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Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 97, Num. 4, 2002, pp. 443-457
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Untitled Document
Mem Inst Oswaldo Cruz, Rio de
Janeiro, Vol. 97(4) 2002, pp. 443-457
Some Aspects of Protozoan Infections
in Immunocompromised Patients - A Review
Marcelo Simão Ferreira/+,
Aércio Sebastião Borges
Disciplina de Doenças Infecciosas
e Parasitárias, Faculdade de Medicina, Universidade Federal de Uberlândia,
Rua Goiás 480, 38400-027 Uberlândia, MG, Brasil
+Corresponding author. Fax: +55-34-3236.3151. E-mail: mferreira@nanet.com.br
Received 20 March 2002
Accepted 22 April 2002
Code Number: oc02087
Protozoa are among the most important
pathogens that can cause infections in immunocompromised hosts. These microorganisms
particularly infect individuals with impaired cellular immunity, such as those
with hematological neoplasias, renal or heart transplant patients, patients
using high doses of corticosteroids, and patients with acquired immunodeficiency
syndrome. The protozoa that most frequently cause disease in immunocompromised
patients are Toxoplasma gondii, Trypanosoma cruzi, different Leishmania
species, and Cryptosporidium parvum; the first two species cause severe
acute meningoencephalitis and acute myocarditis, Leishmania sp. causes
mucocutaneous or visceral disease, and Cryptosporidium can lead to chronic
diarrhea with hepatobiliary involvement. Various serological, parasitological,
histological and molecular methods for the diagnosis of these infections are
currently available and early institution of specific therapy for each of these
organisms is a basic measure to reduce the morbidity and mortality associated
with these infections.
Key words: protozoa - acquired immunodeficiency
syndrome-Aids - opportunistic infections
Since the sixties, opportunistic
infections, which frequently occur in patients under some kind of immunosuppression,
have become very common in daily clinical practice. The number of immunosuppressed
patients susceptible to different infectious or neoplastic processes has increased
each decade and culminated in the advent of the acquired immunodeficiency syndrome
(Aids) at the beginning of the eighties. The increasing use of transplants (kidney,
bone marrow, liver, heart, etc.) and the appearance of new immunosuppressive
drugs, nowadays extensively used in these patients as well as in patients with
neoplasias and autoimmune diseases, has led to the occurrence of a large number
of individuals with chronic immunosuppression in our community, who in turn
are predisposed to developing opportunistic infections. Tens of pathogens have
been described as etiologic agents of these infections, including viruses, bacteria,
protozoa, fungi, and helminths. Immunosuppression, either at the humoral or
cellular level, may have different consequences for the host depending on its
magnitude, including facilitation of the occurrence of these infections, an
increased disease/infection rate, alterations in the clinical manifestation
of the infection or exacerbation of its course, among others (Young 1981). Aids
and lymphoproliferative neoplasias are examples of conditions that lead to abnormalities
in practically all compartments of the immune system; however, T lymphocyte-mediated
immune defects predominate. The therapy to which these individuals are submitted
(e.g., corticosteroids) and malnutrition caused by the base disease itself represent
important cofactors in the predisposition to developing infections. Humoral
immunity defects (hypogammaglobulinemia) and neutropenia (number of serum neutrophils
< 1000/mm3) usually predispose to the occurrence of bacterial
infections caused by Gram-positive cocci, Gram-negative bacilli and some fungi
(Candida, Aspergillus), while infections caused by intracellularly
multiplying agents such as mycobacteria, endemic mycosis-inducing fungi and
protozoa are rare. These last pathogens are frequent agents of infectious processes
that occur in Aids or Hodgkin's disease, where the basic defect is the result
of cellular immune depression (Karp & Neva 1999). Aids produces the most
severe form of immunosuppression known, and more than one hundred microorganisms
causing opportunistic infections in these patients have been identified, many
of them intracellular protozoa, which will be discussed in the present review.
Infection with human immunodeficiency virus (HIV) leads to important alterations
in the clinical course of many disorders caused by these intracellular organisms;
curiously, no significant effects of retrovirus-induced immunosuppression on
the course of disease have been observed for some protozooses such as malaria.
On the other hand, there is evidence that these infections can accelerate the
course of HIV infection due to the capacity of many of these organisms to stimulate
Th2 type cytokines (IL-4, IL-10, etc.), which favor the progression of the disease
caused by HIV (Morrow et al. 1989, Actor et al. 1993, Gilks 1993).
The most frequent protozoan causing
opportunistic infections in immunocompromised individuals is Toxoplasma gondii.
Its association with severe manifestations of immunosuppression has been known
for several decades, and the occurrence of encephalitis, myocarditis and disseminated
disease has since then been observed in different clinical conditions such as
lymphoreticular neoplasias, solid organ transplantation, and, at present, mainly
in patients with Aids. Before the advent of this viral infection, opportunistic
infections caused by this and other protozoa had rarely been observed in immunocompromised
patients. Other coccidia such as Isospora belli and Cryptosporidium
parvum only gained clinical importance after the recognition of Aids at
the beginning of the eighties. Few cases of reactivated Chagas disease in immunosuppressed
patients have been reported in the sixties and seventies, but Trypanosoma
cruzi was never considered to be a true opportunistic agent. The same was
the case for protozoa of the genus Leishmania whose association with
immunosuppressive diseases represented a scientific curiosity in past decades.
This panorama changed after the Aids epidemic, and T. cruzi, and especially
Leishmania species, are currently gaining great importance as agents
of severe opportunistic diseases in patients affected by this retroviral infection.
The advances made during the last few years in the chemotherapy of neoplasias,
in the use of transplants and in the therapy of autoimmune diseases have led
to the reactivation of protozooses under these conditions, thus confirming the
opportunistic character of these pathogens (Ferreira et al. 1997, Borges et
al. 1999, Ferreira 1999, Rosenthal et al. 2000, Morgado et al. 2000).
The objective of this review was
to update and comment upon some aspects of diseases caused by protozoa in immunosuppressed
patients. Four parasites which are important causative agents of severe disease
in these individuals were chosen, and within this context, we basically focus
on pathogenic, clinical, diagnostic and therapeutic aspects of the infections
caused by T. gondii, T. cruzi, Leishmania sp. and C.
parvum.
OPPORTUNISTIC DISEASE CAUSED BY
Toxoplasma gondii
About 50% of the world population
is infected with T. gondii, a protozoan of the coccidian family, an obligate
intracellular parasite that multiplies in any nucleated cell of the vertebrate
host and that shows universal distribution (Cesbron-Delauw 1994). Felines are
the definitive host, with the domestic cat being the most important. This protozoan
is found in nature in three forms: the tachyzoite or intracellular proliferative
form, present during the acute phase of infection; tissue cysts, responsible
for the latent infection of multiple organs and important in disease transmission,
and oocysts found only in felines and eliminated in their feces, with this form
representing the source of infection for susceptible hosts (Krick & Remington
1978). Human infection occurs through the ingestion of cysts in raw or uncooked
meat, mainly pork and beef, ingestion of mature oocysts in food or water contaminated
with cat feces, or through transplacental passage of the parasite from the mother
to the fetus, with acute infection of the latter (Frenkel 1973). Transmission
through blood transfusion, laboratory accidents, and organ transplantation is
less common, and epidemiological evidence exists indicating hematophagous insects
as biological vectors of Toxoplasma (Amato Neto 1970, Herwaldt &
Juranek 1993, Amendoeira 1995).
Toxoplasmosis represents an important
public health problem, considering that 0.25 to 5 cases of congenital infection
occur per 1,000 livebirths, that approximately 10 to 20% of uveitis cases are
caused by this parasite, and that the prevalence of T. gondii-induced
encephalitis can reach up to 40% in patients with Aids (Krick & Remington
1978, Luft & Remington 1988). Therefore, toxoplasmosis is of
great clinical importance in man in two major situations: as a cause of congenital
infection, with 5 to 24% of children becoming ill and dying during the neonatal
period, in addition to the high rate of children with severe neurological and
visual sequelae who require education and special and costly care (Frenkel 1973),
and as an opportunistic infection of high mortality in immunosuppressed individuals
(Carey et al. 1973, Ambroise-Thomas & Pelloux 1993).
In immunocompetent hosts, the infection
is frequently benign, with parasitemia being self-limited, resulting in an asymptomatic
clinical form of the disease in most cases. However, in about 20% of cases acute
infection is accompanied by febrile lymphadenopathy, asthenia and lymphomonocytosis,
with the course of infection being self-limited (Feldman 1968, Darcy & Santouro
1994). After this period, T. gondii remains viable in the form of tissue
cysts, which reproduce slowly throughout the life of the host, thus characterizing
the chronic phase of infection. During this phase, the tissue cysts are controlled
by the humoral and cellular immune system, involving T lymphocytes and macrophages
which are continuously stimulated by parasite antigens, a fact that protects
against reinfection. As a result, parasite multiplication is more active and
persists for longer periods of time in less immunologically active tissues such
as the central nervous system (CNS) (Johnson 1981, Sims & Talbot 1989, Darcy
& Santoro 1994).
Immunocompromised hosts, especially
those with deficient cellular immunity, are at risk of recrudescence of the
chronic infection and dissemination, with the occurrence of fulminating disease.
The preferential reactivation of T. gondii in the CNS has been demonstrated
clinically and experimentally (Van Thiel 1966, Frenkel et al. 1975, Ruskin
& Remington 1976). This fact is probably due to low local immunity,
as well as to the presence of the blood-brain barrier which impairs the flow
of substances such as specific antibodies and interferon-g (IFN-g) that would
inhibit parasite multiplication (Ambroise-Thomas & Pelloux 1993). After
the CNS, the heart and lungs are the most frequently affected organs (Frenkel
1957, Tschirhart & Klatt 1988, Jautzke et al. 1993).
After the occurrence of Aids, toxoplasmosis
became the most common cause of encephalitis in the United States (Luft &
Remington 1988). Until then, this protozoosis was only sporadically observed
in patients with neoplasias, collagen disease or transplant recipients under
immunosuppressive therapy. In these patients, the disease resulted in the reactivation
of chronic infection, although cases of acute infection, including patients
with disseminated disease, have been described for previously seronegative organ
recipients whose donors presented serological evidence of a past infection (Frenkel
et al. 1975, Luft et al. 1983, Gray et al. 1989, Bertoli et al. 1995).
The clinical presentation of toxoplasmosis
ranges from asymptomatic reactivation, commonly observed in previously infected
organ recipients and demonstrable by increased post-transplant antibody titers,
to severe disseminated disease. The disease manifests as diffuse encephalitis,
meningoencephalitis or, more common, tumor lesions with a mass effect. Motor
syndrome, consciousness disturbances, seizures and focal signs are common manifestations
that are clinically indistinguishable from other CNS complications such as reactivated
Chagas disease, primary CNS lymphoma, viral or fungal encephalitis, neurotuberculosis
and others, diseases also frequently observed among these patients (Hakes &
Armstrong 1983, Luft & Remington 1988, Ferreira et al. 1997).
The variety of immune system defects
found in individuals with Aids, such as CD4+ T lymphocyte deficiency, reduced
activity of cytotoxic T and NK cells, and the low production of immunoregulatory
lymphokines such as IFN-g, may explain the high frequency of reactivated T.
gondii infection (Fauci 1984).
The new impact of T. gondii
infection on public health has raised great interest in the understanding of
its immunopathogenesis. The infection triggers both humoral and cellular immune
responses, with the latter being more important for the development of protective
and persistent immunity (Darcy & Santoro 1994). The role of humoral
immunity has been extensively studied. It is known that T. gondii infection
produces IgM, IgA, IgE and IgG class antibodies, with the first three being
detected early during the course of infection. IgM class antibodies are the
first to occur and can be detected 7 to 15 days after infection, with maximal
concentrations being observed during the second month, followed by a progressive
decline and disappearance of these antibodies within a few months. However,
low antibody titers may persist for a prolonged period of time, i.e., months
or years. IgA antibodies can be detected after the first month of infection
in about 95% of cases, reaching a peak concentration between the second and
third months, followed by a decline, which, in most cases, is observed between
the fourth and seventh month before the decrease in IgM antibodies. IgA antibody
detection is therefore of great diagnostic value in acute toxoplasmosis, since
these antibodies are rarely found during the chronic phase of infection (Huskinson
et al. 1990, Gross et al. 1992).
Cellular immunity seems to be the
main mechanism of defense in the control of toxoplasmosis (Johnson 1981). The
role of T lymphocytes in T. gondii infection was first emphasized by
Frenkel in 1957. In 1988, the same author observed that athymic rats do not
develop protective immunity and that depletion of CD4+ cells eliminates any
previously acquired protection (Frenkel 1988). Since then, a series of experimental
studies have demonstrated the importance of CD4+ and CD8+ T lymphocytes, which
act synergistically, in the control of this disease and in the prevention of
its reactivation (Araujo 1991, Gazzinelli et al. 1991, Parker et al. 1991).
This group of lymphocytes represents the major source of IFN-g, which, in turn,
is responsible for resistance during the chronic phase of disease through the
activation of macrophages that promote intracellular death of the parasite (Kaufmann
1995). Reactivation of infection is therefore due to a reduction in the expression
of IFN-g as well as IFN-a, which in turn results in the lack of activation of
macrophages and microglial cells (Gazzinelli et al. 1993).
Activated macrophages, NK and LAK
cells, and the production of different cytokines, such as IL-2, IL-12 and IFN-g,
are of crucial importance for the immune response against T. gondii both
during the acute and chronic phase of the disease (Gazzinelli et al.1992, 1994).
The diagnosis of acute toxoplasmosis
is mainly based on a combination of clinical and laboratory data. In clinical
practice, serological tests are routinely employed to detect IgM- and IgG-specific
antibodies, including indirect immunofluorescence and immunoenzymatic tests
(ELISA), with the latter showing higher sensitivity and specificity (Fuccillo
et al. 1987). However, in immunosuppressed patients, particularly those with
Aids, the early diagnosis of neurotoxoplasmosis has been limited due to the
lack of noninvasive diagnostic tests of high sensitivity and specificity. The
clinical picture is nonspecific and cerebrospinal fluid (CSF) findings are found
to be normal or show nonspecific alterations such as lymphocytic pleocytosis
and discrete CSF hyperproteinorraquia. Imaging analyses such as cranial computed
tomography and magnetic resonance are of great value, demonstrating isodense
or hypodense, single or multiple lesions with a mass effect, and taking up the
contrast dye in a ring-like or nodular manner in more than 90% of cases. Such
findings are highly suggestive of toxoplasmosis reactivation granuloma, but
are not pathognomonic (Figueiredo et al. 1983, Wanke et al. 1987, Luft
& Remington 1988). The serological pattern found in these patients is similar
to that observed for the general population with inactive infection. Since in
basically all cases the disease results in the reactivation of latent and non-acute
infection, IgM antibodies are not habitually detected and IgG antibodies do
not discriminate between latent and active infection (Luft et al. 1984, Wong
et al. 1984, Weiss et al. 1988, Grant et al. 1990), and are even not detectable
in a minority of cases with reactivated disease (Zangerle et al. 1991, Porter
& Sande 1992, Garly et al. 1997).
Individuals under immunosuppressive
therapy such as organ transplant recipients or patients with malignant diseases,
who had been previously infected with T. gondii, might show an altered
serological profile of this protozoan compatible with reactivation, such as
increased IgG antibody titers or, less frequently, increased titers of acute
phase antibodies, i.e., IgM, 4 to 13 weeks after the beginning of immunosuppression,
and the presence or absence of clinical manifestations, a fact not observed
in patients with Aids. On the other hand, seronegative patients receiving organs
from seropositive donors may show seroconversion 4 to 6 weeks after transplantation,
generally accompanied by disseminated infection whose clinical manifestation
usually coincides with the occurrence of antibodies, although late manifestations,
i.e., about 10 months after immunosuppressive therapy, have been reported (Luft
et al. 1983).
The detection of IgA antibodies has
also shown conflicting results. IgA-specific antibodies were detected by immunoblotting
in a group of patients with Aids and neurotoxoplasmosis in 91.6% of serum and
CSF samples analyzed (Gross et al. 1992). Brazilian investigators have demonstrated
the presence of this antibody in serum in 84% of 54 patients with this diagnosis
(Borges & Figueiredo 2000a). In contrast, IgA-specific antibodies were detected
in sera from HIV-infected patients with and without neurotoxoplasmosis (Darcy
et al. 1991).
In cases of reactivation in the CNS,
the detection of anti-Toxoplasma antibodies in CSF should be interpreted
with caution, since their presence may only indicate passive passage from serum
to the CNS. However, the demonstration of local production of specific antibodies,
whose titers were found to be increased in CSF irrespective of a serum increase,
has proved to be of diagnostic value in some situations, such as meningoradiculitis
caused by Borrelia burgdorferi (Wilske et al. 1986), neurosyphilis (Müller
& Moskophidis 1983), encephalitis caused by herpesvirus and paramyxovirus
(Reiber 1980, Felgenhauer 1982), congenital toxoplasmosis (Pinon et al. 1986),
and neurotoxoplasmosis itself (Wong et al. 1984, Orefice et al. 1990). In a
series of 37 patients with Aids and T. gondii-induced encephalitis, antibodies
were detected in CSF in 23 patients. Among 16 patients evaluated, 70% showed
evidence of local production of specific antibodies (Potasman et al. 1988).
In another group of patients, indirect immunofluorescence revealed that IgG
titers in CSF at a dilution higher than 1/64 show 100% specificity for the differential
diagnosis of neurotoxoplasmosis in Aids. In contrast, IgA antibodies detected
in CSF by ELISA showed 72.7% specificity. In the same study, the detection of
antibody production in the CNS using radial immunodiffusion was not useful for
the diagnosis of toxoplasmosis, with a specificity of only 70.8% (Borges &
Figueiredo 2000b).
Several clinical and experimental
studies have reported different results regarding the usefulness of circulating
T. gondii antigen as a diagnostic marker of acute infection, congenital
toxoplasmosis and disease reactivation in immunocompromised patients. However,
its value in routine clinical practice is still controversial due to the divergent
results obtained with animals models and in human infection (Araujo & Remington
1980, Dannemann et al. 1991, Fachado et al. 1994, Hafid et al. 1995,
Letillois et al. 1995).
Parasite identification in blood
through culture media or inoculation into laboratory animals provides questionable
sensitivity, the techniques are difficult to carry out and isolation of the
parasite is time consuming (Derouin et al. 1987, Tirard et al. 1991, Dannemann
et al. 1992).
The use of more sensitive and specific
methods, such as the polymerase chain reaction (PCR), has been shown to be effective
for the diagnosis of congenital and ocular toxoplasmosis (Dupouy-Camet et al.
1993), but PCR detection of parasitemia in patients with Aids and toxoplasmic
encephalitis is only useful in cases of disseminated infection (Khalifa et al.
1994). The usefulness of PCR was also assessed in another study using CSF samples
obtained from 14 patients with Aids. Among 9 cases with a diagnosis of neurotoxoplasmosis,
PCR was positive in 4 patients only, with no false-positive result being detected
(Parmley et al. 1992).
In most cases, the diagnosis of neurotoxoplasmosis
is presumptive and based on clinical presentation, tomographic or magnetic resonance
findings, and the presence of IgG-specific antibodies in serum. The diagnosis
is confirmed based on the therapeutic response which generally occurs between
7 and 14 days (Wanke et al. 1987, Luft et al. 1993). The definitive diagnosis
has been made thus far upon demonstration of the parasite, more precisely tachyzoites,
in brain tissue obtained by biopsy. However, in addition to being an invasive
method which is subject to complications, histopathological analysis confirms
the diagnosis in only 50% of clinically diagnosed cases. Access to the lesion
is often impaired or routine staining techniques (Wanke et al. 1987, Cohn et
al. 1989), and even immunohistochemistry (Conley & Jenkins 1981, Hofflin
& Remington 1985), do not detect the parasite in the material obtained.
In a histopathological study evaluating a series of 85 cases of neurotoxoplasmosis
and Aids, more than 50% of immunoperoxidase-positive cases were negative when
standard techniques were employed (Luft et al. 1984).
In contrast to immunocompetent patients
in whom the course of disease is mainly self-limited, toxoplasmosis is fatal
in immunosuppressed individuals if not recognized and treated early. The drugs
routinely employed in the treatment of toxoplasmosis basically act against the
proliferative forms, or tachyzoites, present during the acute phase of infection
or during reactivation of latent foci in immunocompromised hosts, but do not
eradicate the encysted form of the parasite, the bradyzoites (Israelski &
Remington et al. 1993, Luft et al. 1993). The combination of pyrimethamine and
sulfadiazine is considered to be the most effective scheme, with therapy consisting
of two phases: attack or acute treatment and maintenance therapy. The regimen
of choice is sulfadiazine at the dose of 4 to 6 g/day combined with pyrimethamine
at the dose of 50 to 75 mg/day for 4 to 6 weeks. Maintenance therapy consists
of a 50% reduction in the initial dose of both drugs, i.e., 2 g/day sulfadiazine
plus 25 mg/day pyrimethamine throughout immunosuppression, i.e., in the case
of patients with Aids, throughout life. A response is observed in 70 to 95%
of cases and 91% of patients show objective signs of improvement within the
first 10 to 14 days (Luft et al. 1993). Clindamycin at the dose of 2.4
to 4.8 g/day or 100 mg/day dapsone, plus pyrimethamine at the doses reported
above, are alternative options for patients who develop sulfa intolerance (Katlama
et al. 1996). New macrolides such as clarithromycin (1.5 g/day) and azithromycin
(2 g/day) in combination with pyrimethamine have provided satisfactory results
and even demonstrated some action on the cystic form of this protozoan (Saba
et al. 1993). The use of clarithromycin plus minocycline and of azithromycin
plus sulfadiazine has also been evaluated. A 75% cure rate was achieved with
atovaquone, a hydroxynaphthoquinone acting against cysts and trophozoites, administered
at the dose of 3 g/day, and combination with pyrimethamine may improve this
response (Kovacs 1992). Folic acid should be added to sulfa- and pyrimethamine-containing
schemes at the dose of 10 to 15 mg/day to prevent the myelosuppression provoked
by these drugs.
OPPORTUNISTIC DISEASE CAUSED BY
Trypanosoma cruzi
Chagas disease still represents one of the most important endemic diseases of
the American continent and has been diagnosed from the south of the United States
to the south of Argentina, with an estimated number of 16 to 18 million chagasic
patients. In Brazil, 3 to 5 million people are estimated to be infected with
T. cruzi and, in contrast to what was observed 2 to 3 decades ago, most
of these individuals live today at the periphery of large cities as a consequence
of the migration of infected individuals of low socioeconomic level from rural
areas to urban centers (Pan American Health Organization 1990, Rocha et al.
1994). Even in non-endemic countries such as the United States, more than 100,000
people are estimated to be infected as a result of the massive migration of
Latin Americans to this country (Navin et al. 1985).
Since the end of the sixties, several
authors have observed the occurrence of severe forms of Chagas disease, notably
meningoencephalitis and myocarditis, in patients under severe immunosuppression.
Some cases have been described in Brazil (Amato Neto et al. 1968, França
et al. 1969, Queiroz 1973), others in Latin-American countries where the parasitosis
is endemic (Rivero et al. 1974, Monte Verde et al. 1976, Pizzi et al. 1982),
and one case was documented in the United States (Kohl et al. 1982). Usually,
severe manifestations of trypanosomiasis that occurs in immunosuppressed patients
result in the reactivation of chronic, previously asymptomatic or oligosymptomatic
infection, although severe acute forms resulting from blood transfusions have
sporadically been reported in the literature (Corona et al. 1988, Wanderley
et al. 1988, Grant et al. 1989, Nickersosn et al. 1989). Localized or systemic
exuberant clinical manifestations have been observed in patients with lymphoreticular
neoplasias, renal, heart and bone marrow transplant patients, and in patients
with Aids (Ferreira et al. 1997). Experimental studies conducted on mice and
rats chronically infected with T. cruzi and submitted to different immunosuppressive
drugs have demonstrated reactivation of the disease, accompanied by an increase
in parasitemia, aggravation of myocarditis and increased mortality, thus confirming
the opportunistic character of this parasite (Brener & Chiari 1971, McCabe
et al. 1985, Sinagra et al. 1993). The use of trypanosomicidal drugs in animals
with reactivated infection reduced the magnitude of disease manifestations and
prevented further reactivation, findings that are relevant for clinical practice
(Meckert et al. 1988).
The understanding of the morphological
alterations that occur in immunocompromised chronic chagasic patients has been
based on the study of biopsies and autopsy material carried out in a few cases
described in the literature. The most frequent anatomopathological finding related
to the association between Chagas disease and immunosuppression is acute meningoencephalitis,
which is characterized by the presence of generalized cerebral edema and hemorrhagic
soft pseudotumoral areas of undefined limits measuring several centimeters;
these lesions are generally localized at the brain periphery, affecting the
gray and, predominantly, the white substance; lesions can also occur in the
brain stem and in the cerebellum. Histologically, the presence of a parenchymatous
and perivascular exudate consisting of macrophages, lymphocytes, plasma cells
and, more rarely, neutrophils is noted; necrotic foci, hemorrhage and microglial
nodules are also commonly found. T. cruzi amastigotes are abundant and
parasitize glial cells and, rarely, neurons. Lymphomonocytic meningitis, with
the presence of parasites in the meninges, is a constant finding in these cases
and permits the in vivo diagnosis upon detection of T. cruzi in CSF.
Acute myocarditis is another important anatomopathological finding in immunosuppressed
chagasic patients, which is characterized by cardiomegaly and focal or diffuse
infiltration of the myocardium by mononuclear cells, accompanied by intense
parasitism of cardiac fiber cells. Epicarditis and endocarditis can also be
observed in these patients. Injury of other organs has been rarely documented;
panniculitis might be observed in heart and renal transplant patients in the
presence of the parasite; parasitism of the musculature of the esophagus, stomach,
colon, ocular globe and uterine cervix has also sporadically been reported (Almeida
et al. 1974, Stolf et al. 1987, Oddó et al. 1992, Rocha et al. 1993,
1994).
Few cases of an association between
Chagas disease and lymphoreticular neoplasias have been described in the literature,
most of them occurring in patients with acute lymphocytic leukemia or Hodgkin's
disease. In half these cases, Chagas disease was in fact acute after transfusion
and the course of disease was severe since the patients were under marked immunosuppression
which was not only the result of the base disease but also of the concomitant
use of antineoplastic chemotherapy associated or not with high doses of corticosteroids.
The remaining cases were certainly the results of reactivation of chronic infection,
since the patients were found to be seropositive upon diagnosis. Among 15 cases
selected from the literature, meningoencephalitis was observed in 7/15 cases
(46%), myocarditis in 9/15 (60%), and the concomitant occurrence of both manifestation
was observed in 3/15 cases (20%). The diagnosis was in general confirmed by
the presence of parasites in blood, pericardial fluid, or tissue, particularly
brain, heart and esophageal tissue. The mortality rate was very high in these
cases (8/15, 53%) and survival of the patients directly depended on the early
diagnosis and the rapid institution of specific therapy (Ferreira et al. 1997).
Transplants are increasingly being
performed in patients with Chagas disease. Many of them receive kidney or heart
transplants, the latter for the treatment of dilated myocardiopathy caused by
the parasitosis itself. In renal transplantation, two modalities of trypanosomiasis
can be discussed: (1) the transmission of T. cruzi from living donors
or cadavers to non-chagasic kidney recipients through the transplanted organ
itself (therefore, the donor has Chagas disease) or through the transfusion
of blood or blood derivatives; (2) reactivation of chronic parasitosis after
transplantation as the result of immunosuppression due to the use of corticosteroids,
cyclosporin or tacrolimus. In the case of the first modality, the clinical manifestations
are similar to those observed during the acute phase of infection and consist
of fever, hepatosplenomegaly, myalgias and signs of myocarditis, including the
presence of cardiac arrhythmias. The time interval between transplantation and
the onset of clinical manifestations can be as short as 30 days or as long as
14 months. In all of these patients, T. cruzi is present in peripheral
blood and anti-T. cruzi IgM antibodies are also detectable in serum by
indirect immunofluorescence. In cases of reactivated chronic infection, involvement
of the CNS might be observed in the form of severe meningoencephalitis, which
can lead to death in some cases. It is important to note that positive serology
for Chagas disease of the organ donor or recipient does not represent a contraindication
for transplantation, since long-term follow-up of chagasic transplant recipients
has shown that in most patients the disease is not reactivated and that there
is no need for prophylactic pre- or post-transplant anti-T. cruzi therapy;
this treatment only needs to be initiated if there is evidence of acute or reactivated
infection. Treatment of the clinical disease of any modality caused by T.
cruzi consists of oral benznidazole at the dose of 5 mg/kg per day (in two
doses) for 60 days; alternatively, nifurtimox, currently not available in Brazil,
may be used. The anti-parasitic treatment has been shown to be effective in
these cases (Jost et al. 1977, Chocair et al. 1985, Figueiredo et al. 1990,
Cantarovith et al. 1992, De Arteaga et al. 1992, Lopez Blanco et al. 1992, Luders
et al. 1992).
A few patients with chagasic heart
disease have already received heart transplants; these individuals were submitted
to powerful immunosuppression after transplantation consisting of high doses
of corticosteroids, immunosuppressors (azathioprine, cyclosporin, tacrolimus,
etc.) and anti-lymphocytic globulin. The combination of these drugs, used to
prevent organ rejection, markedly favored reactivation of the protozoosis in
at least two thirds of cases. The time between transplantation and reactivation
might exceed one year. The predominant clinical manifestations were fever, signs
of acute myocarditis accompanied by heart failure and arrhythmias, and infiltrating
erythematous cutaneous lesions, which are histologically characterized by panniculitis
with the presence of a large number of T. cruzi amastigotes. The
diagnosis was in general made by anatomopathological examination of endocavitary
biopsies. Curiously, no parasites were observed in peripheral blood, even after
repeated analyses using different parasitological techniques. Benznidazole administered
at the recommended doses
for 60 days was found to effective in the treatment of reactivated Chagas disease,
leading to the disappearance of signs and symptoms of the disease, but without
curing the parasitosis. Allopurinol has shown some efficacy in a small series
recently studied in Brazil. The prophylactic pre- or post-transplant use of
benznidazole is not indicated since this drug does not eliminate the parasite
from the organism and, therefore, does not prevent reactivation (Stolf et al.
1987, Bocchi et al. 1993, Kirchoff 1993).
Only one case of fulminating Chagas
disease has been described in the literature in a bone marrow transplant recipient
(Geiseler et al. 1987).
The advent of the Aids epidemic at
the beginning of the eighties opened the possibility of the occurrence of reactivation
of this parasitosis in co-infected individuals under profound immunosuppression
as a result of this viral infection.
About 80 cases of reactivation in
patients with Aids have been documented in the literature, most of them reported
in Brazil and Argentina. Only one tenth of these cases have been described in
detail, while the remaining cases have been communicated at congresses or specialty
symposia (Ferreira et al. 1997, Rocha et al. 1997, Sartori et al. 1998). Curiously,
the first Aids case reported in the United States involved an immigrant from
El Salvador who carried both infections (Gluckstein et al. 1992). At the beginning
of the nineties, about 6% of autopsied HIV-positive patients with reactivated
Chagas disease had been recorded in our hospital in Uberlândia, MG, an
area endemic for Chagas disease (Borges et al. 1996). Although in most published
cases no information regarding the CD4 T lymphocyte count is available, recent
findings indicate that practically all patients with reactivated disease have
CD4 T cell levels below 200 cells/mm3, similarly to what is observed
for other opportunistic infections affecting these patients (Ferreira et al.
1997, Sartori et al. 1998). In contrast to heart transplant patients with reactivated
disease in whom myocardial involvement is predominant, involvement of the CNS
is common in patients with Aids, being observed in 75 to 80% of co-infected
individuals. CNS involvement manifests as acute, uni- or multifocal meningoencephalitis
with fever, headache, vomiting, seizures and focal neurological signs. Analysis
of CSF samples demonstrates the presence of mild to moderate pleocytosis (<
100 cells/mm3), predominantly consisting of mononuclear cells, elevated
protein levels and the presence of T. cruzi upon direct examination
of the fluid (Ferreira et al. 1991, 1997). Parasites are also easily detected
in peripheral blood using Giemsa-stained smears, by concentration methods (Strout,
microhematocrit, etc.), and even by the quantitative buffy coat (QBC) assay.
The identification of parasitemia by other techniques such as blood culture
or xenodiagnosis should not be considered as evidence of reactivation, since
these methods may yield a positive result during any phase of the disease, including
chagasic patients not infected with HIV (Ferreira et al. 1997).
Modern imaging methods are frequently
used to diagnose encephalic lesions in HIV-positive patients. In the case of
chagasic meningoencephalitis, cranial computed tomography reveals the presence
of hypodense, predominantly subcortical, single or multiple lesions which have
the shape of a ring after contrast injection. These lesions closely resemble
those seen in neurotoxoplasmosis, although the main areas involved in this parasitosis
are the base nuclei and the thalamus. Magnetic nuclear resonance seems to be
more sensitive than tomography, detecting a larger number of lesions in both
infections (Rocha et al. 1994, Ferreira et al. 1997, Ferreira 1999).
Another organ frequently involved
in the reactivation of American trypanosomiasis is the heart. The frequency
of this occurrence is not known, since no complete autopsy study of cases published
in the literature or communicated at congresses exists. Involvement of the heart
is often discrete and is certainly not detected clinically or radiologically.
Based on the few cases published, about half of the patients are estimated to
present myocarditis during disease reactivation. Clinical manifestations, when
present, include signs and symptoms of congestive heart failure (dyspnea, tachycardia,
edemas, etc.) and the presence of cardiac arrhythmias. An increase in heart
volume, together with the presence of sometimes voluminous pericardial hemorrhage,
can be documented by two-dimensional echocardiography. Parasites may be present
in the pericardial fluid. In biopsy or autopsy studies, the presence of T.
cruzi should be always confirmed by immunohistochemical techniques or by
electron microscopy due to the simultaneous presence of associated infections
(for example, T. gondii) (Ferreira et al. 1997, Sartori et al. 1998).
The diagnosis of Chagas disease reactivation
should be made as early as possible, since anti-parasite treatment can improve
the prognosis and survival of the patient. The identification of T. cruzi
in body fluids (blood, CSF, pericardial or ascitic fluid, etc.) is the key to
the diagnosis of Chagas disease and should be carried out as soon as a suspicion
exists. Brain or myocardial biopsies should also be performed, if possible.
Survival of patients with Chagas disease, even when treated, is low, although
the latest cases published showed remission a long time after treatment owing
to the concomitant administration of antiretroviral drugs that increase and
stabilize serum CD4 T lymphocyte levels (Ferreira et al. 1997, Sartori et al.
1998, Ferreira 1999).
The drugs acting on T. cruzi
are nifurtimox and benznidazole, with only the latter being available in Brazil.
Benznidazole is administered orally at the dose of 5 mg/kg per day in two doses
for a period of 60 days. The drug seems to be effective in the treatment of
disease reactivation under any type of immunosuppression, including HIV-positive
patients. Fever, neurological or cardiac signs, and cutaneous lesions generally
regress within the first 2 or 3 weeks of treatment, with no parasitemia being
detected upon direct examination, blood culture or xenodiagnosis. Adverse effects
commonly occur after the first days of drug use, with cutaneous eruption, peripheral
neuropathy and granulocytopenia being the most frequent. In countries where
nifurtimox is still commercialized, its use is indicated in situations of reactivation
at the dose of 8 to 10 mg/kg per day, orally, for 60 to 90 days. Its efficacy
as a trypanosomicidal drug seems to be similar to that of benznidazole. Triazole
derivatives (itraconazole, fluconazole) have been used for reactivation treatment
by some authors, with apparent success, although they are not recommended as
first-line therapy in these situations (Nishioka et al. 1993, Ferreira et al.
1997, Sartori et al. 1998, Ferreira 1999). After remission and treatment discontinuation,
the introduction of a second prophylaxis is recommended, since further reactivations
may occur later. An expert committee, brought together by the Pan American Health
Organization in 2000, recommended the use of benznidazole at the dose of 5 mg/kg
per day, three times a week, for an undefined period of time as secondary prophylaxis;
nifurtimox might also be used for this purpose. Antiretroviral therapy should
be systematically administered to these patients in order to maintain elevated
CD4 T lymphocyte levels, thus reducing the chance for disease reactivation.
A group of 13 HIV-positive chagasic patients under retroviral therapy have been
followed up by our group for months and none of them has shown any clinical
signs of trypanosomiasis activity thus far. There is currently no consensus
regarding the use of drugs as primary prophylaxis in chagasic patients infected
with HIV (Anonymous 1996).
OPPORTUNISTIC DISEASE CAUSED
BY Leishmania sp.
Leishmaniasis is a parasitic disease
widely distributed throughout the world, which is endemic in the tropical and
subtropical regions of 88 countries. About 2 million cases are estimated to
occur annually worldwide, most of them presenting the cutaneous or mucosal form.
Leishmania is an obligate intracellular parasite and control of this
infection involves a vigorous Th1-depdendent cellular immune response. Therefore,
the observation of the opportunistic character of this protozoosis during the
last few years was no surprise, with this parasite causing mucocutaneous or
visceral disease in immunosuppressed patients, particularly those infected with
HIV (Alvar et al. 1994, 1997). Co-infection with this retrovirus emerged as
a new and interesting pathology, whose frequency is currently increasing. Cases
of HIV-Leishmania co-infection have been reported in more than 25 countries,
particularly those located at the margins of the Mediterranean Sea such as Portugal,
Spain, France, Italy, Greece and North-African countries, and, to a lesser extent,
in Equatorial African, Asian and South American countries (Alvar 1994, Dedet
et al. 1995, Gradoni et al. 1996, Borges et al. 1999). More than 2,000 cases
of visceral leishmaniasis associated with HIV infection have been reported in
European countries alone, a fact due to the simultaneous dissemination of both
diseases and the overlapping geographic distribution of the two infections as
the result of the urbanization of leishmaniasis and the ruralization of Aids
(WHO 1995, Ferreira 1996, Rabelo et al. 1998). In Brazil, about 80 cases of
HIV-Leishmania co-infection have been documented, most of them with the
mucocutaneous form of the disease and few cases with the visceral form. This
number will probably increase during the next few years, since infectologists
are currently more aware of the diagnosis of this co-infection (Rabelo et al.
1998, Borges et al. 1999).
Today, it has been demonstrated that
Aids and leishmaniasis, particularly the visceral form, can interact in a vicious
cycle of mutual aggravation. Aids leads to the dissemination of the parasites
to practically all organs and body systems, while, on the other hand, leishmaniasis
accelerates the course of HIV infection by decreasing the latent period of viral
infection and thus the life expectancy of the patient. Various other opportunistic
infections such as tuberculosis or systemic mycoses are found in co-infected
patients, demonstrating the marked immunosuppression generated in these individuals
(Albrecht 1998, Rosenthal et al. 1999).
The epidemiology of visceral leishmaniasis
in the Mediterranean region suffered profound changes since the advent of Aids.
It has been known for decades that this infection frequently affects children,
but this picture changed radically after the occurrence of Aids, since most
cases diagnosed at present in these countries refer to young adults suffering
from immunosuppression due to HIV. Leishmaniasis has sporadically been detected
in individuals with other types of immunosuppression, such as renal transplant
patients and patients with lym-phoreticular neoplasias, among others (Fernandez-Guerrero
et al. 1987, Alvar 1994). Most HIV-positive co-infected patients are addicted
to injectable drugs. Thus, when an individual with leishmaniasis shares syringes
and needles used for drug injection with other partners, leishmaniasis might
be transmitted through blood remaining on the material, with this fact representing
an alternative form of transmission of this protozoosis between individuals.
Amastigotes are demonstrable in peripheral blood smears in more than 60% of
co-infected patients, thus confirming the existence of this form of transmission.
In addition, these individuals can serve as true reservoirs of the parasite
by easily infecting phlebotomine flies feeding on their blood (Medrano et al.
1993, Alvar 1994, Alvar et al. 1997).
Leishmaniasis is currently known
to frequently manifest in the form of subclinical infections which can persist
in individuals for months or years. Most cases of visceral leishmaniasis that
occur in HIV-positive patients are believed to result from reactivation of latent
infections, although primary infections with L. infantum have been reported
among patients in Italy and Spain (Alvar 1994, Gradoni et al. 1996, Alvar et
al. 1997).
Any Leishmania species can
cause disease in immuno-compromised patients. Parasites isolated from co-infected
patients included strains previously undetected in immunocompetent individuals,
including some species restricted to lower animals. Visceral dissemination of
species that commonly cause the cutaneous form of the disease (e.g., L. braziliensis)
has also been observed by us and others (Coura et al. 1987, Machado et al. 1992,
Alvar et al. 1997).
The clinical-laboratory presentation
of simultaneous HIV and Leishmania infections has been described in detail
in the literature. Many cases show an asymptomatic or oligosymptomatic course
and parasites are casually detected during routine blood and bone marrow examination.
Cutaneous forms of the disease with disseminated lesions, involving the nasal,
oral or pharyngeal mucosa, have been observed in patients with advanced stage
Aids, sometimes accompanied by extensively destructive lesions; lesion recurrence
after treatment has been a common event among patients with an apparent therapeutic
response to a first course of antimonial drugs or amphotericin B. For the visceral
form, classical clinical manifestations include fever, weight loss, hepatosplenomegaly
and peripheral pancytopenia, which are observed in about 75 to 80% of cases;
adenopathies and signs of pulmonary involvement with interstitial pneumopathy
have also been documented. The gastrointestinal tract is frequently found to
be involved (in about 30% of cases), and amastigotes have been isolated from
the esophagus, stomach, small and large bowel, pancreas and, obviously, liver.
In these cases no clinical signs and symptoms might be noted, although many
patients present abdominal pain, diarrhea, vomiting and dysphagia; biopsies
obtained from any part of the digestive tract easily detect the presence of
parasites. Hemorrhagic diathesis due to thrombocytopenia and hepatic involvement
may occur in a small percentage of cases. Most co-infected patients have low
CD4 T lymphocyte counts, usually less than 200 cells/mm3, a fact
that might explain the frequent association with other opportunistic infections
commonly observed in these patients, such as esophageal candidiasis, pneumocystosis,
tuberculosis, toxoplasmosis, cryp-tococcosis, and cytomegalovirus infection.
Some authors have observed that the clinical presentation of visceral leishmaniasis
is influenced by the CD4 T cell count, i.e., the lower the lymphocyte count
the more atypical is the clinical picture. Nontypical localization of the disease
has been frequently found in patients with CD4 T lymphocyte counts < 50 cells/mm3
(La Rosa et al. 2001). The clinical presentation of visceral leishmaniasis itself
should be differentiated from other infections, particularly disseminated histoplasmosis
and miliary tuberculosis, which present highly overlapping clinical manifestations
(Dedet et al. 1995, Rosenthal et al. 1995, 2000, Alvar et al. 1997, Borges et
al. 1999).
The diagnosis of leishmaniasis in
patients with Aids is easy due to the fact that these individuals present a
large number of parasites in their tissues. Detection of Leishmania in
bone marrow or spleen aspirates shows high positivity (70 to 100%), thus permitting
a rapid confirmation of the diagnosis; as mentioned above, peripheral blood
smears stained with Giemsa can reveal the presence of the parasite in up to
60% of cases. A recent study employing the QBC technique, which is widely used
for the parasitological diagnosis of malaria, easily demonstrated the presence
of the amastigote forms of the parasite in bone marrow and peripheral blood
of non-immunosuppressed patients with kala-azar; this method may therefore be
of great diagnostic value in co-infected patients (Liarte et al. 2001). Liver
biopsies may also serve as a tool to confirm the diagnosis of the parasitosis.
Unfortunately, most co-infected patients do not produce sufficient amounts of
antibody, and serological tests (ELISA, immunofluorescence) are positive in
only 40 to 50% of cases, thus being of limited value for the diagnosis of this
infection. In the mucocutaneous form, biopsy almost always leads to a diagnosis
due to the abundance of parasites in the material examined. PCR may be used
for the detection of these protozoa in blood and other body fluids, and tissue
removed for biopsy (Piarroux et al. 1994).
Treatment of HIV-positive patients
co-infected with Leishmania has generally been difficult. Pentavalent
antimony, preferentially N-methylglucamine antimonate, is still considered the
drug of choice for these patients, with 20 mg/kg of antimony base being administered
intravenously, daily for 30 days. This recommendation is valid for both the
mucocutaneous and the visceral form of the disease. In a Spanish study, treatment
with antimonial drugs led to remission in most patients, although recurrence
was later observed for most cases (Lopes-Velez et al. 1998). On the other hand,
French authors only observed a 50% clinical and parasitological response to
antimonial drugs in co-infected patients (Rosenthal et al. 1995). In countries
with proven resistance of the parasite to antimonial drugs, such as India, the
rates of therapeutic failure and recurrence are probably much higher. An increased
rate of side effects upon the use of these drugs has been observed for HIV-positive
patients; myo-cardiotoxicity and elevated serum amylase levels due to pancreatitis
have been reported by several authors (Alvar et al. 1997, Lopez-Velez et al.
1998).
Within this context, amphotericin
B probably represents a more efficient therapy for all forms of leishmaniasis
in HIV-positive patients. In the south of France, practically 100% of patients
with visceral disease responded to an initial course of amphotericin B (Rosenthal
et al. 1995). Total amphotericin B doses of about 1 to 2 g were sufficient to
induce remission in most cases. Liposomal amphotericin B used in these patients
initially showed surprisingly good results, although it did not prevent disease
recurrence. Unfortunately, its high cost limits its use in Brazil (Lopez-Velez
et al. 1998). Classical side effects have been observed with the use of amphotericin
B (fever, shivering, hypopotassemia, nephrotoxicity, etc.), with these effects
being less frequent when lipid formulations are used, which also permit the
use of higher doses (3-4 g/total dose). Pentamidine, allopurinol and paromomycin
are other drugs used for the treatment of co-infected patients, although the
results are not promising. The use of recombinant IFN-g in combination with
antimonial drugs showed a good response in three Spanish cases of kala-azar
associated with HIV infection (De Gorgolas et al. 1993).
Irrespective of the type of drug
used for the treatment of this clinical entity, there is a clear tendency towards
multiple recurrences after the initial therapeutic course (30% after 6 months
and 60-70% after 12 months) (Lopez-Velez et al. 1998). Based on this observation,
several authors have recommended long-term secondary prophylaxis as done for
other opportunistic infections in patients with Aids. Pentavalent antimony administered
once a month seems to be efficient in preventing recurrence in these patients
(Ribera et al. 1996). Pentamidine has also been used for this purpose, with
the advantage of simultaneously acting on Pneumocystis carinii (Lopez-Velez
et al. 1998). Amphotericin B deoxycholate and lipid formulations may be employed
for prophylaxis at weekly doses, particularly in patients who previously developed
systemic mycoses that require long-term maintenance therapy to prevent recurrence
(Davidson & Russo 1994).
With respect to the mortality of
co-infected individuals, about 20% of patients die during the first episode
of visceral disease and about 70% die after one year, during which the disease
relapsed one or more times. Factors leading to a poor prognosis include advanced
immunosuppression (very low CD4 levels) and thrombocytopenia (Lopez-Velez et
al. 1998). The introduction of combined antiretroviral therapy in order to improve
the immunological parameters leads to a reduction in the number of reactivation
episodes and subsequent recurrences in the case of both the visceral and the
mucocutaneous forms of the disease (La Rosa et al. 2001).
OPPORTUNISTIC DISEASE CAUSED BY
Cryptospori-dium parvum
Over the last few years, there has been growing interest on the part of doctors
and parasitologists in human intestinal coccidia, which can cause disease in
both immunocompetent and immunocompromised individuals. Three of these protozoa
have been the subject of numerous publications, not only as true opportunistic
agents of diseases that occur in immunosuppressed patients but also as the etiologic
agent of large epidemics generally associated with contaminated water or food.
C. parvum, I. belli and Cyclospora cayetanensis are the
main coccidian parasites found in the digestive tract of mammals, including
humans. I. belli rarely causes infection in immunocompetent individuals
but is one of the main causes of diarrhea in patients with Aids. In contrast,
C. cayetanensis, discovered only some years ago, has been responsible
for large epidemics in different countries worldwide, causing prolonged diarrhea
in immunocompetent and -suppressed individuals. In the present review we only
focus on some aspects of human cryptosporidiosis (Fayer & Ungar 1986, Guerrant
1997, Griffiths 1998).
C. parvum was described for
the first at the beginning of the 20th century in the digestive tract of the
common mouse. However, its pathogenic role in animals was only recognized many
decades later, during the seventies, when it was shown to be an important agent
of enteritis in cows and fowl (turkeys). The first human cases were described
in 1976, but the disease only gained importance after the occurrence of Aids
in 1982. Despite its opportunistic behavior in these patients, C. parvum
is also known to be an important cause of acute gastroenteritis in immunocompetent
individuals (Fayer & Ungar 1986). The evolutive cycle of this parasite is
completed within a single host; infection starts with the ingestion of water
or food contaminated with oocysts eliminated in the feces of infected individuals
or animals. The oocysts, measuring on average 5 µm, contain 4 infectious
sporozoites. Upon release into the intestinal lumen, the sporozoites penetrate
intestinal cells, where they mature asexually inside extracytoplasmic superficial
parasitophorous vacuoles into type 1 meronts, which, in turn, release merozoites
that again invade enterocytes, generating a cycle of type 2 meronts (type 2
merogony), thus representing a cycle of internal autoinfection. However, some
second generation merozoites may differentiate into macro- and microgametocytes
which are fertilized and produce the egg or zygote after a period of maturation.
This zygote transforms into an oocyst which divides by sporogony, resulting
in the production of sporozoites. Millions of mature oocysts are eliminated
in feces, thus leading to broad contamination of the environment where they
remain viable for many months (Fayer & Ungar 1986, Guerrant 1997, Griffiths
1998).
Cryptosporidiosis is found worldwide,
with the highest prevalence being observed in less developed countries, mainly
Latin America and Africa. Seroprevalence studies have shown a positivity rate
of the order of 30% in North America and Europe, and of up to 60% in Latin-American
countries. The most affected population groups are children aged less than two
years and immunocom-promised individuals, particularly those with Aids. The
prevalence rate varies among these individuals according to the geographical
regions studied, with rates ranging from 2-4% in the United States to 50% in
Africa. Two Brazilian studies, one carried out in Rio de Janeiro and the other
in Uberlândia, MG, found rates of infection with this protozoan of 18.2
and 13%, respectively, considering that all individuals met the criteria for
the diagnosis of Aids. Patients with other types of immunosuppression, such
as congenital hypogammaglobulinemia, protein-calorie malnutrition, diabetes
mellitus and hematological neoplasias, show a high predisposition to developing
severe forms of cryptosporidiosis (Moura et al. 1989, Costa-Cruz & Ferreira
1996, Pedersen et al. 1996, Sorvillo et al. 1998).
The main route of transmission of
cryptosporidiosis is through the ingestion of water or food contaminated with
mature oocysts, with the ingestion of only 10 oocysts being sufficient to produce
infection, and with the parasitosis persisting due to the cycle of internal
autoinfection (Fayer & Ungar 1986). Thousands of people have been infected
in urban epidemics that occurred in England and in the United States due to
contamination of the water sources with fecal material containing oocysts, which
are resistant to the usual chlorination of drinkable water sources available
to the population. Smaller outbreaks were observed in day-care centers, hospitals
and rural areas, where contact with contaminated animals is common (Richardson
et al. 1991, Moore et al. 1993, Goldstein 1996, Hoxie et al. 1997).
The clinical manifestations of cryptosporidiosis
vary according to the host's immunological status. Symptomatic or oligosymptomatic
infections are common in endemic areas and can be identified through serological
population surveys (Fayer & Ungar 1986, Guerrant 1997). The most common
clinical form of this protozoosis in immunocompetent individuals is acute gastroenteritis;
this modality of the disease is self-limited and the incubation period ranges
from 1 to 2 weeks. The patient in general presents with low fever, colic abdominal
pain, headache, loss of appetite, nausea, vomiting and diarrhea, which is secretory
and disabsorptive leading to the loss of various liters of fluid per day. The
duration of the clinical manifestations ranges from 3 to 12 days in most cases,
although in some it may persist for more than 4 weeks. Clinical cure does not
coincide with parasitological cure, since oocyst elimination can last for several
weeks (Fayer & Ungar 1986, Cardell & Adiss 1994).
In immunosuppressed patients, including
patients with Aids, the clinical presentation of this protozoosis is severe
and consists of intense diarrhea, with several daily bowel movements, accompanied
by voluminous loss of fluid, dehydration and marked weight loss. These manifestations
last for several weeks, and cryptosporidiosis can be considered incurable in
HIV-infected patients in the advanced phase of the disease (Pozio et al. 1997,
Griffiths 1998, Manabe et al. 1998).
Similar to other opportunistic infections
that occur in HIV-infected patients, severe cryptosporidiosis also tends to
affect patients with low CD4 T lymphocyte levels (below 100 cells/mm3)
(Flanigan et al. 1992). Extraintestinal manifestations of this coccidiosis are
also observed in patients with Aids, and particularly affect the biliary tract,
liver, pancreas, joints and the respiratory system. Biliary tract infections
include alithiasic cholecystitis, sclerosing cholangitis, papillitis and terminal
bile duct stenosis (Bonacini 1992, Manabe et al. 1998, Griffiths 1998).
The digestive presentation of cryptosporidiosis
should be differentiated from other causes of acute gastroenteritis in immunocompetent
individuals, such as infections caused by bacteria (Escherichia coli,
Cam-pylobacter, Salmonella sp., etc.), viruses (rotavirus) and
other protozoa (Giardia lamblia, I. belli and C. cayetanensis).
In patients with Aids, the differential diagnosis should also be made with isosporiasis
and cyclosporiasis, with diarrhea caused by microsporidia (Enterocytozoon
bieneusi, Encephalitozoon intestinalis), and with chronic diarrhea
induced by HIV itself (Griffiths 1998).
The most practical and easiest way
of diagnosing cryptosporidiosis is the detection of parasite oocysts in feces
or other body fluids. Various techniques have been used to visualize these oocysts,
such as Ziehl-Neelsen staining, modified, Kinyoun carbolfuchsin staining, modified,
and staining with safranin-methylene blue and methenamine silver. Concentration
methods, such as formalin-ether sedimentation or Sheather's sugar flotation
method, increase considerably the sensitivity of oocyst detection. The oocysts
of this protozoon can be visualized in histological sections of intestinal mucosa
obtained by biopsy and stained with hematoxylin-eosin as single cells or grouped
on the mucosal surface, i.e., at the brush border of the intestinal epithelium.
More recent techniques using fluorescent dyes such as acridine orange and auramine
carbolfuchsin provided results comparable to those obtained with the staining
methods described above for diarrheic feces, and are able to detect parasites
even in formed feces. Immunoenzymatic techniques (ELISA) using monoclonal antibodies
have shown a high degree of sensitivity and specificity for the detection of
oocysts in feces and contaminated water (Costa-Cruz et al. 1996, Hoxie et al.
1997, Guerrant 1997, Griffiths 1998). Serological tests for the detection of
antibodies represent an alternative to parasitological methods for the diagnosis
of cryptosporidiosis. Immunoenzymatic assays (ELISA) using crude extract of
ruptured oocysts as antigen have shown good sensitivity, although some studies
have demonstrated that immunoblotting is much more sensitive and specific for
antibody detection. In these cases, IgA type responses are observed which are
directed against antigens found on the surface of sporozoites, the infectious
form of the parasite; such antibodies seem to exert a protective effect against
symptomatic infection (Mooss et al. 1998, Eisemberg et al. 2001). A specific
PCR has been developed and may represent a better option for the diagnosis of
this infection in the future (Griffiths 1998).
The disease is self-limited in immunocompetent
patients who do not require specific treatment in addition to hydration and
adequate water-electrolyte replacement. In patients with Aids, hydration should
be vigorous, particularly in cases with the severe and debilitating form of
the disease. Antidiarrheal agents such as diphenoxylate and loperamide should
be used to reduce the loss of water through feces and the number of evacuations,
thus improving the quality of life of these patients. A somatostatin analog,
octreotide acetate, inhibits intestinal secretion of fluids and improves diarrhea
in these patients, but, obviously, without a parasitological cure (Cello et
al. 1991). Various drugs have been tested for the treatment of cryptosporidiosis,
but none of them has shown a complete curative effect thus far. The orally administered
macrolides spiramycin, roxithromycin and azithromycin have demonstrated partial
efficacy, but without eradication of the parasite in most of the individuals
treated (Soave et al 1990). Paromomycin, an aminoglycoside administered orally
at the dose of 2 g/day, has shown good activity on this coccidium. In some series,
symptomatic improvement was observed in most patients and eradication of the
infection was even reported in a few individuals (Clezy et al 1991, Fichtembaun
et al. 1993). However, a recent controlled study did not demonstrate the expected
efficacy of this drug in the treatment of human cryp-tosporidiosis (Hewitt et
al. 2000).
Since patients with cryptosporidiosis
eliminate large amounts of oocysts in their feces, they might easily contaminate
the environment, the persons in contact with them, water and food. Universal
precautions, such as washing the hands and adequate destination of dejecta and
contaminated material, are fundamental for the prevention of this protozoosis
and epidemic outbreaks. However, in the case of a cryptosporidiosis outbreak,
particularly that transmitted through contaminated water reservoirs, the population
should be advised to consume only boiled or bottled water, a recommendation
that should be also made to patients with Aids. It is important to remember
that chlorination does not eliminate Cryptosporidium oocysts from the
public water reservoirs, which eventually become contaminated through the feces
of domestic animals present in nearby rural areas (Hayes et al. 1989, Moore
et al. 1993).
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