Evaluation of intr athecal synthesis of specific IgG antibodies against
Toxoplasm a go
ndii in the diagnosis assessment of pr esumptive
toxoplasm a
encephalitis in aids patients
Avaliação da síntese intratecal de anticorpos IgG anti-
To xo pla sm a go ndii
para o diagnóstico
da neurotoxoplasmose em pacientes com síndrome da imunodeficiência adquirida
Aer cio Sebastião Bor ges
1and José Fer nando de Castr o Figueir edo
2ABSTRACT
Th e d i a gn o si s o f n e u ro to x o p la sm o si s i n p a ti e n ts w i th a c q u i re d i m m u n o d e f i c i e n c y syn d ro m e i s m a i n ly b a se d o n to m o gra p h i c o r m a gn e ti c re so n a n c e f i n d i n gs a n d o n th e re sp o n se to sp e c i f i c tre a tm e n t. We stu d i e d 5 5 p a ti e n ts wi th AIDS a n d n e u ro to x o p la sm o si s a c c o rd i n g to th e se d i a gn o sti c c ri te ri a ( gro u p 1 ) , 3 7 p a ti e n ts wi th AIDS a n d n e u ro lo gi c a l i n vo lve m e n t o f o th e r e ti o lo gy ( gro u p 2 ) , a n d 1 6 a n ti - HIV- n e ga ti ve i n d i vi d u a ls wi th n e u ro lo gi c a l m a n i f e sta ti o n s ( gro u p 3 ) . Se ru m a n d c e re b ro sp i n a l f lu i d we re e x a m i n e d f o r th e p re se n c e o f a n ti -T. gondii IgG, b y i n d i re c t i m m u n o f lu o re sc e n c e . In 7 2 o f th e m , th e to ta l a m o u n ts o f th e se a n ti b o d i e s we re d e te rm i n e d i n o rd e r to a sse ss lo c a l p ro d u c ti o n o f a n ti -T. gondii
a n ti b o d i e s i n th e c e n tra l n e rvo u s syste m a n d to c o rre la te th e i r ti te rs wi th i n f e c ti o n a c ti vi ty i n p a ti e n ts wi th AIDS a n d n e u r o to x o p la s m o s i s . IgG ti te r s
≥
1 / 6 4 i n c e r e b r o s p i n a l f lu i d r e a c h e d 1 0 0 % s p e c i f i c i ty f o r th e d i a gn o s i s o f n e u ro to x o p la sm o si s i n AIDS. Evi d e n c e o f lo c a l syn th e si s o f th e se a n ti b o d i e s wa s d e te c te d i n 4 2 .8 % o f p a ti e n ts o f gro u p 1 , i n 2 9 .1 % o f p a ti e n ts o f gro u p 2 a n d i n n o p a ti e n t o f gro u p 3 . Th e te st sh o we d 7 0 .8 % sp e c i f i c i ty a n d th e re f o re wa s n o t u se f u l i n o u r stu d y f o r th e d i f f e re n ti a l d i a gn o si s o f n e u ro to x o p la sm o si s i n p a ti e n ts wi th AIDS.Ke y-words: AIDS. Ne u ro to x o p la sm o si s. An ti b o d y syn th e si s. Ce n tra l n e rvo u s syste m .
RESUMO
O d i a gn ó s ti c o d a n e u r o to x o p la s m o s e e m p a c i e n te s c o m s í n d r o m e d a i m u n o d e f i c i ê n c i a a d q u i r i d a b a s e i a - s e f u n d a m e n ta lm e n te n o s a c h a d o s to m o grá f i c o s o u d e re sso n â n c i a m a gn é ti c a e n a re sp o sta a o tra ta m e n to e sp e c í f i c o . Estu da m o s 55 pa c i e n te s c o m SIDA e n e u ro to xo pla sm o se , de a c o rdo c o m e ste s c ri té ri o s di a gn ó sti c o s ( gru po 1) ; 37 pa c i e n te s c o m SIDA e c o m p ro m e ti m e n to n e u ro ló gi c o p o r o u tra e ti o lo gi a ( gru p o 2 ) e 1 6 i n d i ví d u o s a n ti - HIV n e ga ti vo , c o m o u tra s d o e n ç a s n e u ro ló gi c a s ( gru p o 3 ) , p e sq u i sa n d o IgG, a n ti -T. go ndii, n o so ro e n o lí q u o r, u ti li z a n d o a re a ç ã o d e i m u n o f lu o re sc ê n c i a i n d i re ta . Em 7 2 c a so s, d e te rm i n a m o s o s te o re s to ta i s d e ste s a n ti c o rp o s a í p re se n te s, c o m o b je ti vo de a va li a r a pro du ç ã o lo c a l, n o si ste m a n e rvo so c e n tra l, de a n ti c o rpo s e spe c í f i c o s e c o rre la c i o n a r o s tí tu lo s c o m a ti vi da de d a i n f e c ç ã o , e m p a c i e n te s c o m SIDA e n e u ro to x o p la sm o se . Evi d ê n c i a d e p ro d u ç ã o lo c a l d e ste s a n ti c o rp o s f o i d e te c ta d a e m 4 2 ,8 % d o s p a c i e n te s d o gru p o 1 , e m 2 9 ,1 % d o s p a c i e n te s d o gru p o 2 e e m n e n h u m p a c i e n te d o gru p o 3 . O te ste a pre se n to u e spe c i f i c i da de i n te rm e di á ri a ( 70,8%) , po ré m n ã o f o i ú ti l pa ra o di a gn ó sti c o di f e re n c i a l da n e u ro to xo pla sm o se e m pa c ie n te s c o m SIDA, e m n o sso e stu do . Po r o u tro la do , títu lo s de IgG n o líq u o r
≥
1/64 a lc a n ç a ra m 100% de e spe c ific ida de p a ra o d i a gn ó sti c o d e n e u ro to x o p la sm o se n a SIDA.Pal avr as-chave s: SIDA. Ne u ro to x o p la sm o se . Sí n te se d e a n ti c o rp o s. Si ste m a Ne re vo so Ce n tra l.
1 . Centro de Ciênc ias B io médic as da Fac uldade de Medic ina da Universidade Federal de Uberlândia, Uberlândia, MG, B rasil. 2 . Divisão de Mo léstias Infec c io sas e Tro pic ais do Departamento de Clínic a Médic a da Fac uldade de Medic ina de Ribeirão Preto da Universidade de São Paulo , SP, B rasil.
Addr e ss to: Dr. Aérc io S. B o rges. R. Niteró i 1 4 6 5 , bairro B razil, 3 8 4 0 6 -0 1 7 Uberlândia, MG, B rasil. Tel: 3 4 3 2 3 2 -4 0 5 4 , Fax: 3 4 3 2 1 8 -2 3 4 9
e-mail: aerc io sb@ uo l.c o m.br
Neurotoxoplasmosis is one of the most frequent opportunistic infections compromising the central nervous system ( CNS) of patients with acquired immunodeficiency syndrome ( AIDS) , with a prevalence of 3 % to 5 0 % and high morbidity and mortality if not diagnosed and treated early9 1 2.
In most cases the disease results from reactivation of a latent infection, but cases of acute infection with dissemination have been reported2 15. The estimated risk of toxoplasmosis reactivation in
the CNS of patients with AIDS who present anti-To xo pla sm a go ndii
IgG antibodies in serum ranges from 12 to 47%13 14 30.
The clinical presentation is variable, manifesting as diffuse encephalitis, meningoencephalitis or, more commonly, as a tumoral lesion with a mass effect. Motor syndrome, conscience disorders, seizures and focal signs are common manifestations16 32, so that
this e ntity is c linic ally indistinguishab le fr o m o the r CNS complications also frequently occurring in these patients, such as primary CNS lymphoma, viral or fungal encephalitis, reactivation of Chagas’ disease, neurotuberculosis, and others11 23 33.
An early diagnosis of neurotoxoplasmosis in these cases has been limited by the lack of more sensitive and specific noninvasive methods. Cerebrospinal fluid findings are nonspecific, varying from normality to mild lymphocytic pleocytosis, with normal or only slightly elevated spinal fluid protein levels. Imaging studies such as computed tomography ( CT) of the skull and magnetic resonance ( MR) are of high diagnostic value by revealing isodense or hypodense single or multiple lesions with a mass effect that take up contrast in an annular or nodular form. These findings are detected in about 9 0 % of cases and are highly suggestive of neurotoxoplasmosis, although not pathognomonic24 35.
The serologic profile of these patients is similar to that of the general population with c hronic infec tion. IgM antibodies a r e no t c o m m o nly de te c te d a nd I gG a ntib o die s do no t disc riminate between latent and ac tive infec tion1 4 2 3 3 6, and
may be undetec table in a minority of c ases1 3 2 9 3 9.In addition,
the ac tivity of the disease does not seem to c orrelate with IgG antibody titers in serum1 8 2 4 2 7 3 3.
In c ontrast to the reported authors, Hellerbrand et al1 7,
in a series of 8 0 c ases, observed that high IgG titers in patients with T CD4 + c ell number s < 1 5 0 c ells/mm3 indic ate the
pr e s e n c e o f to x o pla s m ic e n c e ph a litis , with a po s itive predic tive value of 8 8 % .
The detec tion of antibodies in c erebrospinal fluid ( CSF) should be interpreted with caution since their presence may simply indicate passive serum antibodies passage to the CSF. Ho wever, the demo nstr atio n o f lo c al synthesis o f spec ific antibodies whose titers increase in the CSF regardless of their increase in serum has proved to be of diagnostic value in some conditions, including neurotoxoplasmosis2 6 2 8 3 1 3 4.
We studied 4 2 patients with AIDS and neurotoxoplasmosis by determining total IgG c onc entrations in serum and CSF and c orrelating them with anti-To x o p la sm a go n d i i antibody levels in these fluids in order to determine the oc c urrenc e of synthe sis o f spe c ific antib o die s at the CNS le ve l and to c orrelate the titers of these antibodies with infec tion ac tivity as a subsidy for the diagnosis of neurotoxoplasmosis in AIDS.
MATERIAL AND METHODS
We studied 1 0 8 patients, 9 2 of them infec ted with human im m uno de fic ie nc y vir us ( HI V- 1 ) as de te r m ine d b y 2 nd generation ELISA ( Abbott) , with a diagnosis of AIDS ac c ording to CDC ( Centers for Disease Control) c riteria5, and 1 6
non-infec ted adult patients of both sexes older than 1 2 years who presented with c linic al manifestations of neurologic al disease were inc luded in the study.
The patients were divided into 3 groups. Group 1 consisted o f 5 5 patients with AIDS and a pr esumptive diagno sis o f neurotoxoplasmosis, group 2 of 3 7 patients with AIDS, 1 9 of them with neurocryptococcosis, 3 with neurotuberculosis, 2 with bacterial meningitis, 1 with AIDS-related demential complex, 2 with metabo lic alteratio ns affec ting the CNS, and 1 0 with undefined etiology of the neurological signs and symptoms. Group 3 consisted of 1 8 anti-HIV-negative patients: 7 with bacterial meningitis, 4 with a diagnosis of lymphomonocytic meningitis, 1 with neurocryptococcosis, 1 with CNS paracoccidioidomycosis, 1 with Guilla in - B a r r é s yn dr o m e , 1 with s ub a r a c h n o id hemorrhage, and the last one evaluated for investigation of headache.
The presumptive diagnosis of neurotoxoplasmosis was e s ta b lis h e d b a s e d o n c lin ic a l s ign s a n d s ym pto m s , o n tomographic findings of single or multiple lesions oc c upying spac e with a mass effec t and annular or nodular appearanc e after c ontrast injec tion, and on c linic al and/or radiologic patient improvement after spec ific treatment with sulfadiazine ( 4 g/day) and pyrimethamine ( 5 0 mg/day) , o r c lindamyc in ( 2 .7 g/day) and pyrimethamine ( 5 0 mg/day) .
The search for anti-T. go ndii antibodies in serum and CSF was performed by indirect immunofluorescence ( IIF) by the method of Camargo4 using an anti-human IgG fluo resc ent
conjugate ( Bio-Meriéux) . Serum samples with
≥
1 /1 6 titers and CSF samples with≥
1 /1 titers were considered to be positive.Total IgG c onc entrations in these fluids were determined in 7 2 patients by simple radial immunodiffusion by the method of Manc ini et al2 5, adapted by B arreto1.
Antibody synthesis at the CNS level was determined using the following index: reciprocal antibody titers in CSF x total IgG c o nc e ntr atio n in se r um/to tal IgG c o nc e ntr atio n in CSF x reciprocal antibody titers in serum. Indices with values higher than 1 indicated local antibody synthesis at the CNS level2 1 3 0 3 3.
Data were analyzed statistic ally using the Epi Info software, version 6 .0 2 . 1 0 /9 4 . The Chi-square test was used, with the level of signific anc e set at p < 0 .0 5 .
RESULTS
while in groups 2 and 3 only 1 3 .5 % and 5 .9 % reac hed these levels, respec tively ( p = 0 .0 0 0 2 ) ( Table 1 ) .
Anti-To xo pla sm a go ndii IgG antibodies were detected in the CSF of 4 5 /5 4 ( 8 3 .4 %) group 1 patients, 1 8 /3 5 ( 5 1 .4 %) group 2 patients and 2/15 ( 13.3%) group 3 patients. Antibody titers
≥
1/64 were detected only in group 1 patients ( Table 2 ) .( 4 2 .8 % ) and spec ific ity ( 7 0 .8 % ) , with a positive and negative predic tive value of 7 2 % ( p = 0 .2 7 ) . The odds ratio was 1 .8 2 ( 9 5 % CI: 0 .5 6 -6 .3 0 ) .
DISCUSSION
Most of the expansive lesions of the CNS detected in patients with AIDS are attributed to reactivation of latent To xo pla sm a go ndii infection caused by HIV-induced immunosuppression.
In these cases, the diagnosis of neurotoxoplasmosis has been based on clinical presentation and on tomographic or magnetic resonance findings, which reveal expansive lesions with annular reinforcement, besides an adequate therapeutic response6 2 4 3 4.
Diagnostic confirmation is difficult because clinical signs and symptoms and radiologic imaging findings may be confused with those of other diseases that compromise the CNS of these patients. Thus, the definitive etiologic diagnosis may require invasive and risky procedures.
The detec tion of spec ific IgM and IgG c lass antibodies in serum is a well-established method for the diagnosis of ac ute primary and c ongenital To x o p la sm a go n d i i infec tion. The value of this method for immunosuppressed individuals is c ontroversial sinc e in most c ases the disease results from reac tivation of latent infec tion oc c urring during an advanc ed phase of immune system dysfunc tion1 4 2 2.
Several sero lo gic tests fo r the detec tio n o f c irc ulating
To x o p la sm a go n d i i antigens fo r the detec tio n o f spec ific antibodies have been used in an attempt to establish the diagnosis of neurotoxoplasmosis in patients with AIDS, although with controversial results7 8 1 0 2 0 3 5 3 7. Thus, it would be difficult to
establish this diagnosis only on the basis of serum antibody levels since, according to some investigators, the absence of elevated titers would also be insufficient to rule out the occurrence of toxoplasmosis reactivation1 7 1 8 3 8.
In the present study, the IIF reaction applied to serum for the detection of anti-To xo pla sm a go ndii IgG antibodies showed high sensitivity ( S = 9 8 .2 %) , but reduced specificity ( 3 5 .1 %) , and 9 3 % positive predictive value ( p < 0 .0 0 0 5 ) . These results, taken together with those obtained in other studies, confirm the idea that the absenc e o f spec ific IgG antibo dies in serum invalidates the diagnosis of toxoplasmosis reactivation1 9 3 4.
When comparing the patient groups studied in terms of serum IgG levels we detected a good correlation between high antibody titers (
≥
1 /4 0 0 0 ) and a diagnosis of neurotoxoplasmosis, with 8 5 % positive predictive value and 8 6 .5 % specificity ( p = 0 .0 0 0 2 ) .Monitoring the kinetics of serum antibody titers could be useful to determine whether these levels increase during the reactivation of disease, not only being very useful for diagnostic purposes, but also permitting the early institution of prophylactic and therapeutic measures.
It has b e e n de mo nstr ate d that appr o ximate ly 5 0 % o f patients with To x o p la sm a go n d i i-induc ed enc ephalitis will present with spec ific antibodies in the CSF 2 0 2 9. However, this
finding should be interpreted with c aution sinc e the rupture
Ta ble 1 - IgG a nti-Toxoplasma gondii a ntibo dies in the serum o f the three gro ups o f pa tients studied ( IIF) .
Titer Group 1 Group 2 Group 3
no % no % no %
Negative 1 1.8 13 35.1 6 35.3
1/16 1 1.8 2 5.4 4 23.5
1/64 4 7.3 5 13.5 4 23.5
1/256 9 16.4 7 19.0 1 5.8
1/1000 12 21.8 5 13.5
-1/4000 18 32.7 5 13.5 1 11.7
1/8000 4 7.2 - - -
-1/16000 4 7.2 - - -
-1/32000 2 3.6 - - -
-Total* 55 100.0 37 100.0 16 100.0
* Included patients in whom test for anti-T. go ndii antibodies in serum was performed
Ta ble 2 - IgG a nti-Toxoplasma gondii a ntibo dies in the cerebro spina l fluid o f the three pa tient gro ups studied ( IIF) .
Titer Group 1 Group 2 Group 3
no % no % no %
Negative 9 16.6 17 48.5 13 86.7
1/1 3 5.5 1 2.8 1 6.6
1/2 4 7.4 2 5.7
-1/4 8 14.8 4 11.4 1 6.6
1/8 8 14.8 6 17.1 -
-1/16 12 22.2 4 11.4 -
-1/32 - - 1 2.8 - -
-1/64 5 9.2 - - -
-1/128 2 3.7 - - -
-1/256 1 1.8 - - -
-1/1000 2 3.7 - - -
-Total* 54 100.0 35 100.0 15 100.0
* Included patients in whom test for anti-T. go ndii antibodies in the cerebrospinal fluid was performed
Anti-To x o p la sm a go n d i i antibody synthesis at the CNS level was detec ted in 1 8 /4 2 ( 4 2 .8 % ) group 1 patients, in 7 / 2 4 ( 2 9 .1 ) group 2 patients, and in no patient of group 3 ( Table 3 ) .
When we c ompared group 1 with group 2 , c alc ulation of the loc al rate of antibody synthesis showed low sensitivity
Ta ble 3 - Index o f a nti-Toxoplasma gondii a ntibo dy pro ductio n in the CNS in the three pa tient gro ups studied.
Titer Group 1 Group 2 Group 3
no % no % no %
≤ 1 24 57.2 17 70.8 6 100.0
> 1 18 42.8 7 29.2 0
Total* 42 24 6
* Included patients in whom index of anti-T. go ndii antibody production was performed
of the blood-CSF barrier due to any type of etiology may be accompanied by passive passage of antibodies from serum to CSF. In the present study, the IIF reaction applied to the CSF for the detection of anti-To xo pla sm a go ndii IgG proved to be more spec ific than serum detec tion, with a statistic ally signific ant difference between groups ( p < 0 .0 0 5 ) . Considering the reaction titer, we observed that for titers
≥
1 /6 4 the test reached 1 0 0 % specificity ( p = 0 .0 0 4 ) , thus representing a good diagnostic marker of neurotoxoplasmosis in AIDS.Antibody synthesis at the CNS level has been demonstrated in some neurological diseases regardless of alteration of the blood brain barrier responsible for the passage of blood proteins into the CSF 2 0 2 5 2 6 3 0 3 7.Orefice et al2 8 detected active antibody
synthesis at the CNS level in a series of 4 patients with AIDS and neurotoxoplasmosis compared with 8 patients also with AIDS, but without clinical evidence of neurological disease.
Another study c onduc ted on a larger number of c ases including 3 7 patients with AIDS and toxoplasmic encephalitis, 1 1 patients with AIDS without neurologic al disease and 1 5 individuals with no HIV antibodies but with serologic evidence of To xo pla sm a go ndii infection demonstrated the presence of IgG antibodies in the CSF of 2 3 ( 6 2 .2 %) of the patients with ne ur o to xo plasmo sis and in no ne o f the patie nts witho ut neurological disease. Local antibody synthesis was demonstrated in 1 1 of 1 6 ( 6 8 .7 %) neurotoxoplasmosis cases and in none of the 4 patients of the control group who showed the presence of antibodies in CSF2 9.
In the present study we detected local antibody synthesis in 1 8 /4 2 ( 4 2 .8 %) patients of the group with neurotoxoplasmosis. Among group 2 and 3 patients, 7 /2 4 ( 2 9 .1 %) and 0 /6 showed evidence of anti-To xo pla sm a go ndii antibody synthesis at the CNS level, respectively.
The c alc ulation of the index of loc al antibody synthesis showed intermediate spec ific ity ( 7 0 .8 % ) and low sensitivity ( 4 2 .8 %) for the diagnosis of toxoplasmosis reactivation at the CNS level in AIDS when group 1 patients were compared to group 2 patients, thus being of no use for the differential diagnosis of neurotoxoplasmosis in patients with AIDS. However, there was a statistically significant difference between group 1 and group 3 patients ( p < 0 .0 5 ) .
We cannot justify these results based only on the advanced immunosuppression of these patients because in many there was no c o r r elatio n b etween ser um antib o dy levels and indic es o f antibody synthesis at the CNS level. Another fac tor to be c o n s ide r e d is th a t to xo pla s m o s is is a pr e do m in a n tly parenchymatous disease and that the presence or absence of loc al antibody produc tion detec ted by CSF examination may depend on the proximity of the lesion to the meninges.
We observed that 2 9 % of the patients in group 2 presented evidenc e of produc tion of anti-To xo pla sm a go n di i antibodies in the CNS. These patients wer e in the same situatio n o f immuno suppr essio n as the patients in gr o up 1 and mo st ( 6 4 .8 % ) demonstrated previous infec tion with To x o p la sm a go n di i. Therefore, they may have low toxoplasmosis ac tivity in th e CNS, with n o a ppa r e n t o r in c ipie n t c lin ic a l o r
tomographic manifestation sinc e the presenc e of 2 or more c onc omitant opportunistic infec tions is frequently observed in these patients3 2 1. Thus, it would be opportune to evaluate
these patients prospec tively in order to determine signs of disease reac tivation in the future.
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