Toxoplasmosis Prueba de Avidez

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Hindawi Publishing CorporationInterdisciplinary Perspectives on Inectious DiseasesVolume , Article ID ,pageshttp://dx.doi.org/.//

Review ArticleThe Importance of IgG Avidity and the PolymeraseChain Reaction in Treating Toxoplasmosis during Pregnancy:Current Knowledge

Joo Bortoletti Filho, Edward Araujo Jnior, Natlia da Silva Carvalho,

Talita Micheletti Helfer, Priscila de Oliveira Nogueira Serni,

Luciano Marcondes Machado Nardozza, and Antonio Fernandes Moron

Department of Obstetrics, Federal University of Sao Paulo (UNIFESP), Rua Carlos Weber, Apartment, Visage, Vila Leopoldina, - Sao Paulo, SP, Brazil

Correspondence should be addressed to Edward Araujo Junior; [email protected]

Received May ; Revised August ; Accepted September

Academic Editor: Lucia Galvao

Copyright Joao Bortoletti Filho et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

A brie report on the nature and epidemiology oT. gondiiinection is rstly presented. Te importance o the specic IgG aviditytest and polymerase chain reaction (PCR) or toxoplasmosis is discussed, along with their signicance and importance as auxiliary

methods or determining the most likely time or the initial inection by this coccidian and or dening the therapeutic strategy.Lastly, practical comments are made in relation to the classical therapeutic regimens, with special attention to the indications oretal treatment, when this is necessary.

1. Introduction

oxoplasmosis is an inection caused by the intracellularprotozoonT. gondii, or which the primary host is cats. It isknown that approximately % o all cats are contaminated byT. gondii. Sexual reproduction o this parasite takes place inthe intestinal environment o cats, and the oocysts producedare eliminated together with the eces. Te oocysts remain

viable in the external environment or up to one year.Within this setting, T. gondii contaminates secondary

hosts through these hosts contact with sand, oods, or plantsthat have been contaminated by the oocysts. Afer ingestiono the oocysts, the oocyst wall becomes thinned by the diges-tive juices, thereby leading to release o sporozoites into theintestinal lumen. Te sporozoites rapidly invade the intestinalepithelium, though the vascular endothelium. At this stage othe evolution, they are transormed into tachyzoites, whichare the invasive orm o the parasite. Trough tachyzoitedissemination, the parasite will lodge in a wide variety otissues in the secondary host, in which large numbers o cyststhat are rich in bradyzoites areproduced. Te secondary hosts

are commonly humans, rodents, birds, crustaceans, domesticanimals, and practically all other warm-blooded animals,which explains why consumption o raw or undercookedmeat can contaminate other hosts with bradyzoites romtissue cysts. Ingestion o sporozoites occurs mainly througheating poorly washed ruits or vegetables, doing gardening,coming into contact with children who were playing on theground or on sand, and so on [].

Data in the literature consistently draw attention to theimportance o proper guidance regarding the commonestmeans o becoming inected with T. gondii, with the aimo preventing this event within the pregnancy cycle and thepossible harm done to the etus [, ]. A study conductedin the Economic Research Service in the United Statesconcluded that approximately hal o the cases o toxoplas-mosis occurred due to consumption o raw or undercookedmeat and that the annual cost o treating such cases inthat country was approximately U . billion. Tis highamount was due mainly to the congenitalcomplication result-ing rom vertical transmission o the parasite to the etus[].


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Interdisciplinary Perspectives on Inectious Diseases

Although toxoplasmosis is extremely benign amongimmunocompetent women, there is a risk o vertical trans-mission o the parasite when this inection occurs duringpregnancy. Te risk increases with advancing gestationalage in the ollowing manner: rst trimester %, secondtrimester %, and third trimester %. Tis seems

to occur as a unction o the increase in the mass o theplacenta, thus increasing the tissue available or tachyzoitesto invade. On the other hand, the increase in the vol-ume o the placenta also contributes towards increasingthe quantity o cysts rich in bradyzoites, which implies agreater risk o etal inection in cases o reactivation o thepathological condition. However, the congenital complica-tions become greater with earlier inection during pregnancy[].

2. Serological Diagnosis

Investigation o IgG and IgM levels should be incorpo-rated into the prenatal routine or the commonest inec-tions and or teratogenic inections, including rubella,cytomegalovirus, and toxoplasmosis.

Diagnoses o acute or progressive toxoplasmosis inectionare based on detection o its specic antibodies, with the aimo making an early diagnosis o maternal seroconversion andinstituting appropriatetreatment. Tis is extremely importantor preventing vertical transmission oT. gondiiand its dele-terious effects on the etus []. Findings o toxoplasmosis-specic IgMindicate occurrences o acute inection, althoughthese antibodies may be present in the maternal serum romone week to months afer the date o invasion by theparasitic tachyzoites. Specic IgG appears in the maternalserum between one andtwo months afer the initial inection.

In this light, it is clear that it is absolutely impossible orclinicians to dene the starting time o the acute inectionbased only on the presence o IgG and IgM. Moreover, thespecicity and sensitivity o IgM are not %, but in theranges o . to % and . to .%, respectively, accord-ing to evaluations on the six ELISA kits most commonly usedin the United States, in a studycommissioned by the Food andDrugs Administration (FDA).

Te IgG avidity test is the laboratory resource currentlyaccepted or the diagnosis o the approximate time when theinitialinectionoccurred.Tis measures theaffinity o IgG orbinding to the antigens oT. gondii, and it tends to increase

with the length o time that has elapsed since the initialinection []. A Mexican study on pregnant womenshowed that there was no correlation between IgM levelsand the IgG avidity test results. Tus, it was demonstratedin that study that the IgG avidity test is useul or inerringthe inection phase and assisting in managing toxoplasmosisduring pregnancy []. In this manner, avidity test results oup to %allow it to be said that the initial inection occurrednot more than our months earlier. On the other hand,results o more than % indicate that the initial inectionoccurred at least six months earlier. Results o between and% are inconclusive regarding the exact time o the initialinection. However, in practice, all the antibodies discussed

above only allow conclusions consisting o suppositions andprobabilities.

A prospective study assayed IgG avidity or toxoplasmosisamong pregnant women who presented with IgM positiveor T. gondii. Te patients underwent a multiplex nestedpolymerase chain reaction (PCR) or DNA oT. gondiiin the

amniotic uid, maternal blood, and blood o the umbilicalcord. Fify (.%) o the pregnant women presented withlow IgG avidity (less than %). Te PCR perormed onthe amniotic uid or perormed at birth was positive inthe cases o nine patients with low IgG avidity. Amongthese nine patients, only three presented with congenitaltoxoplasmosis. None o the pregnant women with highor threshold avidity presented positive PCR results in theamniotic uid or congenital toxoplasmosis. Tere were nodiagnoses o congenital toxoplasmosis among the patientswith negative PCR results in the amniotic uid. Tus, itwas concluded rom that study that using IgG avidity inassociation with PCR on the amniotic uid was important ordiagnosing congenital toxoplasmosis [].

A prospective cohort study evaluated women with tox-oplasmosis inection that had been detected in the prenatalscreening at three centers, by means o real-time PCR onthe amniotic uid. PCR analysis was perormed on o the patients who were included in the study. Tesensitivity and negative predictive values were, respectively,.% (% condence interval, CI: %) and .% (%CI: .%). Tere was no signicant association with thetrimester o pregnancy in which the inection occurred. Tespecicity and positive predictive values were % in allthree trimesters. Tus, real-time PCR was considered to be animportant tool or predicting etal inection due to T. gondiiand or making more appropriate treatment decisions [].

In a study conducted in France, at the University Hospitalo oulouse, amniocentesis procedures were perormedon pregnant women who were inected with T. gondii. Tesensitivity and specicity o the diagnosis o congenitaltoxoplasmosis by means o PCR on the amniotic uid were% and .%, respectively. PCR was also perormed onthe placenta, which showed specicity o % and sensitivityo %. Te specic IgG and IgM tests on the cord bloodpresented specicity o % and % and sensitivity o %and%, respectively. Itwas concludedin that studythat PCRon the amniotic uid has higher sensitivity and specicity ordiagnosing congenital toxoplasmosis, thus enabling a morecertain diagnosis o etal inection []. A study conducted at

the University o the Suez Canal, in Egypt, on pregnantwomen with toxoplasmosis, showed sensitivity o .% andspecicity o .% or PCR on the amniotic uid, with apositive predictive value o .% and a negative predictive

value o .% or the diagnosis o congenital toxoplasmosis[].

Based on these studies, it has been accepted that the gold-standard examination or identiying etal inection is PCR,which has high sensitivity and specicity when perormed onamniotic uid samples obtained rom the sixteenth week opregnancy onwards. In this manner, diagnosing the presenceo DNA particles rom T. gondii in this medium can bedone with great certainty []. Since colonization o the etal


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kidneys occurs around two to three weeks afer invasion bythe tachyzoites oT. gondii and production o the amnioticuid occurs basically by means o etal diuresis, it can beconcluded that a positive PCR indicates the presence oinection in the etus, which has been eliminating T. gondiiDNA into the amniotic environment, in its urine.

Attention has also been drawn to the possibility oreactivation o latent toxoplasmosis in immunosuppressedpatients []. Maternal immunosuppression and contamina-tion byT. gondii may also be related to higher risk o etaldisruption disorders []. Likewise, i it is considered thatthe pregnancy cycle naturallyconers immunosuppressiononpregnant women, it would not, in our view, be unreasonableto consider that reactivation o latent toxoplasmosis mightoccur in some pregnant women [].

3. Treatment of Toxoplasmosisduring Pregnancy

Te World Health Organization and the Centers or DiseaseControl and Prevention recommend pyrimethamine, sula-diazine, and olinic acid as the standard o care or peoplewith congenital toxoplasmosis []. Tese medications wereproven to be effective in a randomized prospective studycalled the National Collaborative Chicago Based Congenitaloxoplasmosis Study (NCCBS). Tis study ound thattreatment with the three aorementioned medications sig-nicantly decreased adverse signs and symptoms associatedwith congenital toxoplasmosis, including ocular and centralnervous system symptoms and sensorineural hearing loss[]. Forpatients with sensitivity to suladiazine, clindamycincan be used in combination with pyrimethamine as analternative [].

When a diagnosis o acute maternal toxoplasmosis inec-tion is made,spiramycin should immediately be administeredto the mother, at a dose o to g per day. Tis medicationdoes notgo beyond the placental barrier, but it diminishes therisk o vertical transmission by up to %. Likewise, i PCRon the amniotic uid is positive, institution o bacteriostatictherapy that crosses the placental barrier is essential, withthe aim o diminishing the etal malormations that resultrom acute toxoplasmosis. Te ollowing drugs can then beadministered: suladiazine, at a dose o . g per day, andpyrimethamine, at a dose o mg per day []. However,these medications have high teratogenic potential, since they

noticeably diminish etal serum olate synthesis. It is knownthat insufficient concentration o serum olates noticeablydiminishes synthesis o the enzyme tetrahydroolate reduc-tase. Tis enzyme acts within the cell medium to transormhomocysteine, which is a cytotoxic and teratogenic agent,into methionine, which is an essential amino acid. High tissueconcentration o homocysteine is thereore one o the causeso higher incidence o structural abnormalities in etuses[]. For this reason, the administration o suladiazine andpyrimethamine should not be continuous and should bealternated with spiramycin administration every three weeks.In addition, a precursor o serum olate synthesis should beadministered: olinic acid, at a dose o to mg, two to

three times a week, while the patient is receiving suladiazinaand pyrimethamine. Administration o these three drugsdecreases the risk that the etus might develop disruptionabnormalities due toT. gondii inection, by % [].How-ever, a major adverse effect o this treatment regimen is bonemarrow suppression []. Bone marrow suppression leads to

neutropenia, anemia, and thrombocytopenia. Tis adverseeffect may be avoided with the simultaneous administrationo olic acid during treatment [, ]. Despite these pre-

ventative measures, weekly monitoring o cell counts andplatelet counts should be done to assess the level o marrowsuppression and adjust these medications as necessary [].

Recently, the Society o Obstetricians and Gynecologistso Canada proposed a clinical practice guideline to thetoxoplasmosis in pregnancy. Tis guideline reinorces theconclusion that the combination o pyrimethamine, sula-diazine, and olinic acid should be offered as treatment orwomen in whom etal inection has been conrmed or ishighly suspected, usually by a positive amniotic uid PCR(level I-B o evidence). Women who are immunosuppressedor HIV-positive should be offered screening because o therisk o reactivation and toxoplasmosis encephalitis (level I-Ao evidence) []. Te necessity o the treatment oT. gondii inhuman immunodeciency-virus inected pregnant women isproved by several case reports [].

In study realized in Brazil that presents high incidence otoxoplasmosis in pregnancy, Porto and Duarte [] analyzedthe correlation between toxoplasmosis in pregnant womenand incidence o congenital toxoplasmosis. Among the preg-nant women classied as conrmed cases o toxoplasmosisin pregnancy ( = 19), the congenital toxoplasmosis riskwas six times greater than that in the probable/possiblegroup. No case o congenital toxoplasmosis was identied inthe group o pregnant women classied as unlikely to havetoxoplasmosis in pregnancy. Te children with no prenataltreatment (.% = 242/) presented a risk almost ocongenital toxoplasmosis three times greater than the treatedchildren (odds ratioOR .; % CI ..; = 0.001).Complete prenatal treatment was identied as a protectingactor or congenital toxoplasmosis (OR .; % CI ..; = 0.001) [].

In study realized in Germany with pregnant womenand children with positive serological tests or T. gondiiinection, the overall transmission rate oT. gondiirom theinected motherto her child was.%. Te prenatal treatmentwith spiramycin until sixteenth week was ollowed by at

least weeks o combination therapy with pyrimethamine,suladiazine, and olinic acid independent o the inectionstage o the etus []. Tese results are consistent with otherstudies in which only a small study population was included[,].

Other alternative proposed treatment to toxoplasmosis inpregnancy is the spiramycin/cotrimoxazole association. Tisassociation was used in pregnant women with positiveserological tests or T. gondii. Te treatment consisted ospiramycin , g times a day, cotrimoxazole mg(sulamethoxazole mg plus trhmetroprim mg)twice aday, and olinic acid mg/day. Te intrauterine transmissionrate was only .% (two babies) and none o them showed


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MaternalSerology

Serologicalfollowing

SeroconversionSpiramycin

Amniocentesis

Amniocentesisto PCR

Spiramycin3 g/d

Acute infectionSusceptible

Fetal infectionSulfadiazine 3 g/d + pyrimethamine

50 mg/d + folinic acid 10 mg/d (3 weeks)Spiramycin 2-3 g/d

No fetal infectionSpiramycin 2-3 g/d

Prenatal careroutine

Immune

IgG (+) IgG ()

IgM ()IgM ()

IgG (+)

IgM (+)

F : Diagram o serological screening o toxoplasmosis duringpregnancy and its treatment.

signs or symptoms o congenital inection at birth or duringollowup. Te treatment did not need to be stopped inany mother because o adverse drug effects []. In a case

report, amaru et al. [] used azithromycin as etal therapyin a case o severe symptomatic etal toxoplasmosis. Teultrasound realized at weeks o pregnancy evidenced etalascites, cardiac effusion, cardiomegaly, enlarged lateral ven-tricles, and thickened placenta.Suladoxine ( mg/day)andpyrimethamine ( mg/day) were administered rom to weeks. Cyclic administration o azithromycin ( mg/dayor days ollowed by an interval o no medication or days)was subsequently started at weeks and continued or weeks ollowed by an interval o no medication or a weekuntil delivery. Ten cyclic administration o acetylspiramycin(. g/day or weeks ollowedby an interval o no medicationor weeks) was combined with azithromycin or weeks.

Fetal ascites, cardiomegaly, enlarged lateral ventricles, andthickened placenta persisted until delivery; cardiac effusiono the etus completely disappeared at weeks, which theauthors considered to be the partial effect o administrationo azithromycin started at weeks.

Figure shows a diagram with the sequence o serologicalscreening o toxoplasmosis during pregnancy and its treat-ment.

4. Conclusion

From a critical analysis on the data presented, we canconclude that it is essential to have results available rom

the IgG avidity test and rom PCR on the amniotic uid,so that treatment o pregnant women affected byT. gondiican be adequately managed. Without these test results, noconclusions regarding the presence or absence o verticaltransmission o T. gondii to the etus can be reached anddoubts will remain regarding whether medications that cross

the placental barrier, to treat the etus, should be introduced.Tis uncertainty thereore could condemn a etus that mighthave become contaminated across the placenta to developa variety o congenital abnormalities, with serious postnatalrepercussions or the amily and or society as a whole, giventhat the ensuing costs to the public healthcare system are arrom small.

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