Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 97(4): 443-457, June 2002 443 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 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 hemato- logical 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 mucocutane- ous 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 fre- immunity defects (hypogammaglobulinemia) and neutro- quently occur in patients under some kind of immuno- penia (number of serum neutrophils < 1000/mm3) usually suppression, have become very common in daily clinical predispose to the occurrence of bacterial infections caused practice. The number of immunosuppressed patients sus- by Gram-positive cocci, Gram-negative bacilli and some ceptible to different infectious or neoplastic processes fungi (Candida, Aspergillus), while infections caused by has increased each decade and culminated in the advent intracellularly multiplying agents such as mycobacteria, of the acquired immunodeficiency syndrome (Aids) at the endemic mycosis-inducing fungi and protozoa are rare. beginning of the eighties. The increasing use of trans- These last pathogens are frequent agents of infectious plants (kidney, bone marrow, liver, heart, etc.) and the ap- processes that occur in Aids or Hodgkin’s disease, where pearance of new immunosuppressive drugs, nowadays the basic defect is the result of cellular immune depres- extensively used in these patients as well as in patients sion (Karp & Neva 1999). Aids produces the most severe with neoplasias and autoimmune diseases, has led to the form of immunosuppression known, and more than one occurrence of a large number of individuals with chronic hundred microorganisms causing opportunistic infections immunosuppression in our community, who in turn are in these patients have been identified, many of them in- predisposed to developing opportunistic infections. Tens tracellular protozoa, which will be discussed in the present of pathogens have been described as etiologic agents of review. Infection with human immunodeficiency virus these infections, including viruses, bacteria, protozoa, (HIV) leads to important alterations in the clinical course fungi, and helminths. Immunosuppression, either at the of many disorders caused by these intracellular organ- humoral or cellular level, may have different consequences isms; curiously, no significant effects of retrovirus-in- for the host depending on its magnitude, including facili- duced immunosuppression on the course of disease have tation of the occurrence of these infections, an increased been observed for some protozooses such as malaria. On disease/infection rate, alterations in the clinical manifes- the other hand, there is evidence that these infections tation of the infection or exacerbation of its course, among can accelerate the course of HIV infection due to the ca- others (Young 1981). Aids and lymphoproliferative pacity of many of these organisms to stimulate Th2 type neoplasias are examples of conditions that lead to abnor- cytokines (IL-4, IL-10, etc.), which favor the progression malities in practically all compartments of the immune sys- of the disease caused by HIV (Morrow et al. 1989, Actor tem; however, T lymphocyte-mediated immune defects et al. 1993, Gilks 1993). predominate. The therapy to which these individuals are The most frequent protozoan causing opportunistic submitted (e.g., corticosteroids) and malnutrition caused infections in immunocompromised individuals is Toxo- by the base disease itself represent important cofactors plasma gondii. Its association with severe manifestations in the predisposition to developing infections. Humoral of immunosuppression has been known for several de- cades, and the occurrence of encephalitis, myocarditis and disseminated disease has since then been observed in different clinical conditions such as lymphoreticular +Corresponding author. Fax: +55-34-3236.3151. E-mail: neoplasias, solid organ transplantation, and, at present, [email protected] mainly in patients with Aids. Before the advent of this Received 20 March 2002 viral infection, opportunistic infections caused by this Accepted 22 April 2002 and other protozoa had rarely been observed in 444 Aspects of Protozoan Infections MS Ferreira, AS Borges immunocompromised patients. Other coccidia such as Isos- reach up to 40% in patients with Aids (Krick & Remington pora belli and Cryptosporidium parvum only gained clini- 1978, Luft & Remington 1988). Therefore, toxoplasmosis cal importance after the recognition of Aids at the begin- is of great clinical importance in man in two major situa- ning of the eighties. Few cases of reactivated Chagas dis- tions: as a cause of congenital infection, with 5 to 24% of ease in immunosuppressed patients have been reported children becoming ill and dying during the neonatal pe- in the sixties and seventies, but Trypanosoma cruzi was riod, in addition to the high rate of children with severe never considered to be a true opportunistic agent. The neurological and visual sequelae who require education same was the case for protozoa of the genus Leishmania and special and costly care (Frenkel 1973), and as an op- whose association with immunosuppressive diseases rep- portunistic infection of high mortality in immunosup- resented a scientific curiosity in past decades. This pan- pressed individuals (Carey et al. 1973, Ambroise-Thomas orama changed after the Aids epidemic, and T. cruzi, and & Pelloux 1993). especially Leishmania species, are currently gaining great In immunocompetent hosts, the infection is frequently importance as agents of severe opportunistic diseases in benign, with parasitemia being self-limited, resulting in an patients affected by this retroviral infection. The advances asymptomatic clinical form of the disease in most cases. made during the last few years in the chemotherapy of However, in about 20% of cases acute infection is accom- neoplasias, in the use of transplants and in the therapy of panied by febrile lymphadenopathy, asthenia and autoimmune diseases have led to the reactivation of lymphomonocytosis, with the course of infection being protozooses under these conditions, thus confirming the self-limited (Feldman 1968, Darcy & Santouro 1994). After opportunistic character of these pathogens (Ferreira et al. this period, T. gondii remains viable in the form of tissue 1997, Borges et al. 1999, Ferreira 1999, Rosenthal et al. cysts, which reproduce slowly throughout the life of the 2000, Morgado et al. 2000). host, thus characterizing the chronic phase of infection. The objective of this review was to update and com- During this phase, the tissue cysts are controlled by the ment upon some aspects of diseases caused by protozoa humoral and cellular immune system, involving T lym- in immunosuppressed patients. Four parasites which are phocytes and macrophages which are continuously stimu- important causative agents of severe disease in these in- lated by parasite antigens, a fact that protects against dividuals were chosen, and within this context, we basi- reinfection. As a result, parasite multiplication is more cally focus on pathogenic, clinical, diagnostic and thera- active and persists for longer periods of time in less im- peutic aspects of the infections caused by T. gondii, T. munologically active tissues such as the central nervous cruzi, Leishmania sp. and C. parvum. system (CNS) (Johnson 1981, Sims & Talbot 1989, Darcy & Santoro 1994). OPPORTUNISTIC DISEASE CAUSED BY TOXOPLASMA GONDII Immunocompromised hosts, especially those with deficient cellular immunity, are at risk of recrudescence of About 50% of the world population is infected with T. the chronic infection and dissemination, with the occur- gondii, a protozoan of the coccidian family, an obligate rence of fulminating disease. The preferential reactiva- intracellular parasite that multiplies in any nucleated cell tion of T. gondii in the CNS has been demonstrated clini- of the vertebrate host and that shows universal distribu- cally and experimentally (Van Thiel 1966, Frenkel et al. tion (Cesbron-Delauw 1994). Felines are the definitive host, 1975, Ruskin & Remington 1976). This fact is probably with the domestic cat being the most important. This pro- due to low local immunity, as well as to the presence of tozoan is