Aids and Chagas Disease
Héctor Freilij, M.D.
American trypanosomiasis or Chagas disease is an antropozoonosis distributed from south of USA to south of Argentina and Chile (1). It is caused by the Trypanosoma cruzi, a flagellated protozoan transmited to humans and animals by a group of haematophagus triatominae insects. It was discovered by a Brazilian physician Carlos Chagas in 1909.
The vectors have been reported in the Americas from 42 N to 46 S (1). When triatominae bite the tegument to suck blood, the parasite is depossited in the bugs faeces and penetrates into the host. Species of hemipteras live in rural precariously built houses, and leave their shelters during the night to feed by biting domestic animals and man.
Moreover, humans being may acquire this parasite by blood transfusion (2), transplacental route (3)(4) or from a contaminated transplanted organ. (5)
The disease affects 16-18 million people and some 100 millions, about 25% of the population of Latin América, is at risk of acquiring Chagas disease. (6) It is estimated that population with chronic infection is in Argentina 7.2 %, Bolivia 22 %, Brasil 4.3 %, Chile 10 %.(7)(8) In Américas 45.000 death annually are atributed to this parasitosis.(9)
From a global perspective represents the third largest tropical disease burden after malaria and schistosomiasis. According to the UNDP Human Development Report (10) the estimated average annual per capita gross domestic product in Latin America is U$ 2966. Thus, the economic loss for the continent due to early mortality and disability by this disease in economically most productive young adults currently amounts to U$ 8.156 millons which is equivalent to 2.5 % of the external debt of the whole continent in 1995.
Due to migration from endemic area to developed countries USA and Europe, many cases of Chagas disease have been communicated, some of them due to blood transfusion. (10-12).
In USA there are about 370.000 people with this infection (13).
The situation in European countries, Japan and Australia is still unknown. In Japan at least 150.000 Brazilians have inmigrated from 1982 till 1992 and 80.000 Latin Americans live in Australia and at least 300.000 in Europe (14).
Trypanosoma cruzi is a flagellate of the Kinetoplastida Order, Family Tripanosomatidae characterized by the presence of one flagellum and a big single mitochondrion. T. Cruzi is not a homogeneous population and is composed rather by a pool of strains wich circulate in humans, vectors and over 100 mammal species including wild and domestic reservoirs (15).
It is a rather ubiquitous parasite, invade "in vivo" and "in vitro" a large range of host cells including macrophages, fibroblasts, epithelial cells, muscle cells and neurons. T. cruzi invades the cells to multiply, at this moment is rounded without flagellum (2 um). The blood stage in enlarged, free with a flagellum ( 25 um x 2 um). This protozoa induce in humans an acute phase with patent parasitemia which is followed by a lifelong chronic phase characterized by subpatent parasitemia and scarce tissue parasitism.
The diagnosis point out to search the protozoan or to study the host immune response by serum antibodies.
A) Parasitologic tests: try to detect the parasite or fraction of it.
- Direct tests: Fresh blood, Microhematocrit test (MH) (16), Strout (17).
These thecnics detecte T.cruzi trypomastigote bloodform by microscopic examination.They are useful during the acute stage and in reactivation because in these phases large numbers of parasite circulate in the bloodstream. It may be also employed in CSF in brain ilness. The diagnosis made in half an hour, is simple and cheap.
- Indirect methods: Xenodiagnosis (18), Hemoculture. They have more sensitivity than the direct methods but the results are obtained in 15-60 days. They are fairly used in the chronic stage when parasitemia is low.
- Biopsy: In this procedure amastigotes can be observed inside the cells and it allows to perform the diagnosis in cerebral and skin tumors.
- Detection of circulating antigens: Parasites antigen are demostrated in serum or concentrated urinary specimens (19).
- P.C.R.: detect nucleic acid, it is no yet used frequently.
B) Antibodies studies.
The technics used are Indirect hemoagglutination, Direct agglutinations, Complement fixation, Indirect immunofluorescence, ELISA, Indirect immunofluorescence (20)
Serological test are used for:
-diagnosis during chronic stage,
- to screen blood donors,
- to evaluate the evolution of drug treatment and
- for seroepidemiological purpose.
Chagas disease is diagnosed if a patient has a blood sample with two different serological tests positive. IgM antibodies is unuseful during the actue stage.
Actually these assays are quite sensitive, but the ocurrence of false positive and false negative reactions has been shown. Most of test are made with parasite fraction, now are assaying with recombinant antigens.
Two different phases are considered in Chagasdisease: acute and chronic.
The acute phase lasts for 1or 2 months, being in most cases asymptomatic except in very young children, who may develop myocarditis, meningoencefalitis, the latter being fatal in 30-50 % of cases (21)(22).
During the chronic phase the infection may remain quiescent, one or two decades later 10-15 % develop cardiac (23,24) and or digestive tract alterations (25).
Three syndromes are characteristic of the chronic chagasic cardiopathy: the arrhythmic, the cardiac failure and the thromboembolic. These syndromes may be present alone or in an associated form in the same patient.
Megaesophagus and principally megacolon are the main GI. disturbance, caused by a loss of ganglion cells of autonomic nervous system in the gut.
Nifurtimox 8-12 mg/Kg per day for 60-90 days and Benzdinazol 5-8mg/Kg per day for 30-60 days are the drugs actually used for treatment during acute, chronic and congenital stages. Actually Nifurtimox is discontinued.
During the last decades, various events such as the use of cytoststatic agents and immunosuppressors, the progress in organ transplantation and specially AIDS have set conditions for reactivation of chronic asymptomatic T.cruzi infection (26-28).
Main and most relevant clinical finding is CNS involvement due to its high morbidity and mortality.
It is relevant to recognize these patients because some of them live in non endemic countries.The firsts cases published of Chagas disease causing a brain mass in AIDS was in Argentine and in USA (29).
The morphologic features of chagasic meningoencephalitis in patients whit T.cruzi infection and AIDS are very similar to those described previously for chagasic patients with leukemia, lymphomas, kidney transplatation and in congenital immunosuppression. (26-28)
Lazo et al. (30) described the morfological differences in the brains of chagasic patients with and without immunodeficiency.
- Some acute chagasic patients who present neurological manifestations develop meningoencephalitis including multifocal brain lesions in white and grey matters. The microscopy reveals diffuse lymphocytic leptomeningitis with few plasma cells, macophages and polimorphonuclear leukocytes. Amastigote forms of T. Cruzi are found within glial cells, perivascular inflammatory cell infiltrates in deeper cortical and subcortical white matter.
- During chronic phase some chagasic patients may present mild encephalitis with few inflammatory foci without parasites. Pitella (31) found it in 6 % of brain from chronic chagasic patients and suggest that are residual lesions from acute phase .
- In patients with HIV infection the brain show an increased weight and volume (with enlargement and flattering of the gyri and narrowing of the sulci) They present hemorragic and poorly limited areas ranging up to several centimeters in diameter envolving white and grey matters. The lesions are mostly located in the cerebral lobes and less frequently in the cerebellum and brain stem; no basal ganglia impact was ever described (30).
Microscopy shows meningoencephalitis with tendency to necrosis and hemorrahges, microglial nodules within the grey and white matters, edema, necrosis or old focal hemorrahges. Whitin the perivascular space are dense exudates of macrophages, lymphocytes and plasma cells. Vascular necrosis may be present, but no thromboses are observed.
Amastigote of T. cruzi are easily found within the glial cells and macrophages or free around microglial nodules. Neuronal parasitism is uncommon; the leptomeningitis ranges from slight to moderate. Parasites tends to lump within the necrohemorragic areas.
The heart is another organ that shows alterations, sometimes severe, when there are recurrent infections with T. cruzi and AIDS. (32-34)
Histologic paterns are similar to chronic or acute myocarditis. Chronic infection is characterized by focal predominantly intrafascicular or endomysial mononuclear cell infiltrates. Some myocelll present degenerative-necrotic phenomena. Parasites are not encountered.
Severe blood congestion, edema, mononuclear cell infiltrates, numerous T.cruzi amastigotes either filling up the myocell cytoplasms or are lying free in the interstitium are observed in acute myocarditis.
The main clinical findings in HIV infected patients with T.cruzi exacerbation are neurologic symptoms. (35-40)
In 1994 Rocha (32) published the first review including 23 patients with HIV and Chagas disease most of them from Brazil Chile and Argentine. Twenty (87%) developed severe multifocal or diffuse acute meningoencefalitis with necrosis and hemorrage associated with a large number of amastigotes. T.gondii, CMV and Herpes was also identified in one brain biopsy.
CSF findings was available only for nine cases. Pleocytosis with lymphocytes occurred in most cases, few had presence of neutrphilic and eosinophilic granulocytes. Proteins was increased in 8 out 9.
In 16 patients computorized tomograms were performed. Fifteen showed evidence of pseudotumoral lesions. Four of them had multiple lessions, 4 had two imágenes and 7 only one.
In all seven hearts examined, myocarditis was present. Four of them had acute chagasic myocarditis, two had focal lesions similar to that found in patients with chronic Chagasdisease, and one had acute and chronic features in different areas.
There is no question that T. cruzi caused the acute myocarditis in the four cases in which the parasite was found. One patient with chronic and other with acute myocarditis had not histologic studies.
In 17 patients serum antibodies study was performed, fifteen were reactives. Two out of five CSF antibodies searching were positive.
Parasitologic tests were assayed in 12 patients, 8 were positive, 4 of them by direct methods (high parasitemia). Presence of the protozoa was confirmed in 9 of 10 CSF investigated.
Di Lorenzo et al. (35) described two patients with HIV infection and chagoma; etiology was performed by brain biopsy. T1 weighted MRI showed hypointense lesions that enhanced with gadolinium, corresponding to extensive hyperintense area on T2 weighted images, producing mass effect. The imaging pattern of brain chagoma is similar to that of cerebral toxoplasmosis.
Pagano M. et al. (42) evaluated 10 patients with AIDS and CNS involvement due to T.cruzi infection. All had clinical manifestation as a cerebral tumor, 9 were men, aged 21 to 50 years. Two patients acquired the protozoa by blood transfusion.
Histological examination of the intacerebral masses were performed in 8 cases. The pattern varied from case to case, but all had amastigotes. Some tissue samples showing predominant granulomatous inflammatory cell infiltration; the other pattern was necrotic tissue with macrophage infiltration. In the two patients in whom biopsy were not performed, the parasite was present in CSF.
All patients presented neurologic symptoms or signs, six underwent brain descompression and total or partial resection of the masses. Most of these patients (8/10) had single supratentorial lesion and one had multiple supra e infratentorial localizations. At the begining 9 patients recieved antitoxoplasmic treatment based upon medical and neuroimaging findings. After failure of this treatment, Chagas disease was diagnosed. Then, all patients recieved specific antiparasitic treatment (Nifurtimox or Benzdinazol). Eigth cases died before seven months, three not relationated to T.cruzi. One survived for more than 12 months.
Heart disease is rarely associated with clinical manifestations, however anatomopathologic examinations demonstrate acute myocarditis with an intense inflammatory infiltrate, cardiac fiber aggresion, and T.cruzi amastigote forms.
Myocarditis as the main clinical manifestation of reactivation of T.cruzi infection in HIV infection is rare (32).
Sartori et al. (39) published a follow up of 18 patients with these agents with exacerbation of Chagas disease causing cardiac illness in three patients. These 18 patients were followed for 2 to 66 months, they had serologic tests reactive for Chagas (two methods) and for HIV infection; Xenodignosis was positive for 81,8% cases. Reactivation of Chagas disease defined by the finding of T.cruzi by parasitologic direct test and manifestated by heart disease was observed in three patients. One patient presented arrhytmia and cardiogenic shock, other congestive heart failure class IV (New York Heart Association), and the third had worsening of a previous cardiac disease. Myocarditis was observed by histological examination in 2 out of 3 cases. Treatment with Benznidazol was effective for controlling the clinical manifestations attributed to T.cruzi, and for reducing the level of parasitemia in these patients.
Labarca et al. has reported other case whose clinical findings relapse was myocarditis. Amastigotes were find only in heart tissue (32).
Freilij et al (43) studied six infants born from mother infected with HIV and T.cruzi. Four of them acquired both agents.
Three presented serious clinical manifestations, specially of CNS. They were under three months old; diagnosis was performed detecting the protozoa by MH in blood; only one had specfic antibodies. HIV diagnosis was performed in two cases by cocultivation, in the other by P24 Ag. They had good response to Nifurtimox, but they died due to different etiologies.
The fourth patient was 17 months old, he was asymptomatic and HIV and Chagas disease diagnosis was performed by serologic tests.
Loooking forward to the third millenium, improvement of social conditions, vector´s erradication and provision of adequate housing, sanitation and medical care is a sine qua non requirement in order to erradicate this parasitosis and alleviate -at least partially- unnecessary suffering of millions of human beings.
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