Malaria (see Chapter 90) remains one of the most important infectious diseases in the world today, causing 100 to 200 million new cases and 1 to 2 million deaths each year. Evidence from both murine and human studies suggests an important role for CD4+ T cells in protective immunity to blood-stage malaria. With large areas of shared endemnicity and prevalence, a medically significant interaction between HIV and malaria was thus expected and feared.80 Initial studies were negative; falciparum malaria did not appear be an OI or to accelerate the progression of HIV disease.80, 81, 82, 83, 84, 85 However, follow-up studies have revealed significant bidirectional interactions between Plasmodium falciparum and HIV.
HIV replication in peripheral blood cells is enhanced by exposure to P. falciparum antigens in vitro, in part through induction of TNF-α.86 Increased HIV replication in dendritic cells has also been seen after the in vivo infection with Plasmodium chabaudi of mice transgenic for the HIV genome in a process that appears to be dependent on CD4+ T-cell activation.87 The production of TNF-α during malarial paroxysms,88 along with the antigenic exposure of parasitemia, might thus reasonably be expected to increase HIV viral load. Indeed, clinical studies from Malawi have shown that P. falciparum infection is associated with increased HIV viral burden in peripheral as well as placental blood.89,
90 Treatment was associated with a reduction in viral load, although it remained elevated compared to controls for the 4-week duration of the study.89 Whether or not malaria-mediated increases in HIV replication accelerate the course of HIV disease remains to be determined.
The first significant clinical effect of HIV on malaria was found in the setting of pregnancy. In areas of high malarial endemnicity, the high degree of immunity that women of childbearing age have developed to severe malaria is compromised by pregnancy. The placental vasculature shields parasitized erythrocytes from the systemic immune response, allowing localized erythrocytic replication of the parasite. Placental parasitemia has been associated with low birth weight and, hence, increased infant mortality. Local uteroplacental immune responses do restrict parasite replication, however, and the effectiveness of these local responses increases in subsequent pregnancies under pressure of recurrent malarial exposure. In 1996, a study performed in rural Malawi demonstrated that the beneficial effects (maternal, placental, and neonatal) of parity in the control of parasitemia during pregnancy were markedly attenuated in the face of HIV coinfection.22 Since then, multiple studies performed in sub-Saharan Africa have probed the effects of coinfection on the outcome of pregnancy.90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 Such studies have shown that (1) HIV infection is associated with increased rates and levels of peripheral and placental parasitemia, clinical malaria, and maternal anemia in pregnant women, and (2) coinfection is associated with a higher risk of low birth weight, preterm birth, intrauterine growth retardation, and postnatal infant mortality.101 Although placental parasitemia is associated with increased placental HIV viral loads in coinfected patients,90 it remains unclear as to whether malaria infection increases the risk of mother-to-child transmission of HIV. Conflicting results (enhancement, protection, and no effect) have been published.96,
100 A World Health Organization (WHO) technical consultation has recommended that HIV-infected pregnant women who are at risk for malaria should always have protection with insecticide-treated bed nets, along with (according to HIV stage) either intermittent preventive treatment with sulfadoxine/pyrimethamine or daily trimethoprim– sulfamethoxazole (cotrimoxazole; TMP–SMX) prophylaxis.102
HIV infection is associated with an increased incidence of parasitemia, the risk of clinical malaria is significantly higher in HIV-infected adults, and this risk increases with decreasing CD4 cell count.103, 104, 105 Notably, HIV infection has also been found to be a risk factor for severe malaria in nonimmune populations (in an area of unstable transmission).106 Finally, although early studies found no evidence that the treatment or prophylaxis of malaria was altered by HIV coinfection,81,
83 the risk of malaria treatment failure has recently been found to be higher in CD4-depleted HIV positive individuals.107,
HIV protease inhibitors currently used for HAART have understudied interactions with a variety of drugs used for malaria prophylaxis and treatment. A variety of protease inhibitors, as well as the nonnucleoside reverse transcriptase inhibitors delaviradine and efavirenz, inhibit hepatic cytochrome P-450 enzymes. Principal effects are on the CYP3A4 isoform (with ritonavir being the most potent inhibitor), although the CYP2D6 isoform may also be affected.109,
110 Nevirapine and efavirenz cause secondary induction of CYP3A4, an effect of ritonavir and nelfinavir as well.109,
110 Most antimalarial agents are largely metabolized via P-450 enzymes. Mefloquine appears to be no exception, although the details remain poorly understood.111 Proguanil and chloroquine metabolism appears to be largely by the CYP2C19 and CYP2D6 isoforms, respectively.112, 113, 114, 115 Chloroquine also undergoes appreciable renal excretion, whereas doxycycline largely avoids these pathways in vivo. A detailed understanding of atovaquone metabolism appears to be lacking. Actual published pharmacokinetic data suggest that (1) there are no significant drug–drug interactions between nelfinavir or indinavir and mefloquine116; (2) ritonavir has minimal effects on mefloquine pharmacokinetics, whereas mefloquine suppresses ritonavir plasma levels117; and (3) atovaquone increases serum zidovudine (AZT) levels by approximately 30%, although AZT has no effect on the pharmacokinetics of atovaquone.118 In summary, the actual pharmacokinetics are not easily predictable from theoretical considerations, and there is a paucity of data. Based on the current data, mefloquine, doxycycline, chloroquine, and malarone (atovaquone + proguanil) are likely to be safe and to retain efficacy for prophylaxis of sensitive strains of malaria.
Among other malaria treatment options, quinidine, quinine, and β-artemether are all predominantly metabolized through CYP3A4 isoforms.110 Large (more than threefold) increases in the area under the curve (AUC) for quinidine are expected for ritonavir.119 As a result, quinidine has been considered to be contraindicated for those on ritonavir,119 and this likely applies to quinine as well. There are no actual data, however. Whether there are clinically relevant effects of these protease inhibitors on the metabolism of artemisinin compounds (dependent at least in part on CYP3A4) remains unknown. Uncomplicated malaria can probably be safely treated with chloroquine (if sensitive), pyrimethamine/sulfadoxine, or mefloquine. Use of quinine, quinidine, or artemisinin compounds remains essential for the parenteral therapy of severe chloroquine-resistant malaria. For those on ritonavir (and/or other protease inhibitors, delaviridine, or efavirenz), the normal loading dose of quinine or quinidine should probably be given, along with some reduction of the maintenance infusion dose. Obviously, careful monitoring needs to be done for the potentially fatal arrhythmic consequences of quinine/quinidine overdosage in this setting. Given the lack of data, however, underdosing may also be a potential problem. The “washout” period for the metabolic effects of ritonavir is thought to be 24 to 48 hours.
A higher incidence of allergic responses to sulfonamides makes pyrimethamine–sulfadoxine (Fansidar) less attractive as a malaria therapy in HIV-seropositive patients, at least in North American populations.120 Furthermore, Stevens–Johnson syndrome and related adverse mucocutaneous reactions to the long-acting sulfa compound, sulfadoxine, have contraindicated its benefits for use in malaria prophylaxis in developed countries.121
The presence of HIV infection alters the predictive value of fever in the empirical diagnosis of malaria. In areas with a high prevalence of both HIV and malaria, the common practice of empirically treating febrile adults for malaria leads to gross overestimation and overtreatment of malaria.103 Finally, treatment of severe anemia due to malaria is one of the most common reasons for blood transfusion in sub-Saharan Africa. Malaria thus provides an indirect but very important risk factor for the acquisition of HIV infection by children where the blood supply is not well screened.73
The genus Babesia contains more than 70 known species of tick-borne intraerythrocytic protozoans that parasitize wild and domestic vertebrates, predominantly in tropical and subtropical areas. Human babesial disease has been reported mostly from temperate climates (see Chapter 91). A significant clinical interaction with HIV infection has been suggested for Babesia microti, raising the possibility that disease with tropical babesial species may be a risk for AIDS patients and providing the rationale for the current discussion. There are five reported cases of babesiosis due to B. microti in HIV-infected people.122, 123, 124, 125, 126 Two cases occurred in splenectomized patients; in one, chronic low-level hemolysis due to Babesia prior to splenectomy was likely. Patients with intact spleens presented with fevers of unknown origin (FUOs) in the face of CD4 counts less than 200/μL. In one, the FUO lasted for months and was associated with night sweats, dry cough, weight loss, and dyspnea on exertion. Persistent parasitemia after clinically successful chemotherapy led to the need for chronic suppressive therapy. In another patient, recurrent disease led to retreatment 8 months after initial therapy. Quinine plus clindamycin and atovaquone plus azithromycin both have therapeutic efficacy in acute disease.127 In HIV-infected patients, chronic suppressive therapy appears to be indicated. As with all vector-borne diseases, vector avoidance is the most efficient way to prevent disease. Significant interactions with HIV infection remain to be described for European bovine Babesia species (Babesia bovis and Babesia divergens) and the emerging agents of human babesiosis (WA1, CA1, MO1) in North America.
With the exception of Toxoplasma gondii, Leishmania is the most common tissue protozoan causing OI in patients with AIDS (see Chapter 94). This is not surprising because cellular immune responses (in particular, Th1-mediated immune responses) are critical for protection from Leishmania. The competence of the Th1 axis of cellular response becomes increasingly compromised during the progression of HIV-related immunosuppression, providing a favorable environment for disease due to Leishmania species. Furthermore, in vitro evidence suggests that coinfection of macrophages with HIV and Leishmania can directly upregulate parasite replication.128 In vivo, the overall loss of immunological control of parasite infection is reflected by often aberrant manifestations of visceral leishmaniasis (VL) in AIDS, including peripheral parasitemia (found in more than 50% of coinfected people) and parasite dissemination to unusual body compartments.129 An AIDS-related OI occurring at low CD4+ T-cell counts, leishmaniasis may be due either to primary Leishmania infection or to the reactivation of clinically latent infection.130,
131 Although the published data on the interaction of HIV and Leishmania focus largely on the effects of HIV on leishmanial infection and disease, it should be noted that there is also both in vitro and in vivo evidence that Leishmania can augment HIV replication.132, 133, 134, 135
Although leishmaniasis has a worldwide distribution in the tropics and subtropics, it normally requires an arthropod vector, the sandfly, to move the organism from its sylvatic (zoonotic) cycle to the human host. With certain species of Leishmania (Leishmania tropica and Leishmania donovani) and in some locations (e.g., Syria and India, respectively), an anthroponotic human-to-human cycle via the sandfly can exist. In situations in which intravenous drug use is practiced, transmission is simplified even further by direct person-to-person transfer via contaminated needles and syringes. Generally, however, leishmaniasis is a rural or periurban zoonosis.
The experience with VL complicating HIV/AIDS in Mediterranean countries indicates that many, perhaps most, of the leishmanial infections are acquired with HIV or after HIV infection has already occurred. The transmission of both agents that occurs by sharing of needles and syringes by intravenous drug users could theoretically be reduced by an aggressive program of education and provision of clean needles and syringes. An effective program of sandfly vector control will interrupt transmission from heavily infected human reservoirs to other humans as well as the more usual cycle of infected dogs to humans. Vector control is also the only way to prevent coinfection with Leishmania in those who acquire HIV sexually.
From the relatively high prevalence of latent leishmanial infections, it would appear that reactivation of latent infections could account for the increasing numbers of HIV–Leishmania coinfections; however, this concept is not always supported by epidemiologic evidence. A greater variability in zymodemes (enzyme markers) has been found in parasite isolates from HIV-infected than -uninfected patients. In one series, five isolates were recovered from HIV-infected patients that had previously not been encountered in immunocompetent people with either VL or cutaneous leishmaniasis (CL).136 The finding that certain strains of Leishmania typically causing cutaneous disease are being recovered from the bone marrow of coinfected patients could support either the primary or the reactivation hypothesis.137
Normally, the age distribution of VL caused by L. donovani includes adults as well as children. In contrast, VL due to Leishmania infantum affects children predominantly, often age 5 years or younger. In Spain, where intravenous drug use accounts for the majority of HIV–Leishmania coinfections, the age distribution of VL has been reversed, with most cases occurring in young adult males.138 The fact that 50% of coinfected patients have demonstrable organisms in peripheral blood smears139 and the fact that sandflies can readily be infected by feeding on coinfected patients140 provide evidence for an additional anthroponotic cycle of transmission in this setting.137 In summary, although reactivation of latent leishmanial infection is difficult to exclude, increasing evidence—in southern Europe, at least—favors primary infection by certain strains of Leishmania as the main mechanism for coinfection with HIV/AIDS.
With the spread of the HIV pandemic, there is increasing epidemiological overlap of areas in which HIV and leishmania occur, particularly in eastern Africa, India, Brazil, and Europe. Cases have been reported from approximately 40 countries, although the bulk of cases have been reported from southern Europe.129, 130, 131
142 Of note, relatively few cases of American mucocutaneous leishmaniasis have been recognized in HIV-infected subjects.143,
144 The propensity for disseminated disease in the presence of HIV appears to be limited to certain species of Leishmania. The bulk of the information on VL complicating HIV infection involves L. infantum in the Mediterranean region. Presumably, the ability to visceralize under the influence of HIV also applies to L. donovani in southern Asia and Africa and to L. chagasi in Latin America; however, documentation for this is still somewhat meager, one of the possible reasons being the poor overlap between geographic distribution of leishmaniasis caused by these species and the distribution, as well as prevalence, of HIV infection. The species of Leishmania that cause CL have been implicated only rarely as OIs in HIV/AIDS. In one instance, L. braziliensis was recovered from the bone marrow of a patient with a CD4+ T-cell count of less than 10/μL,145 but the main clinical picture in this case, as well as in others,146, 147, 148 including a patient infected with Leishmania major,
149 has been one of multiple cutaneous lesions resembling diffuse CL.
A febrile illness of longer than 2 weeks’ duration in an HIV-infected person with a lifetime history of travel to Leishmania-endemic regions of the world should certainly raise suspicion of leishmaniasis complicating HIV infection. If the patient is an intravenous drug user, travel to southern Europe, especially Spain, France, and Italy, would be particularly pertinent. Clinical diagnosis of VL in leishmania–HIV coinfected people may be difficult. Only 75% of HIV-infected patients, as opposed to 95% of non-HIV-infected patients, exhibit the characteristic clinical pattern, namely fever, splenomegaly, and hepatomegaly.130,
150 With increasing immunosuppression, clinically evident ectopic localization of parasites becomes common.151 Gastrointestinal, laryngeal, pulmonary, and peritoneal involvement has been reported.151, 152, 153, 154, 155, 156, 157, 158 Single and multiple cutaneous forms and/or mucosal and mucocutaneous lesions have also been described in AIDS patients worldwide.148,
In immunocompetent people, tests for antileishmanial antibodies have been very useful in the diagnosis of VL because B cell activation is prominent, with large amounts of both specific and nonspecific antibody being produced. In contrast, approximately 50% of coinfected patients lack detectable antibody levels.130,
160 The situation may be different in instances in which leishmanial infection has preceded HIV infection and the impaired immune response that ensues. Gradoni and associates161 suggested that this type of serologic data could be used as an indicator of the sequence of acquisition of the two infections. Support for this concept is provided by a report from Ethiopia of seven cases of VL with HIV coinfection, all with highly elevated antileishmanial antibody titers.162 All patients had lived for many years in a leishmaniasis-endemic area of Ethiopia.162 The recombinant antigen rK-39 appears to be highly sensitive and specific for immunodiagnosis of VL due to L. donovani and L. chagasi in patients without complicating HIV infection; however, the sensitivity of rK-39 for immunodiagnosis of cutaneous cases from Turkey was greatly reduced compared with most cases of VL.163 The utility of rK-39-based diagnostics is not clear in HIV-seropositive people. The peripheral parasitemia displayed by many HIV coinfected individuals allows the detection of parasites from the blood in approximately 50% of cases. Cultures and polymerase chain reaction (PCR) of buffy-coat preparations are positive in 70% and up to 100%, respectively.130,
There is abundant evidence that successful treatment of leishmanial disease, regardless of the drugs used, ultimately requires intact CMI. The coinfected patient is the victim of a double insult to the immune system. VL is associated with antigen-specific T-cell unresponsiveness165 and dysfunctional cytokine responses.166 This situation is further compounded by the immunologic abnormalities associated with HIV infection.
Therapy for VL in the face of HIV coinfection remains controversial, largely due to a lack of firm data. The same drugs used for treatment of VL in normal hosts (including pentavalent antimonials and amphotericin B preparations) have utility in the treatment of HIV coinfected patients, albeit with significantly less efficacy.150 Amphotericin B is a conventional drug for all forms of leishmaniasis, including visceral disease. Liposomally encapsulated amphotericin has the theoretical advantage of being targeted to monocyte/macrophages, host cells for leishmanial parasites. Between 40% and 65% of coinfected patients have initial parasitological cure after treatment with pentavalent antimonials, amphotericin B deoxycholate, or amphotericin B lipid complex.150,
168 Among these options, treatment with lipid formulations of amphotericin B appears to have similar efficacy, but less severe toxicity, than the other drugs. However, the experience with lipid formulations of amphotericin B in coinfected patients remains meager.168 These lipid formulations are also quite expensive. Trials aimed at optimizing the therapy of VL in AIDS are clearly needed.168 Even with initial cure, relapse is predictable over time, occurring in up to 80% of coinfected individuals within 1 year.150,
169 The optimal drug for secondary prophylaxis remains unclear. Pentamidine given once every 3 or 4 weeks170 and liposome-encapsulated amphotericin every 2 weeks171 or 3 weeks169 have been used for secondary prophylaxis.
Miltefosine, an oral agent that is safe and effective for the treatment of Indian patients with VL,172 has shown some promise in early compassionate-use treatments for VL in HIV-infected subjects.173 Further optimization of treatment and suppressive regimens of miltefosine in HIV patients may establish roles for this new antileishmanial agent for therapy and suppressive prophylaxis of VL in HIV-infected patients.
The fact that significant reductions in the incidence of AIDS-related VL have been seen in southern Europe after the advent of HAART,174,
175 along with the fact that HAART-related immune reconstitution has allowed the discontinuance of secondary prophylaxis for other OIs, has raised hope that HAART will allow for safe discontinuance of secondary prophylaxis for VL. Details of the levels of immunological and virological responses needed for termination of such secondary prophylaxis remain to be determined.176, 177, 178
American Trypanosomiasis (Chagas’ Disease)
American trypanosomiasis, or Chagas’ disease (see Chapter 93), is a well-recognized OI in AIDS.179 The causative organism, Trypanosoma cruzi, and the blood-sucking vector (triatomine) bugs that transmit this protozoan are restricted to the Western Hemisphere but are widely distributed from the United States to Chile and Argentina. Because the HIV-related Chagas’ disease reported to date largely represents reactivation of chronic infection during the course of HIV-induced immunosuppression and not primary infection in the face of AIDS (which is not surprising given the differing patterns of epidemiological risk for these infections: largely rural for T. cruzi and largely urban for HIV), this OI can be expected to appear outside these geographic bounds. It should be noted that activation of latent T. cruzi infection, as well as exacerbated primary infection (transmitted by blood transfusion), is also well described in the face of the iatrogenic immunosuppression used for solid organ transplantation and therapy for hematological malignancies.
Available data suggest that clinical T. cruzi reactivation in the face of HIV coinfection occurs largely in those with CD4+ T-cell counts less than 200/μL. Clinically, such reactivation most commonly involves the central nervous system.179,
Trypanosoma cruzi was probably late in being recognized as an opportunistic pathogen in those with HIV infection because the most prominent features of central nervous system disease are similar to those of toxoplasmic meningoencephalitis. Enlargement of hemorrhagic foci can produce mass effects simulating brain tumors. Lesions are often multiple, with computed tomographic (CT) scans and magnetic resonance imaging (MRI) showing ring enhancement and preferential involvement of the white matter. Toxoplasmic encephalitis may also be present in the same patient.181 The cerebrospinal fluid (CSF) findings include a slight pleocytosis, increased protein, slightly decreased glucose in some patients, and the presence of trypanosomes. Histologically, the brain lesions show necrotic foci with hemorrhage and infiltration of inflammatory cells. Amastigote forms of the parasite are abundant in glial cells and macrophages and only occasionally in neuronal cells. Myocarditis is a common autopsy finding in those dying of AIDS-related T. cruzi meningoencephalitis.178 Such myocarditis is often clinically silent. Clinical manifestations, when present, involve arrhythmias and congestive heart failure.179,
183 Correct diagnosis of reactivated T. cruzi infection depends, first, on considering the possibility based on the geographic origin of the patient and on an appreciation of the clinical picture. If neurologic signs are present, performing a CT scan or MRI is key.184 The imaging pattern of central nervous system (CNS) T. cruzi infection is indistinguishable from that of toxoplasmic encephalitis. Direct microscopic examination of centrifuged sediment of CSF will often show motile trypanosomes. If fever and other systemic signs are present, direct examination of the buffy coat from the microhematocrit tube may also show motile trypanosomes. Since serum antibodies to T. cruzi indicate previous infection with the parasite, this test is only useful for ruling out reactivated infection if it is negative. If other tests are inconclusive, biopsy of a brain lesion to demonstrate characteristic organisms can be done. PCR on blood or CSF requires research laboratory facilities.
Clinically, differentiating HIV-related reactivation of Chagas’ disease reactivation from chronic chagasic disease may be difficult. HIV-related reactivation is associated with high parasitemia, however, whereas the parasitemia of chronic disease is very low.185 Indeed, even in the absence of overt, clinical reactivation, chronic Chagas’ disease is associated with a higher percentage and level of parasitemia in those coinfected with HIV (independent of CD4 count) than in HIV seronegatives.186 The effects of coinfection appear to be bidirectional. HIV viral load was carefully documented to increase simultaneously with an asymptomatic increase in T. cruzi parasitemia, subsequently returning to baseline in the face of successful antiparasitic treatment.187 Nifurtimox and benznidazole, both of which have moderate antitrypanosomal activity, are the standard drugs recommended for treatment of Chagas’ disease. There simply is not enough experience to evaluate the effectiveness of these drugs in the treatment of T. cruzi infections complicating HIV or AIDS, especially in cases with meningoencephalitis. No information is available on the penetration of these drugs into the CNS, and the survival time of reported cases of coinfection has been short. A patient reported by Nishioka and coworkers188 survived for 92 days, with disappearance of trypanosomes from the blood and CSF as well as clearance of a brain lesion while being treated with benznidazole at a dose of 8 mg/kg/day for 80 days. Clinical improvement and reduction in size of a brain lesion were attributed to treatment with benznidazole plus, later, itraconazole and fluconazole in another patient with coinfection who survived for at least 6 months.189 Although there is no other reported experience with the use of itraconazole or fluconazole in the treatment of American trypanosomiasis in humans, itraconazole was reported to be very effective in experimental infections.190 Infected mice given as little as 15 mg/kg/day were protected against death, and concentrations of itraconazole as low as 0.001 μg/mL inhibited replication of the parasites in macrophages. It has been recommended that treatment of T. cruzi infection in HIV-positive individuals be started early in the reactivation process, when parasitemia is detectable, but before irreversible end-organ damage has occurred.187 Such a strategy would hinge on serological identification of those at risk, something indicated in all HIV-infected individuals with appreciable risk of T. cruzi infection. Although data are lacking, it should be noted that immunological reconstitution through HAART therapy is likely to provide considerable prophylactic and therapeutic benefit in this disease.
No significant interactions between the agents of African trypanosomiasis (see Chapter 92) and HIV have been delineated. Although T cell and macrophage responses are not thought to be important in the protective host response to trypanosomiasis, trypanosomiasis can suppress cellular immune responses, so a biologic interaction between the two is plausible. No significant epidemiologic association between Trypansoma brucei gambiense and HIV has been found.191, 192, 193, 194 Whether HIV alters the clinical course of either West or East African trypanosomiasis is unclear.193 There is anecdotal evidence that HIV may complicate the therapy of West African trypanosomiasis, however. Of 18 patients treated with melarsoprol in a rural hospital in the Congo, all 14 HIV-negative patients recovered, whereas 3 of 4 HIV-positive patients died during treatment (likely due to treatment-related encephalopathy) and the fourth failed to respond to therapy.195
In addition to the two genera, Leishmania and Trypanosoma, known to cause disease in humans, the Trypanosomatidae family includes other genera of protozoa that parasitize other vertebrates, insects, and plants. There have been three reports of HIV-infected individuals presenting with symptoms typical of visceral leishmaniasis in which ultrastructural, isoenzyme, and/or kinetoplast DNA analyses of the isolated lesional parasites have indicated that the responsible organism actually belongs to one of these latter genera.196 The strong implication is that HIV-related immunosuppression can render humans vulnerable to normally nonpathogenic lower trypanosomatids.
Toxoplasma gondii is a ubiquitous parasite of mammals throughout the world (see Chapter 97). Latent infection lasts for the lifetime of the host. Maintenance of latency is dependent on CMI responses. Reactivation of latent infection is common with increasing immunosuppression in AIDS. The principal manifestation of such reactivation, toxoplasmic encephalitis (TE), is thus a common OI in AIDS patients throughout the world. The incidence of TE is proportional to the prevalence of latent infection in the population at risk of or with AIDS.197 In the United States, the rate of latent infection varies between 10% and 40%; in Paris, the rate is 90%.197 Acquisition of Toxoplasma infection is age dependent, but there is wide variation in infection rates even over narrow geographic areas.198,
199 Prevalence rates in the tropics vary from 0% to 90%, with most measured communities falling in a broad middle range.200, 201, 202, 203, 204, 205, 206
In the United States, prior to the advent of HAART, one-third of Toxoplasma-seropositive AIDS patients developed TE in the absence of prophylaxis,207 90% of such cases were in patients with less than 200 CD4+ T cells/μL and 70% in those with less than 100 CD4 T cells/μL.208 The prevalence of TE in AIDS patients in the tropics is unclear, but the burden is thought to be immense and underdiagnosed. Autopsy series that have included examination of the brain have suggested disease prevalence rates in late-stage AIDS patients of 15% in Abidjan, Côte d’Ivoire,209 25% in Mexico City,210 and 36% in Kampala, Uganda.211
The presumptive diagnosis of TE is based on clinical presentation, positive Toxoplasma serologies, and characteristic neuroradiologic features.212 A final clinical diagnosis is made based on the clinical and radiographic response to specific chemotherapy. Less common manifestations of toxoplasmosis in AIDS include pneumonia, retinochoroiditis, myocarditis, orchitis, and gastrointestinal involvement. The reader is referred to one of many excellent reviews on Toxoplasma in AIDS for information on the clinical management of this cosmopolitan OI.76, 77, 78, 79
Five percent of TE occurs not as reactivation but as an acute infection.207 Preventing the transmission of T. gondii to Toxoplasma-seronegative, HIV-infected people has two facets: (1) avoiding the ingestion of tissue cysts of other intermediate mammalian hosts (i.e., cooking meat well) and (2) avoiding the oocysts of the definitive host, the cat. Avoiding cat feces in and around dwellings is probably not sufficient because the oocysts are viable for up to 18 months in moist soil. Contamination of fresh vegetables may be a common method of human infection, and such foodstuffs should probably be washed well or cooked or both.
Primary prophylaxis (TMP–SMX is preferred)213 should be taken by all Toxoplasma-seropositive HIV patients with a CD4+ T-cell count less than 100/μL. It is safe to discontinue both primary and secondary prophylaxis after HAART-related immune reconstitution (sustained CD4+ T-cell counts >200/μL).76, 77, 78, 79
Free-living amebae of the Acanthamoeba and Balamuthia genera (see Chapter 95) are rare causes of opportunistic encephalitis and cutaneous disease in late-stage AIDS. Most case reports have been from the United States, but the worldwide environmental distribution of these ubiquitous protozoans and the fact that diagnosis is often postmortem suggest that underdiagnosis is widespread in the tropics and elsewhere.
Granulomatous amebic encephalitis (GAE), a subacute to chronic disease of compromised hosts caused by multiple species of Acanthamoeba as well as Balamuthi mandrillaris, generally causes death in weeks to months. Clinical and pathologic data, as well as animal models, suggest that the pathogenesis of GAE involves hematogenous dissemination to the brain from initial upper or lower respiratory (or perhaps cutaneous) sites of infection.214 Pathologic changes, in the form of necrotizing granulomatous inflammation, are found predominantly in the posterior neuraxis.
Acanthamoeba and Balamuthia have been isolated from soil, water (including tap water, bottled water, chlorinated pools, and natural sources of fresh- and seawater), and air throughout the world.215 The isolation of Acanthamoeba from the nasopharynx of healthy adults indicates that these organisms may be a common constituent of normal flora.216 Cellular immunity, along with antibody and complement, appears to be critical to protective immunity to Acanthamoebae.
217 Invasive disease occurs in the immunocompromised and debilitated.214 Occasionally, encephalitis with Balamuthia mandrillaris has occurred in apparently normal hosts.218,
More than 20 cases of GAE have been reported in AIDS patients.214,
220, 221, 222, 223, 224, 225, 226, 227, 228, 229 Implicated Acanthamoeba organisms include Acanthamoeba castellani, Acanthamoeba culbertsoni, Acanthamoeba polyphaga, Acanthamoeba rhysodes, and Acanthamoeba divionensis. Disseminated cutaneous disease [subacute granulomatous dermatitis (SGD)] has been a feature of many of these cases and has preceded clinical cerebral involvement by weeks or months in some. SGD has been the sole manifestation of invasive disease in some patients.230, 231, 232, 233, 234 Reported CD4+ T-cell counts have been less than 250/μL (median, 24/μL) at the time of presentation. Where CD4 counts have not been reported, the histories reveal clinical evidence of late-stage AIDS.214,
GAE in AIDS patients is marked by a more rapid course (with death in 3 to 40 days)214 and a paucity of well-formed granulomas in comparison to other hosts with the disease.214,
233 Symptomatic involvement of the nasopharynx, paranasal sinuses, or the skin prior to development of GAE is common in AIDS patients.214 Cutaneous lesions are usually nodular, with subsequent enlargement, ulceration, and metastatic spread. Such lesions can be quite pleomorphic (pustules, plaques, eschars, and cellulitis), however, and have been confused with cat-scratch disease, cryptococcosis, sporotrichosis, bacillary angiomatosis, mycobacterial infections, and vasculitis.214 The most common presentation of cerebral disease is that of fever and headache.214,
232 Focal neurologic deficits and profound changes in mental status are also frequent. Neuroradiologic findings mimic those of toxoplasmic encephalitis, with multiple enhancing mass lesions and surrounding edema. CSF findings are quite variable.214,
A high index of suspicion and tissue or microbiologic diagnosis is key to the antemortem identification of disseminated Acanthamoeba infection. Wet mounts of CSF are occasionally useful. Both trophozoites and cysts can be found in tissue biopsies. Cysts have been mistaken for the sporangia of Rhinosporium or Prototheca or for cryptococci; trophozoites have been mistaken for tissue macrophages.214
Acanthamoebae can be isolated by culture on Escherichia coli–seeded nonnutrient agar or in tissue culture medium.214,
232 Identification of species (and even differentiation of Acanthamoeba from Balamuthia) is not possible morphologically. Immunofluorescence techniques can differentiate Acanthamoeba to the group level in tissue section or with cultured organisms. Treatment of disseminated disease due to these organisms is difficult. No chemotherapeutic regimen is clearly efficacious. Agents with possible clinical utility in combination therapy include pentamidine, 5-fluorocytosine, sulfamethazine, sulfadiazine, fluconazole, itraconazole, ketoconazole, macrolides, phenothiazines, and rifampin.214,
231 There may be value in testing clinical isolates for drug sensitivities. With isolated cerebral lesions, there may be a role for surgical excision.229
In a possible foreshadowing of a newly emerging OI, a case of primary amebic meningoencephalitis due to an apparently newly recognized ameba and not associated with thermally polluted water was reported in a patient with late-stage AIDS in Spain.235,
Enteric Coccidiosis (Isospora, Cryptosporidium, and Cyclospora)
A trio of coccidian protozoa—Isospora belli, Cryptosporidium spp., and Cyclospora (Eimeria) cayetanensis—are all prominent causes of self-limited, small bowel diarrhea in immunologically normal hosts as well as causes of chronic, severe disease in the face of HIV coinfection. All are cosmopolitan infections. Infection with a fourth organism, Sarcocystis hominis, responsible for both enteric and disseminated coccidioisis in humans, does not appear to have been reported in HIV-infected individuals.
Cryptosporidium spp. (see Chapter 88).
In addition to the most common human pathogen Cryptosporidium hominis (previously Cryptosporidium parvum human genotype, or genotype 1), a variety of zoonotic species also infect humans, including Cryptosporidium parvum (previously bovine genotype, or genotype 2), Cryptosporidium canis, Cryptosporidium felis, Cryptosporidium meleagridis, and Cryptosporidium muris.237, 238, 239 Zoonotic species may cause more severe human disease and may occur more commonly in immunocompromised people. Because of the high prevalence of disease and the lack of effective specific treatment, cryptosporidiosis is a particularly common and severe problem as an OI throughout the world. Chronic infection and disease are most frequent with CD4+ T cell counts less than 180/mL240 and are associated with increased mortality.241, 242, 243 The use of HAART therapy has led to a decreasing prevalence of cryptosporidial disease in HIV-infected individuals.244,
Four clinical syndromes of cryptosporidial diarrheal disease in patients with AIDS have been limned: chronic diarrhea (36%), cholera-like disease (33%), transient diarrhea (15%), and relapsing illness (15%). The severe end of the spectrum is seen largely in those with CD4+ T-cell counts less than 180/μL.246,
247 Less commonly, extraintestinal sites are secondarily involved, including biliary tract, stomach, pancreas, lung, paranasal sinuses, and middle ear.246, 247, 248, 249 Of these, biliary tract involvement (presenting with right upper quadrant pain, nausea, vomiting, and fever) represents the most common, clinically important site, being found in up to one-fourth of patients with AIDS-related intestinal disease prior to the use of HAART.250 Individuals with CD4+ T-cell counts less than 50/μL are at a particular risk for development of symptomatic biliary disease.250
No antimicrobial agent has demonstrable, consistent efficacy in HIV-related cryptosporidiosis. Immune reconstitution with HAART should be pursued.251,
252 If HAART fails or is not available, a variety of antimicrobial agents (including nitazoxanide, azithromycin, paromomycin, and atovaquone) may be tried. Supportive treatment with fluids, nutrition, and antimotility agents plays an obvious therapeutic role.76, 77, 78, 79
Isospora belli (see Chapter 88).
Disease due to Isospora is less cosmopolitan than that due to Cryptosporidia, being most common in tropical and subtropical areas.253 Isosporiasis usually presents with chronic watery diarrhea and weight loss, with or without vomiting, abdominal pain, and fever.254 Invasion of gallbladder tissue, similar to that described with Cryptosporidium, has been described, along with disseminated involvement of mesenteric and tracheobronchial lymph nodes, in the setting of HIV coinfection.254,
255 Prominent tissue eosinophilia of the involved lamina propria is often present.253 Diagnostic and therapeutic issues are covered in Chapter 88. TMP–SMX provides effective therapy.256 Pyrimethamine (with leucovorin) provides a second option.257 Clinical response is usually rapid, but relapses are common. In the absence of immune reconstitution, suppressive therapy is indicated.76, 77, 78, 79
Cyclospora (Eimeria) cayetanensis (see Chapter 89).
The clinical picture of enteric infection with C. cayetanensis in AIDS appears to be similar to that due to other coccidia.258 It is of interest that biliary tract involvement—as evidenced by right upper quadrant pain, elevated alkaline phosphatase, and thickened gallbladder by ultrasound—has also been described in Cyclospora infection.259 Thus, all three of the enteric coccidia of humans are capable of invading the gallbladder. Diagnostic and therapeutic issues are covered in Chapter 89. As with isosporiasis, cyclosporiasis in AIDS is treatable with TMP/SMX.258 Subsequent suppressive therapy is indicated.76, 77, 78, 79
Microsporidia are intracellular protozoans that, due to HIV and AIDS, have emerged from their relative obscurity as pathogens of insects, fish, and laboratory animals to occupy a new role as important OIs of humans. These cosmopolitan emerging pathogens of the immunosuppressed (including Enterocytozoon bienusi, Enterocytozoon [Septata] intestinalis, Entero-cytozoon cuniculi, Enterocytozoon hellem, as well as pathogens from several other genera) are considered in Chapter 96.
Other Protozoan Infections
This intestinal parasite (see Chapter 86) was initially associated with HIV because of its high prevalence in men who have sex with men (MSM). Despite considerable evidence that immunity in amebiasis requires the participation of CMI, there is no evidence that patients with HIV infection or AIDS are more likely to develop invasive disease.
As with E. histolytica, a high prevalence of infection with G. lamblia (see Chapter 87) was found in the 1980s among MSM.260 A study of MSM performed at that time revealed no increased prevalence or severity of giardiasis in patients with AIDS.261 Since then, no evidence has been found of a significant effect of HIV coinfection. Although some studies have indicated a higher prevalence of giardiasis in HIV seropositives, this has not been a consistent finding. Therapy of giardiasis in people with AIDS is usually successful. Some patients, immunocompromised as well as immunocompetent, are refractory to standard therapeutic regimens for giardiasis. It may well be that such refractoriness to standard therapy is found more commonly in the face of HIV coinfection.262
Controversy continues to exist as to the role of this organism as a cause of diarrheal disease in either immunocompetent patients or HIV-infected people.263
Blastocystis hominis has a cosmopolitan distribution; there is no association with the tropics.
No information is available as to whether this organism can serve as an OI in HIV-infected people.