingesting contaminated meat, • 5 to 20 days after exposure to infected cats. Clinical Signs – In immunocompetent non-pregnant individuals, • usually asymptomatic. • App 10-20% develop lymphadenitis or a mild, flulike syndrome characterized by fever, malaise, myalgia, headache, sore throat, lymphadenopathy and rash. In some cases, may mimic infectious mononucleosis • symptoms usually resolve without treatment within weeks to months, although some cases may take up to a year. • Severe symptoms, including myositis, myocarditis, pneumonitis and neurologic signs including facial paralysis, severe reflex alterations, hemiplegia and coma, are possible but rare. • Ocular toxoplasmosis with uveitis, often unilateral, can be seen in adolescents and young adults; this syndrome is often the result of an asymptomatic congenital infection or the delayedresult of a postnatal infection. In immunosuppressed patients • Toxoplasmosis is often severe. • Neurologic disease is the most common sign, particularly in reactivated infections. • Symptoms are: – Encephalitis, – Necrosis from multiplication of the parasite can cause multiple abscesses in nervous tissue, with the symptoms of a mass lesion. – Chorioretinitis, myocarditis and pneumonitis Toxoplasmosis during pregnancy • Tox is a part of TORCH syndrome. • It is not a cause of habitual abortion. • Only pregnent women with primary active infection leads to congenital tox. • Development of active immunity once, protects subsequent pregnancies. Rate of Transmission • Develop infection at least 6-9 months before pregnancy – Pt immune – rare transmission • within 2–3 months before conception - 1% or below risk of transmission but a high risk of miscarriage • The first trimester - 15% chance but Severity of disease in neonate is more • Second trimester - 25% risk • Third trimester - 65% chance but Severity of disease in neonate is less usually asymptomatic Congenital toxoplasmosis The consequences of the infection of foetus can be very different between subclinical to very serious. - - Abortion or still birth. Overt disease - Symptoms with classical triad. Hydrocephalus Intracranial calcification Chorioretinitis Sub clinical infection - Usually asymptomatic at birth Later on develops hearing defects, visual defects, mental retardation and learning disabilities, even severe, life-threatening infections later in life, if left untreated • Up to 90 percent of infected babies appear normal at birth, 80 to 90 percent will develop sightthreatening eye infections months to years after birth. About 10 percent will develop hearing loss and/or learning disabilities, 60% of infected may suffer from Long Term Sequella Contd • mild cases with only slightly diminished vision. Ocular disease is usually bilateral; • The most common symptom is chorioretinitis but strabismus, nystagmus and microphthalmia may also be seen. • Infants infected late in gestation may have a fever, rash, hepatomegaly, splenomegaly, pneumonia or a generalized infection. Prenatal Management • • • • • Screening for Toxo during pregnancy Frequent Antenatal visits Surveillance for Fetal growth & health Ultrasound for signs of foetal infection PCR on an amniotic fluid sample when infection in utero is suspected • Foetal blood sampling has now been abandoned at the expense of amniocentesis with PCR and mouse inoculation of amniotic fluid Prenatal Management • Routine neonatal screening for toxoplasmosis identifies congenital and early subclinical infections. Treatment may reduce the severe long term sequelae • The diagnosis of congenital toxoplasmosis is confirmed by demosntrating the presence of T. gondii in blood, body fluid or specific IgM antibodies • Special hearing and eye exams will be done, as well as a sonogram or CAT scan of his head and other tests as needed Criteria for Screening •Ideally all women of child-bearing age should know their serological status before conception. •Once the maternal serological status is known, screening is necessary •As maternal infection is most often clinically silent, repeated serological testing is the only way to diagnose all acute infections • All the these facts proof that myth that toxoplasmosis causes recurrence abortion or BOH are wrong. It is not mandatory to do screening in all the patients. • As Toxo is not very common,Screening should be only in patient – "High effluent society“ – Non vegetarians – eating habits and hygiene practices have been clearly identified as risk factors. – Immunocompromised patient • Mothers who tested positive before the pregnancy do not need monitoring • Mothers who tested negative should be monitored until term to avoid missing a clinically silent infection Diagnosis of toxoplasmosis • May be established by – Serological tests, – Polymerase chain reaction (PCR), – Histological demonstration of the parasite and/or its antigens (i.e. immunoperoxidase stain), – Or isolation of the organism Serodiagnosis • Presence of IgM antibodies or a four fold rise in IgG titres at 2-3 wks interval indicates a relatively recent infection. • Significant levels of IgM antibodies indicate infection acquired within the past 3 months. • IgG antibodies usually appear within 1 to 2 wks of infection, peak within 1 to 2 months, fall at variable rates, and usually persist for life • The titer does not correlate with the severity of illness Specific Toxoplasma Antibody Tire : Some interpretations Antibody Titre IgM IgM-IFA > 1:80 IgM-ELISA > 1:256 IgG IFA/Dye IgG and IgM Single high titre Rising titers at IFA > 1:1000 3 week interval IFA/Dye Titre < 1:1000 IgM-IFA/ELISA Negative Recent Acute Probably Recent Definite Recent Exclude Recent Infection Acute Infection Acquired Infection Acute Infection Blood test procedure flow chart blood test positive negative sample sent to lab for further testing positive to current infection positive to previous infection expert advice about risks and further action immune not at risk from toxo treatment scans/further tests to see if baby is infected not immune take precautions because preg could be at risk from toxo Serological Tests • IgM test – Determine recent infection or in the distant past. – Significant potential of misinterpretation of +ve result, should be confirmed by other tests. – Kits often have low specificity – IgM antibodies can persist for months to more than one year. – Persistence of these IgM antibodies does not appear to have any clinical relevance IgA Antibodies • IgA antibodies may be detected in sera of acutely infected adults and congenitally infected infants using ELISA or ISAGA methods. • May persist for many months to more than one year. • Of little additional assistance for diagnosis of the acute infection in the adult. • Has increased sensitivity of IgA assays over IgM assays hence useful for diagnosis of congenital toxoplasmosis IgE Antibodies • Detectable by ELISA in sera of acutely infected adults, congenitally infected infants, and children with congenital toxoplasmic chorioretinitis. • The duration of IgE seropositivity is less than with IgM or IgA antibodies and hence appears useful as an adjunctive method for identifying recently acquired infections confirmatory test, the Toxoplasma Serological Profile (TSP) • TSP, differentiate between recently acquired and chronic infection, is superior to any single serological test. • TSP consist of – Sabin-Feldman Dye Test (DT) – double sandwich IgM ELISA or IgM-immunosorbent (IgM-ISAGA) , IgA ELISA, IgE ELISA, – and AC/HS test. Sabin-Feldman Dye Test (DT). • DT is a sensitive and specific neutralization test in which live organisms are lysed in the presence of complement and the patient's IgG T. gondii-specific antibody Contd: • A positive DT establishes that the patient has been exposed to the parasite. • A negative DT essentially rules out prior exposure to T. gondii (unless the patient is hypogammaglobulinemic). • in a few patients, IgG antibodies might not be detected within 2 to 3 weeks after the initial exposure. • In rare cases of toxoplasmic chorioretinitis and toxoplasmic encephalitis in immunocompromised patients have been documented in patients negative for T. gondii-specific IgG antibodies. Differential agglutination (AC/HS) • uses two antigen preparations that express antigenic determinants found in early acute infection (AC antigen) or in the later stages of infection (HS). • Ratios of titers using AC versus HS antigens are interpreted as acute, equivocal, non-acute patterns of reactivity or non-reactive. • The acute pattern may persist for one or more years following infection. • This test is useful in helping differentiate acute from chronic infections but is best used in combination with a panel of other tests (e.g.: the TSP). Avidity Test • The functional affinity of specific IgG antibodies is initially low after primary antigenic challenge and increases during subsequent weeks and months. • Protein-denaturing reagents including urea are used to dissociate the antibody-antigen complex. • The avidity result is determined using the ratios of antibody titration curves of urea-treated and untreated serum • avidity test is an additional confirmatory diagnostic tool in the TSP for those patients with a positive and/or equivocal IgM test or acute and/or equivocal pattern in the AC/HS test. Polymerase Chain Reaction (PCR) • Used to detect T. gondii DNA in body fluids and tissues. • Used to diagnose congenital, ocular, cerebral and disseminated toxoplasmosis. • PCR performed on amniotic fluid has revolutionized the diagnosis of fetal T. gondii infection • PCR has allowed detection of T. gondii DNA in brain tissue, cerebrospinal fluid (CSF), vitreous and aqueous fluid, bronchoalveolar lavage (BAL) fluid, urine, amniotic fluid and peripheral blood Histologic Diagnosis • A rapid and technically simple method is the detection of T. gondii in air-dried, Wright-Giemsastained slides of centrifuged sediment • The presence of multiple tissue cysts near an inflammatory necrotic lesion probably establishes the diagnosis of acute infection or reactivation of latent infection. • It is often difficult to demonstrate tachyzoites in conventionally stained tissue sections. The immunoperoxidase technique, which uses antisera to T. gondii, has proven both sensitive and specific Isolation of T. gondii • Isolation of T. gondii by mouse inoculation from blood or body fluids establishes that the infection is acute. Ultrasound signs of foetal infection • Cerebral ventricular dilatation, usually symmetrical and bilateral- poor prognostic sign • starts in the posterior horns of the lateral ventricles and leads, sometimes in the space of a few days, to hydrocephalus • Intracranial densities are found less frequently. - well correlated with the presence of chorioretinitis at birth. • Hyperechogenic foetal bowel • Placental thickening with a“frosted glass” aspect, • hepatosplenomegaly and hepatic densities, pleural and pericardic effusions and ascites Ultrasound Myths & Facts • Foetal ultrasound is essential to the management of gestational infection and its role is both diagnostic and prognostic. • Signs of foetal infection are present in about 65% of pregnancies when infection occurred in the first trimester and in 20% in the second trimester • cannot be used as a screening tool as it detects only major signs of infection • Ultrasound signs of foetal infection after a negative amniocentesis is also of value in indicating a second sampling as a few foetuses are infected after the timeof prenatal diagnosis, • Following a negative amniocentesis, scans should be performed monthly. • When amniocentesis is positive scans should be performed fortnightly • Repeated scans are mandatory during an at risk pregnancy. HYDROCEPHALUS INTRACRANIAL CALCIFICATION CHORIORETINITIS Treatment Non-pregnant women desirous of pregnancy: • • • If IgM is positive, they should conceive after it becomes negative and until IgG titres should be stable and less than or equal to 1:1000. IgM positive titres and rising IgG titres mean recent infection. If these women are asymptomatic, no treatment required. Avoiding toxoplasmosis • only eat meat which has been thoroughly cooked (i.e. with no trace of blood or pinkness) • avoid raw cured meat, like Parma ham • wash hands, chopping boards and utensils thoroughly after preparing raw meat • wash all fruit and vegetables thoroughly to remove all traces of soil • don’t drink unpasteurised goats’ milk or eat dairy products made from it • wear gloves when gardening and wash hands and gloves afterward • if you eat while gardening wash your hands first, and try to avoid gardening in areas which may have been soiled with cat faeces • cover children’s sandpits to prevent cats using them as litter boxes • remove faeces from cat litter tray every day wearing rubber gloves and wash gloves and hands afterwards – or have someone else do this • do not handle lambing ewes and do not bring lambs into the house Treatment of pregnant women • Spiramycin is drug of choice can be given before 26 weeks no teratogenic effects • If fetus is infected there can be replaced by or addition of Sulfadiazine + pyrimethamine • Clindamycin or Dapson : If patient has sulfa drug allergy. • Higher dose therapy, continue for 4-6 weeks. • Lower dose maintenance therapy given there after : Medications • Medicine for toxoplasmosis is only needed when the infection affects an unborn baby (fetus) or someone with a very weak immune system. • diagnosed with toxoplasmosis during pregnancy, treat with antibiotics. • antibiotic treatment reduces the chances of transmission to fetus • fetus becomes infected (diagnosed using amniocentesis), another antibiotic replaces or is added. This treatment lessens the severity of fetal toxoplasmosis and related problems after birth. • If newborn has toxoplasmosis, will have antibiotics for the first year of life. This is needed to lower the risk of brain damage and blindness from the infection. Contd: • Spiramycin collects in the placenta, the site where the Toxoplasma gondii parasites travel to the fetus. • Antibiotic treatment during pregnancy (given to the mother) may not cure an infected fetus. However, it greatly reduces the risk and severity of fetal brain and eye damage. Foulon W, et al. (2000). • Infected infants who are not treated with antibiotics after birth can develop increasingly severe infection during the first 20 years of life. This can lead to mental retardation, eye damage, and sometimes blindness. Contd: • Studies show that although treatment after birth may not reverse all the damage that occurred before birth, it will greatly reduce a baby's risk of developing new problems during infancy and beyond. Drug Spiramycin Toxo during pregnancy 6-9 MIU/day in 2 or 3 divided doses for 3 wks followed by 2 wks intervals until parturition Pyrimethamine After 16 weeks in combination pyrimethamine 25 with mg/day with sulphonamides sulphadiazine 1-2 gm gid alternating with the cycles of spiramycin 6-9 MIU/day for 3 weeks until parturition Remarks safest amongst the antitoxoplasma agents Pyrimethamine is teratogenic. used in pregnancy only if potential benefit justifies the risk to foetus. Drug Spiramycin Congenital toxoplasmosis 0.15-0.30 MIU/Kg/day for 12 months Pyrimethamine 15 mg/square metre or 1 mg/kg/day in combination (maximum 25 mg/day), with with sulphadiazine or sulphonamides trisulphapyrimidine, 50-100 mg/kg/day alternation with the cycles of spiramycin 0.15-0.3 MIU/kg/day for 3 wks for 12 months Conclusion • Toxoplasmosis remains a serious disease although recent advances in diagnosis and treatment have greatly ameliorated the prognosis for the affected infants. • Routine screening is currently controversial • If IgM +ve or 3-4 fold increase in IgG, start Spiramycin • When infection in utero is documented, using PCR on an amniotic fluid, Add or replace a combination of pyrimethamine and sulfadiazine with folinic acid supplementation to antibiotic. • Infected infants should be treated postnatally up to one year of age with the same drugs, Education programmes may be preventing acquisition of toxo cases, only routine screening of all pregnant women or all newborn infants at birth would prevent or detect a higher proportion of congenital infections. 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