Serodiagnosis of toxoplasmosis. The impact of measurement of IgG avidity?

Comment by InpharmD Researcher

The development of IgG avidity assays has revolutionised serological diagnosis of Toxoplasma infections. The measurement of IgG avidity has shown its power in various clinical settings, especially in situations where timing and differentiation of primary and secondary infections is crucial. However, no laboratory test performed alone is self-sustained, whereby the diagnostic strategy of choice is sequential (or combinatorial) use of high-quality IgG, IgM, IgA and IgG-avidity assays. The impact of IgG avidity measurement will be discussed in five clinical scenarios: acute acquired infection, primary infection during pregnancy, congenital toxoplasmosis, ocular toxoplasmosis and Toxoplasma infection in immunocompromised patients. All in all in toxoplasmosis, superior diagnostic performance is achieved by appropriate combinations of serological, culture-based and PCR techniques.

PCR has been successfully used to diagnose Toxoplasma encephalitis in immunocompromised patients (cerebral biopsy is the only diagnostic method) and in ocular toxoplasmosis. In this evenience it is useful the study of IgG, IgM, IgA profile of paired serum and aqueous humor.

Background

Diagnosis of toxoplasmosis is useful for human and animal health. Several techniques are employed for the diagnosis in feline and canine population. Coprological tests for the detection of oocysts in cat faeces are of little significance owing to short patency (15 days). Histological examinations of biological samples show a lack of reliability when the animals are infected with few parasites; the mouse inoculation is the most reliable method even if the detection of cysts in mice brain require 40 days. However tachyzoites of virulent strains can be isolated from peritoneal exudate 3-4 days after inoculation. Samples inoculation in cell cultures (VERO, human fibroblasts) requires specialized laboratories and fails if non viable parasites are present due to tissutal autolysis. Serological tests are the most used diagnostic methods; Dye test and IFAT that require intact tachyzoites are more sensitive and specific compared to IHA, LA, ELISA because, during the infection, the first significant increase of IgM and IgG antibodies was observed against cuticolar antigens. A PCR to identify T. gondii DNA in canine and feline biological samples was developed. The B1 PCR performed on blood samples was less sensitive than when it was performed on other biological fluids requiring 100 tachyzoites, instead of 10. Aqueous humor PCR results could be negative if the infection is low grade or is restricted to the posterior segment or the animal was previously treated with anti-Toxoplasma drugs. SNC disease may be also difficult to diagnose because an high serum IgG titer may be associated with locally production or leakage from serum through a compromised blood-CSF barrier. AB1 PCR was successfully applied for the diagnosis of Toxoplasma abortion in ewes requiring only 10 parasites in placental cotyledon samples; the test compared with mouse inoculation showed similar sensitivity. [1]

Discrepancies may have been due to a low and focal distribution of parasites in the tissues or to the presence of non viable parasites if the tissues are autolysed. In regard to diagnostic methods adaptable to slaughter testing, several serological tests have been studied (IFAT, ELISA, IHA) for detection of IgG in sheep, pigs, cattle using also recombinant antigens (gene fragments H4 and H11) to lack the cross reactivity. The problem is the antibodies fall to near background levels as the infection became chronic (6-10 months p.-i.). A highly sensitive and specific method (Toxo Taq Man) has been developed to detect and quantitate T. gondii burden in animal tissue samples (0.1 pg of T. gondii genomic DNA, which is equivalent to 1 bradyzoite) using T. gondii ITS1-derived primers and a fluorogenic probe via Real-Time PCR. This assay is compatible with automation technology for potential slaughterhouse use. The diagnosis of acute infection in human pregnancy is difficult since IgM antibodies can be detected for a very long time after the acute phase; an IgA increase is of more diagnostic value because can be detected only for 6-7 months while the short kinetics of IgE can be useful only to date the infection precisely. In addition an IgG seroconversion is essential for the diagnosis. Among the most reliable tests, IgG avidity test is useful when a single serum sample, in the first months of gestation, is available, but low avidity results may persist for as long as 1 year. For this purpose a panel of serologic tests must be performed (ELISA, EIA, ISAGA, IgG avidity, IFAT, Dye test) for IgM, IgA, IgG and IgE. The serological diagnosis of prenatal infection is difficult since maternal IgG are passively transferred in utero to the foetus and caution must be exercised in interpretation of IgM or IgA results. A technique of Western blots of paired maternal and baby sera for evidencing different bands in the blots of two sera was developed for this purpose (specificity 97-100%, sensitivity 96-98%). The most reliable methods for prenatal diagnosis are PCR, mouse inoculation and cultural techniques performed on amniotic fluid, foetal blood and peripheral maternal blood in pregnants serologically positive. PCR (targets B1, SAG-1, rDNA) with amniotic fluid performed from 18 weeks of gestation is more sensitive and more rapid than conventional diagnostic procedures. [2]

Toxoplasmosis has been well known as an important human infection to consider especially in pregnant women. Although many serologic methods are available, the diagnosis of toxoplasmosis can be extremely difficult. The presence of increased levels of Toxoplasma-specific IgG antibodies indicates an infection, but it does not differentiate between a recent and past infection. The purpose of our study was to compare the performance of the ELISA T. gondii IgG/IgM test, a widely used enzyme-linked immunosorbent assay, to the ELISA IgG avidity method. One hundred and four serum samples (from 38 males and 66 females) were tested and evaluated from symptomatic patients (chorioretinitis, lymphadenopathy), and from women in their first trimester of pregnancy who were suspected of having toxoplasmosis. The high IgG avidity and ELISA IgG antibody levels were in agreement for 51 of the specimens (49.0%). Thirty-eight discrepant (borderline) results from the IgG avidity method were positive for IgM (3 specimens) and IgG (37 specimens). Interestingly, out of the eight serum samples that were positive for both IgG and IgM antibodies, two samples were low IgG avidity, and three samples were borderline. There was no statistically significant relation observed between the results of the IgG avidity method and the ELISA IgG test, and the IgG avidity method and ELISA IgM test (chi2 = 1.987; p = 0.370 and chi2 = 2.152; p = 0.341, respectively). The IgG avidity method was considered easy to perform and an acceptable approach for the differentiation of discrepant results (recent/chronic) and for the current detection of T. gondii antibodies. [3]

The usefulness of testing for IgG avidity in association with Toxoplasma gondii was evaluated in a US reference laboratory. European investigators have reported that high-avidity IgG toxoplasma antibodies exclude acute infection in the preceding 3 months. In this US study, 125 serum samples taken from 125 pregnant women in the first trimester were chosen retrospectively, because either the IgM or differential agglutination (AC/HS) test in the Toxoplasma serologic profile suggested or was equivocal for a recently acquired infection. Of 93 (74.4%) serum samples with either positive or equivocal results in the IgM ELISA, 52 (55.9%) had high-avidity antibodies, which suggests that the infection probably was acquired before gestation. Of 87 (69.6%) serum samples with an acute or equivocal result in the AC/HS test, 35 (40.2%) had high-avidity antibodies. Forty women were given spiramycin, to prevent congenital transmission, and 7 (17.5%) had high-avidity antibodies. These findings highlight the value of testing a single serum sample obtained in the first trimester of pregnancy for IgG avidity. [4]

References: [1] Piergili Fioretti D. Parassitologia. 2004 Jun;46(1-2):177-81.
[2] Tanyuksel M, Guney C, Araz E, Saracli MA, Doganci L. J Microbiol. 2004 Sep;42(3):211-5.
[3] Tanyuksel M, Guney C, Araz E, Saracli MA, Doganci L. J Microbiol. 2004 Sep;42(3):211-5.
[4] Liesenfeld O, Montoya JG, Kinney S, Press C, Remington JS. J Infect Dis. 2001 Apr 15;183(8):1248-53. doi: 10.1086/319672. Epub 2001 Mar 16.
Relevant Prescribing Information

An assay measuring the avidity of T. gondii-specific IgG is a useful serological indicator of toxoplasmosis which in many cases allows on the basis of single serum sample testing to confirm or exclude acute infection. IgG antibodies against T. gondii produced in the recent primary infection are of low-avidity while IgG antibodies in the chronic toxoplasmosis are of high-avidity. In the present study 80 sera: 47 sera of patients with suspected acute toxoplasmosis, 23 sera of pregnant women and 10 sera of healthy blood donors, were evaluated for the presence of IgM, IgA and IgG antibodies and for the avidity of IgG. Among the 80 tested sera IgM antibodies were present in 34 (42.5%) cases of which 22 (64.7%) showed low-avidity of IgG and the presence of IgA antibodies confirming acute toxoplasmosis. In the rest of these 34 sera three of them showed low avidity index and nine other high avidity in spite of the presence of IgM antibodies. In these 12 sera IgA antibodies were not present. In 46 (57.5%) examined sera IgM or IgA antibodies were not detectable and the present the IgG antibodies showed high-avidity what is characteristic of chronic infection. An assay for evaluation of avidity of IgG antibodies specific for T. gondii is valuable in complementing existing tests and in many cases it has decisive value for interpretation of results. [5]

Toxoplasma gondii is an intracellular protozoan infecting humans and animals. Infection in adults usually causes mild disease but greater importance lies in preventing transplacental transmission which can cause major foetal anomalies and is vital to identify infection in pregnancy. Research on this regard in Sri Lanka is scarce and would be beneficial in developing antenatal care strategies for improved foetal outcome. A random sample of 536 pregnant women attending antenatal care in Teaching Hospital Peradeniya from 2010 to 2013 was recruited for this study. Blood samples were tested for Toxoplasma gondii IgG and IgM antibodies from the participants by using a commercial ELISA kit with a cut-off OD value of >1 and a structured questionnaire was used to identify the exposure to risk. Bivariate analysis using the Chi Square test was used to calculate associations between documented risk factors and seropositivity and a p value of <0.05 was taken as significant. Among the participants 160 (29.9%) were positive for T. gondii IgG antibodies and 2 (0.37%) were IgM positive. The seroprevalence in the first, second and third trimesters were 30.4%, 30.6% and 26.1% respectively. Of the risk factors studied, preparation and selling raw meat (p = 0.05) and household gardening (p = 0.01) were significant whereas the presence of domesticated cats and dogs, eating locally produced meat or dairy products did not show significant associations. [6]

References: [5] Sobieszczańska BM. Pol Merkur Lekarski. 2002 Aug;13(74):111-5.
[6] Iddawela D, Vithana SMP, Ratnayake C. BMC Public Health. 2017 Dec 4;17(1):930. doi: 10.1186/s12889-017-4941-0.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Serodiagnosis of toxoplasmosis. The impact of measurement of IgG avidity?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

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Design

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Objective

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Study Groups

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Inclusion Criteria

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Exclusion Criteria

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Methods

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Duration

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Baseline Characteristics

 

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Age, years

     

Female

     

White

     

---

     

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Results

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p-Value

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----

     

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Adverse Events

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Serious Adverse Events: (or those deemed high risk; if not listed in study, use N/A or “Not disclosed”)

Percentage that Discontinued due to Adverse Events: (if not listed in study, use N/A or “Not disclosed”)

Study Author Conclusions

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InpharmD Researcher Critique

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Summary of Seroprevalence of toxoplasmosis and risk factors of Toxoplasma gondii infection among pregnant women in Sri Lanka: a cross sectional study

Design

Primary gestational toxoplasmosis can be transmitted to the fetus with deleterious effects on the pregnancy. There is very little information regarding gestational toxoplasmosis in Sri Lanka. This survey was done to determine the prevalence and awareness of toxoplasmosis and to identify risk factors of infection among pregnant women in the Gampaha district, Sri Lanka.

Objective

Women attending obstetric clinics at the Colombo North Teaching Hospital in 2014 were tested for Toxoplasma gondii (T. gondii) specific Immunoglobulins G (IgG) and M (IgM) subtypes using the OnSite Toxo IgG/IgM Rapid Test-Dip Strip(®). Disease awareness and risk behaviors of the participants were investigated.

Study Groups

Of the 293 participants (mean age 27 years, SD ± 5.92), 38% were primigravidae with a mean gestational age of 16.2 weeks (SD 7). The prevalence of anti-T. gondii IgG and IgM antibodies was 12.3% (n = 36) and zero, respectively. Unadjusted and adjusted odds ratios were calculated to determine risk factors of infection (cat-ownership, handling cats, consumption of meat, commercial meals and unwashed raw vegetables and fruits, handling soil and not washing hands after handling soil). On bivariate analysis, eating commercially prepared meals weekly or more was associated with toxoplasma seroprevalence with marginal statistical significance. On multivariate analysis, none of the considered risk factors were significant. Toxoplasma awareness was 4.4% (n = 13); health personnel (46.2%, n = 6) and media (53.8%, n = 7) being sources of information.

Inclusion Criteria

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii. It is acquired by consumption of raw or undercooked meat containing tissue cyst, food or water contaminated with oocyst and congenital infection through the placenta leading to serious congenital abnormalities in the fetus like miscarriage, stillbirth, intrauterine death and neurologic defects. Therefore; this study was aimed to determine the prevalence of toxoplasmosis infection and its possible risk factors associated with pregnant women attending antenatal clinics in Hawassa and Yiregalem Hospitals, Southern Ethiopia.

Exclusion Criteria

A hospital-based cross-sectional study was conducted from December 2016 to May 2017. The study was done in antenatal care clinics of Hawassa and Yiregalem Hospitals in Southern, Ethiopia. Five hundred pregnant women were interviewed with a pretested structured questionnaire to collect risk factors and socio-demographic data. Blood samples were collected and serum was separated and tested for anti- Toxoplasma gondii antibodies using ELISA (Enzyme-linked Immunosorbent Assay). Data were analyzed using SPSS version 20 statistical software. The risk factors were tested for significance using Bivariate and multivariate analysis. P-value < 0.05 was considered statistically significant.

Methods

The weighted prevalence of this study was 81.8% for the anti- Toxoplasma gondii antibody. Almost all participants (99.6%) had no information about the disease. A significant association was observed between seroprevalence and contact with domestic cats (OR = 1.206, 95% CI (1.627-2.206, P = 0.043), consumption of raw meat (OR = 0.848, 95% CI: 1.517-2.941, P = 0.019) and unpasteurized milk (OR = 0.871, 95% CI 1.531-2.221, P = 0.032). A significant association was not observed between seroprevalence and age, history of abortion, and blood transfusion.

Duration

The findings of this study demonstrated a relatively higher prevalence of seropositivity than studies reported from other countries. Existence of domestic cats at home, consumption of undercooked meat and unpasteurized milk were identified as risk factors for T. gondii infection. Therefore, a health education program to increase the mother's knowledge about toxoplasmosis towards avoiding eating undercooked meat, contact with cats and consumption of unpasteurized milk during pregnancy is recommended. Furthermore, our results suggested that the implementation of newborn screening and follow-up testing can lead to reducing of toxoplasmosis associated complications.

Outcome Measures

If the primary outcome measure isn’t explicit from the study, all outcome measures applicable to the inquiry can be listed in this section. If the primary outcome measure is explicit, then make separate sections for ‘Primary’ and ‘Secondary’ Outcome Measures.  


All outcome measures listed should correlate directly/exactly with the results presented later.

Baseline Characteristics

 

A

B

 

Age, years

     

Female

     

White

     

---

     

Include relevant baseline characteristics that will provide a general (big picture) view of the patients in the study.

Results

Endpoint

A

B

p-Value

----

     

----

     

All results listed should correlate directly/exactly with the outcome measures presented previously.Results that do not have to do with the inquiry should not be included; just the stated outcomes need corresponding results.


Tables are encouraged to display the most info using the least space/words.

Adverse Events

Common Adverse Events: (or those deemed frequent; if not listed in study, use N/A or “Not disclosed”)

Serious Adverse Events: (or those deemed high risk; if not listed in study, use N/A or “Not disclosed”)

Percentage that Discontinued due to Adverse Events: (if not listed in study, use N/A or “Not disclosed”)

Study Author Conclusions

Copy and paste the author’s conclusions on the question at hand, using full sentences. Don’t include any conclusions that don’t correspond to results we list.

InpharmD Researcher Critique

As the expert, add 1-2 sentences on strengths, weaknesses, and takeaways from this study. Focus on insight as “more research is needed” is obvious.