InternalMed_Harrison

InternalMed_Harrison. Immunopathogenesis As in VL, the proinflammatory (TH1) response in CL may result in either asymptomatic or subclinical infection. However, in some individuals, the immune response causes ulcerative skin lesions, the majority of which heal spontaneously, leaving a scar. Healing is usually followed by immunity to reinfection with that species of parasite.


InternalMed_Harrison

InternalMed_Harrison. Clinical Features A few days or weeks after the bite of a sandfly, a papule develops and grows into a nodule that ulcerates over some weeks or months. The base of the ulcer, which is usually painless, consists of necrotic tissue and crusted serum, but secondary bacterial infection sometimes occurs. The margins of the ulcer are raised and indurated. Lesions may be single or multiple and vary in size from 0.5 to >3 cm (Fig. 251-5). Lymphatic spread and lymph gland involvement may be palpable and may precede the appearance of the skin lesion. There may be satellite lesions, especially in L. major and L. tropica infections. The lesions usually heal spontaneously after 2–15 months. Lesions due to L. major and L. mexicana tend to heal rapidly, whereas those due to


InternalMed_Harrison

InternalMed_Harrison. L. major and L. mexicana tend to heal rapidly, whereas those due to L. tropica and parasites of subspecies Viannia heal more slowly. In CL caused by L. tropica, new lesions—usually scaly, erythematous papules and nodules—develop in the center or periphery of a healed sore, a condition known as leishmaniasis recidivans. Lesions of L. mexicana and Leishmania (Viannia) peruviana closely resemble those seen in the Old World; however, lesions on the pinna of the ear are common, chronic, and destructive in the former infections. L. mexicana is responsible for chiclero’s ulcer, the so-called self-healing sore of Mexico. CL lesions on exposed body parts (e.g., the face and hands), permanent scar formation, and social stigmatization may cause anxiety and depression and may affect the quality of life of CL patients.


InternalMed_Harrison

InternalMed_Harrison. Differential Diagnosis A typical history (an insect bite followed by the events leading to ulceration) in a resident of or a traveler to an endemic focus strongly suggests CL. Cutaneous tuberculosis, fungal infections, leprosy, sarcoidosis, and malignant ulcers are sometimes mistaken for CL. Laboratory Diagnosis Demonstration of amastigotes in material obtained from a lesion remains the diagnostic gold standard. Microscopic examination of slit skin smears, aspirates, or biopsies of the lesion is used for detection of parasites. Culture of smear or biopsy material may yield Leishmania. PCR is more sensitive than microscopy and culture and allows identification of Leishmania to the species level. This information is important in decisions about therapy because responses to treatment can vary with the species. Isoenzyme profiling is used to determine species for research purposes.


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InternalMed_Harrison. FIGuRE 251-5 Cutaneous leishmaniasis in a Bolivian child. There are multiple ulcers resulting from several sandfly bites. The edges of the ulcers are raised. (Courtesy of P. Desjeux, Retired Medical Officer, World Health Organization, Geneva, Switzerland.) Although lesions heal spontaneously in the majority of cases, their spread or persistence indicates that treatment may be needed. One or a few small lesions due to “self-healing species” can be treated with topical agents. Systemic treatment is required for lesions over the face, hands, or joints; multiple lesions; large ulcers; lymphatic spread; New World CL with the potential for development of ML; and CL in HIV co-infected patients.


InternalMed_Harrison

InternalMed_Harrison. A pentavalent antimonial is the first-line drug for all forms of CL and is used in a dose of 20 mg/kg for 20 days, as for VL. The exceptions to this rule are CL caused by Leishmania (Viannia) guyanensis, for which pentamidine isethionate is the drug of choice (two injections of 4 mg of salt/kg separated by a 48-h interval), and CL due to


InternalMed_Harrison

InternalMed_Harrison. L. aethiopica, which responds to paromomycin (16 mg/kg daily) but not to antimonials. Relapses usually respond to a second course of treatment. In Peru, topical imiquimod (5–7.5%) plus parenteral antimonials have been shown to cure CL more rapidly than antimonials alone. Azoles and triazoles have been used with mixed responses in both Old and New World CL but have not been adequately assessed for this indication in clinical trials. In L. major infection, oral fluconazole (200 mg/d for 6 weeks) resulted in a higher rate of cure than placebo (79% vs 34%) and also cured infection faster. Adverse effects include gastrointestinal symptoms and hepatotoxicity. Ketoconazole (600 mg/d for 28 days) is 76–90% effective in CL due to L. (V.) panamensis and L. mexicana in Panama and Guatemala. Miltefosine has been used in CL in doses of 2.5 mg/kg for 28 days. This agent is effective against L. major infections. In Colombia, where CL is due to L. (V.) panamensis, miltefosine was also effective, with


InternalMed_Harrison

InternalMed_Harrison. has been used in CL in doses of 2.5 mg/kg for 28 days. This agent is effective against L. major infections. In Colombia, where CL is due to L. (V.) panamensis, miltefosine was also effective, with a cure rate of 91%. For L. (V.) braziliensis infections, however, the results with miltefosine are less consistent. In Brazil, miltefosine cured 71% of patients with L. (V.) guyanensis infection. Other drugs, such as dapsone, allopurinol, rifampin, azithromycin, and pentoxifylline, have been used either alone or in combinations, but most of the relevant studies have had design limitations that preclude meaningful conclusions.


InternalMed_Harrison

InternalMed_Harrison. Small lesions (≤3 cm in diameter) may conveniently be treated weekly until cure with an intralesional injection of a pentavalent antimonial at a dose adequate to blanch the lesion (0.2–2.0 mL). An ointment containing 15% paromomycin sulfate, either alone or with 0.5% gentamicin or 12% methylbenzonium chloride, cured 70–82% of lesions due to L. major in 20 days and may be suitable for lesions caused by other species. Heat therapy with an FDA-approved radio-frequency generator and cryotherapy with liquid nitrogen have also been used successfully.


InternalMed_Harrison

InternalMed_Harrison. Diffuse Cutaneous Leishmaniasis (DCL) DCL is a rare form of leishmaniasis caused by L. amazonensis and L. mexicana in South and Central America and by L. aethiopica in Ethiopia and Kenya. DCL is characterized by the lack of a cell-mediated immune response to the parasite, the uncontrolled multiplication of which thus continues unabated. The DTH response does not develop, and lymphocytes do not respond to leishmanial antigens in vitro. DCL patients have a polarized immune response with high levels of immunosuppressive cytokines, including IL-10, transforming growth factor (TGF) β, and IL-4, and low concentrations of IFN-γ. Profound immunosuppression leads to widespread cutaneous disease. Lesions may initially be confined to the face or a limb but spread over months or years to other areas of the skin. They may be symmetrically or asymmetrically distributed and include papules, nodules, plaques, and areas of diffuse infiltration. These lesions do not ulcerate. The overlying skin is


InternalMed_Harrison

InternalMed_Harrison. of the skin. They may be symmetrically or asymmetrically distributed and include papules, nodules, plaques, and areas of diffuse infiltration. These lesions do not ulcerate. The overlying skin is usually erythematous in pale-skinned patients. The lesions are teeming with parasites, which are therefore easy to recover. DCL does not heal spontaneously and is difficult to treat. If relapse and drug resistance are to be prevented, treatment should be continued for some time after lesions have healed and parasites can no longer be isolated. In the New World, repeated 20-day courses of pentavalent antimonials are given, with an intervening drug-free period of 10 days. Miltefosine has been used for several months with a good initial response. Combinations should be tried. 1393 In Ethiopia, a combination of paromomycin (14 mg/kg per day) and sodium stibogluconate (10 mg/kg per day) is effective.


InternalMed_Harrison

InternalMed_Harrison. The subgenus Viannia is widespread from the Amazon basin to Paraguay and Costa Rica and is responsible for deep sores and for ML (Table 251-1). In L. (V.) braziliensis infections, cutaneous lesions may be simultaneously accompanied by mucosal spread of the disease or followed by spread years later. ML is typically caused by L. (V.) braziliensis and rarely by L. amazonensis, L. (V.) guyanensis, and L. (V.) panamensis. Young men with chronic lesions of CL are at particular risk. Overall, ~3% of infected persons develop ML. Not every patient with ML has a history of prior CL. ML is almost entirely confined to the Americas. In rare cases, ML may also be caused by Old World species like L. major, L. infantum (L. chagasi), or L. donovani.


InternalMed_Harrison

InternalMed_Harrison. Immunopathogenesis and Clinical Features The immune response is polarized toward a TH1 response, with marked increases of IFN-γ and TNF-α and varying levels of TH2 cytokines (IL-10 and TGF-β). Patients have a stronger DTH response with ML than with CL, and their peripheral-blood mononuclear cells respond strongly to leishmanial antigens. The parasite spreads via the lymphatics or the bloodstream to mucosal tissues of the upper respiratory tract. Intense inflammation leads to destruction, and severe disability ensues. Lesions in or around the nose or mouth (espundia; Fig. 251-6) are the typical presentation of ML. Patients usually provide a history of self-healed CL preceding ML by 1–5 years. Typically, ML presents as nasal stuffiness and bleed ing followed by destruction of nasal cartilage, perforation of the nasal septum, and collapse of the nasal bridge. Subsequent involvement of the pharynx and larynx leads to difficulty in swallowing and phonation.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 251-6 Mucosal leishmaniasis in a Brazilian patient. There is extensive inflammation around the nose and mouth, destruction of the nasal mucosa, ulceration of the upper lip and nose, and destruction of the nasal septum. (Courtesy of R. Dietz, Universidade Federal do Espírito Santo, Vitória, Brazil.) in the New World. Chagas disease and African Trypanosomiasis Louis V. Kirchhoff, Anis Rassi Jr. Although the genus Trypanosoma contains many species of protozo-ans, only T. cruzi, T. brucei gambiense, and T. brucei rhodesiense cause 252 1394 The lips, cheeks, and soft palate may also be affected. Secondary bacterial infection is common, and aspiration pneumonia may be fatal. Despite the high degree of TH1 immunity and the strong DTH response, ML does not heal spontaneously.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Diagnosis Tissue biopsy is essential for identification of parasites, but the rate of detection is poor unless PCR techniques are used. The strongly positive DTH response fails to distinguish between past and present infection.


InternalMed_Harrison

InternalMed_Harrison. The regimen of choice is a pentavalent antimonial agent administered at a dose of 20 mg of SbV/kg for 30 days. Patients with ML require long-term follow-up with repeated oropharyngeal and nasal examination. With failure of therapy or relapse, patients may receive another course of an antimonial but then become unresponsive, presumably because of resistance in the parasite. In this situation, AmB should be used. An AmB deoxycholate dose totaling 25–45 mg/kg is appropriate. There are no controlled trials of liposomal AmB, but administration of 2–3 mg/kg for 20 days is considered adequate. Miltefosine (2.5 mg/kg for 28 days) cured 71% of ML patients in Bolivia. The more extensive the disease, the worse the prognosis; thus prompt, effective treatment and regular follow-up are essential.


InternalMed_Harrison

InternalMed_Harrison. No vaccine is available for any form of leishmaniasis. Inoculation with live L. major (“leishmanization”) is practiced in Iran. Anthroponotic leishmaniasis is controlled by case finding, treatment, and vector control with insecticide-impregnated bed nets and curtains and residual insecticide spraying. Control of zoonotic leishmaniasis is more difficult. Use of insecticide-impregnated collars for dogs, treatment of infected domestic dogs, and culling of street dogs are measures that have been used with uncertain efficacy to prevent transmission of


InternalMed_Harrison

InternalMed_Harrison. L. infantum. In Brazil, a canine vaccine has been found to promote a decrease in the human and canine incidence of zoonotic VL. Two vaccines, Leishmune and Leish-Tec®, are licensed in Brazil; Leishmune provides significant protection to vaccinated dogs. CaniLeish® is the first licensed canine vaccine developed in Europe. Personal prophylaxis with bed nets and repellants may reduce the risk of CL infections disease in humans. T. cruzi is the etiologic agent of Chagas disease in the Americas; T. b. gambiense and T. b. rhodesiense cause African trypanosomiasis.


InternalMed_Harrison

InternalMed_Harrison. Chagas disease, or American trypanosomiasis, is a zoonosis caused by the protozoan parasite T. cruzi. Acute Chagas disease is usually a mild febrile illness that results from initial infection with the organism. After spontaneous resolution of the acute illness, most infected persons remain for life in the indeterminate phase of chronic Chagas disease, which is characterized by subpatent parasitemia, easily detectable IgG antibodies to T. cruzi, and an absence of associated signs and symptoms. In 10–30% of chronically infected patients, cardiac and/or gastrointestinal symptoms develop that can lead to serious morbidity and even death.


InternalMed_Harrison

InternalMed_Harrison. In 10–30% of chronically infected patients, cardiac and/or gastrointestinal symptoms develop that can lead to serious morbidity and even death. T. cruzi is transmitted among its mammalian hosts by hematophagous triatomine insects, often called reduviid bugs. The insects become infected by sucking blood from animals or humans with circulating parasites. Ingested organisms multiply in the gut of the triatomines, and infective forms are discharged with the feces at the time of subsequent blood meals. Transmission to a second vertebrate host occurs when breaks in the skin, mucous membranes, or conjunctivae become contaminated with bug feces that contain infective parasites. T. cruzi can also be transmitted by transfusion of blood donated by infected persons, by organ transplantation, from mother to unborn child, by ingestion of contaminated food or drink, and in laboratory accidents.


InternalMed_Harrison

InternalMed_Harrison. Initial infection at the site of parasite entry is characterized by local histologic changes that include the presence of parasites within leukocytes and cells of subcutaneous tissues and the development of interstitial edema, lymphocytic infiltration, and reactive hyperplasia of adjacent lymph nodes. After dissemination of the organisms through the lymphatics and the bloodstream, primarily muscles (including the myocardium) (Fig. 252-1) and ganglion cells may become heavily parasitized. The characteristic pseudocysts present in sections of infected tissues are intracellular aggregates of multiplying parasites.


InternalMed_Harrison

InternalMed_Harrison. In persons with chronic T. cruzi infections who develop related clinical manifestations, the heart is the organ most commonly affected. Changes include thinning of the ventricular walls, biventricular enlargement, apical aneurysms, and mural thrombi. Widespread lymphocytic infiltration, diffuse interstitial fibrosis, and atrophy of myocardial cells are often apparent. Although parasites are difficult to find in myocardial tissue by conventional histologic methods, more sensitive techniques of parasite detection, such as immunohistochemistry and polymerase chain reaction (PCR), have more frequently demonstrated T. cruzi antigens and parasite DNA in chronic lesions. Conduction-system abnormalities often affect the right branch and the left anterior branch of the bundle of His. In chronic Chagas disease of the gastrointestinal tract (megadisease), the esophagus and colon may exhibit varying degrees of dilation. On microscopic examination, focal inflammatory lesions with lymphocytic


InternalMed_Harrison

InternalMed_Harrison. Chagas disease of the gastrointestinal tract (megadisease), the esophagus and colon may exhibit varying degrees of dilation. On microscopic examination, focal inflammatory lesions with lymphocytic infiltration are seen, and the number of neurons in the myenteric plexus may be markedly reduced. Accumulating evidence implicates the persistence of parasites and the accompanying chronic inflammation—rather than autoimmune mechanisms—as the basis for the pathology in patients with chronic


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InternalMed_Harrison. T. cruzi infection. FIGuRE 252-1 Trypanosoma cruzi in the heart muscle of a child who died of acute Chagas myocarditis. An infected myocyte containing several dozen T. cruzi amastigotes is in the center of the field (hematoxylin and eosin, 900 ×). T. cruzi is found only in the Americas. Wild and domestic mammals harboring T. cruzi and infected triatomines are found in spotty distributions from the southern United States to southern Argentina. Humans become involved in the cycle of transmission when infected vectors take up residence in the primitive wood, adobe, and stone houses common in much of Latin America. Thus human T. cruzi infection is a health problem primarily among the poor in rural areas of Mexico and Central and South America. Most new


InternalMed_Harrison

InternalMed_Harrison. T. cruzi infections in rural settings occur in children, but the incidence is unknown because most cases go undiagnosed. Historically, transfusion-associated transmission of T. cruzi was a serious public health problem in many endemic countries. Transmission by this route has been largely eliminated, however, as effective programs for serologic screening of donated blood have been implemented. Several dozen patients with HIV and chronic T. cruzi infections who underwent acute recrudescence of the latter have been described. These patients generally presented with T. cruzi brain abscesses, a manifestation of the illness that does not occur in immunocompetent persons. Currently, it is estimated that 8 million people are chronically infected with T. cruzi and that 14,000 deaths due to the illness occur each year. The resulting morbidity and mortality make Chagas disease the most important parasitic disease burden in Latin America.


InternalMed_Harrison

InternalMed_Harrison. In recent years, the rate of T. cruzi transmission has decreased markedly in several endemic countries as a result of successful programs involving vector control, screening of donated blood, and education of at-risk populations. A major program, which began in 1991 in the “southern cone” nations of South America (Uruguay, Paraguay, Bolivia, Brazil, Chile, and Argentina), has provided the framework for much of this progress. Uruguay and Chile were certified free of transmission by the main domiciliary vector species (Triatoma infestans) in the late 1990s, and Brazil was declared transmission-free in 2006. Transmission has been reduced markedly in Argentina as well. Similar control programs have been initiated in the countries of northern South America and in the Central American nations.


InternalMed_Harrison

InternalMed_Harrison. Acute Chagas disease is rare in the United States, where 22 cases of autochthonous transmission and seven instances of transmission by blood transfusion have been reported. Moreover, T. cruzi was transmitted to five recipients of organs from three T. cruzi–infected donors, two of whom became infected through cardiac transplants. Acute Chagas disease has been reported in only one tourist returning to the United States from Latin America, although three such instances have been reported in Europe as well as one in Canada. In contrast, the prevalence of chronic T. cruzi infections in the United States has increased considerably in recent years. An estimated 23 million immigrants from Chagas-endemic countries currently live in the United States, ~17 million of whom are Mexicans. The total number of


InternalMed_Harrison

InternalMed_Harrison. T. cruzi–infected persons living in the United States is estimated to be 300,000. Screening of the U.S. blood supply for T. cruzi infection began in January 2007. The overall prevalence of T. cruzi infection among donors is ~1 in 13,300, and to date nearly 3000 infected donors have been identified and deferred permanently (see “Diagnosis,” below).


InternalMed_Harrison

InternalMed_Harrison. The first signs of acute Chagas disease develop at least 1 week after invasion by the parasites. When the organisms enter through a break in the skin, an indurated area of erythema and swelling (the chagoma), accompanied by local lymphadenopathy, may appear. Romaña sign— the classic finding in acute Chagas disease, which consists of unilateral painless edema of the palpebrae and periocular tissues—can result when the conjunctiva is the portal of entry. These initial local signs may be followed by malaise, fever, anorexia, and edema of the face and lower extremities. Generalized lymphadenopathy and hepatosplenomegaly may develop. Severe myocarditis develops rarely; most deaths in acute Chagas disease are due to heart failure. Neurologic signs are not common, but meningoencephalitis occurs occasionally, especially in children <2 years old. Usually within 4–8 weeks, acute signs and symptoms resolve spontaneously in virtually all patients, with commencement of the asymptomatic or


InternalMed_Harrison

InternalMed_Harrison. occurs occasionally, especially in children <2 years old. Usually within 4–8 weeks, acute signs and symptoms resolve spontaneously in virtually all patients, with commencement of the asymptomatic or indeterminate form of chronic T. cruzi infection.


InternalMed_Harrison

InternalMed_Harrison. Symptomatic chronic Chagas disease becomes apparent years 1395 or even decades after the initial infection. The heart is commonly involved, and symptoms are caused by rhythm disturbances, segmental or dilated cardiomyopathy, and thromboembolism. Right bundle branch block is a common electrocardiographic abnormality, but other types of intraventricular and atrioventricular blocks, premature ventricular contractions, and tachyand bradyarrhythmias occur frequently. Cardiomyopathy often results in biventricular heart failure, with a predominance of right-sided failure at advanced stages. Embolization of mural thrombi to the brain or other areas may take place. Sudden death is the main cause of death in Chagas heart disease; congestive heart failure and stroke are next most common. Patients with megaesophagus suffer from dysphagia, odynophagia, chest pain, and regurgitation. Aspiration can occur (especially during sleep) in patients with severe esophageal dysfunction, and repeated episodes


InternalMed_Harrison

InternalMed_Harrison. megaesophagus suffer from dysphagia, odynophagia, chest pain, and regurgitation. Aspiration can occur (especially during sleep) in patients with severe esophageal dysfunction, and repeated episodes of aspiration pneumonitis are common. Weight loss, cachexia, and pulmonary infection can result in death. Patients with megacolon are plagued by abdominal pain and chronic constipation, which predisposes to fecaloma formation. Advanced megacolon can cause obstruction, volvulus, septicemia, and death.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of acute Chagas disease requires the detection of parasites. Microscopic examination of fresh anticoagulated blood or the buffy coat is the simplest way to see the motile organisms. Parasites also can be seen in Giemsa-stained thin and thick blood smears. Microhematocrit tubes containing acridine orange as a stain can be used for the same purpose. When used repeatedly by experienced personnel, all of these methods yield positive results in a high proportion of cases of acute Chagas disease. Serologic testing does not play a major role in diagnosing acute Chagas disease. PCR assays often give positive results in infected patients in whom traditional parasitologic tests are negative, including infants with congenital Chagas disease.


InternalMed_Harrison

InternalMed_Harrison. Chronic Chagas disease is diagnosed by the detection of specific IgG antibodies that bind to T. cruzi antigens. Demonstration of the parasite is not of primary importance. In Latin America, ~30 assays are commercially available, including several based on recombinant antigens. Although these tests usually show good sensitivity and reasonable specificity, false-positive reactions may occur—typically with samples from patients who have other infectious and parasitic diseases or autoimmune disorders. In addition, confirmatory testing has presented a persistent challenge. For these reasons, the World Health Organization recommends that specimens be tested in at least two assays and that well-characterized positive and negative comparison samples be included in each run. The Chagas radioimmune precipitation assay (RIPA), a highly sensitive and specific confirmatory method for detecting antibodies to T. cruzi, is approved under the Clinical Laboratory Improvement Amendment and available in


InternalMed_Harrison

InternalMed_Harrison. precipitation assay (RIPA), a highly sensitive and specific confirmatory method for detecting antibodies to T. cruzi, is approved under the Clinical Laboratory Improvement Amendment and available in the laboratory of one of the authors (L.V.K.). In 2006, the U.S. Food and Drug Administration (FDA) approved a test to screen blood and organ donors for T. cruzi infection (Ortho T. cruzi ELISA Test System; Ortho-Clinical Diagnostics, Raritan, NJ). Since January 2007, the vast majority of U.S. blood donors have been screened, and positive units have undergone confirmatory testing with the Chagas RIPA. A second test for donor screening was approved by the FDA in 2010 (Abbott PRISM® Chagas Assay; Abbott Laboratories, Abbott Park, IL), as was an enzyme strip assay (Abbott ESA Chagas) in 2011. The use of PCR assays to detect T. cruzi DNA in chronically infected persons has been studied extensively; unfortunately, the sensitivity of this approach has not been shown to be reliably greater than


InternalMed_Harrison

InternalMed_Harrison. use of PCR assays to detect T. cruzi DNA in chronically infected persons has been studied extensively; unfortunately, the sensitivity of this approach has not been shown to be reliably greater than that of serology.


InternalMed_Harrison

InternalMed_Harrison. Therapy for Chagas disease is still unsatisfactory. For many years now, only two drugs—nifurtimox and benznidazole—have been available for this purpose. Regrettably, both drugs lack efficacy and may cause bothersome side effects. In acute Chagas disease, nifurtimox markedly reduces the duration of symptoms and parasitemia and decreases the mortality rate.


InternalMed_Harrison

InternalMed_Harrison. 1396 Nevertheless, limited studies have shown that only ~70% of acute infections are cured by a full course of treatment. Common adverse effects of nifurtimox include anorexia, nausea, vomiting, weight loss, and abdominal pain. Neurologic reactions to the drug may include restlessness, disorientation, insomnia, twitching, paresthesia, polyneuritis, and seizures. These symptoms usually disappear when the dosage is reduced or treatment is discontinued. The recommended daily dosage is 8–10 mg/kg for adults, 12.5–15 mg/kg for adolescents, and 15–20 mg/kg for children 1–10 years of age. The drug should be given orally in four divided doses each day, and therapy should be continued for 90–120 days. Nifurtimox is available from the Drug Service of the Centers for Disease Control and Prevention (CDC) in Atlanta (telephone number, 404-639-3670). The efficacy of benznidazole is similar or even superior to that of nifurtimox. A cure rate of >90% among congenitally infected infants treated before


InternalMed_Harrison

InternalMed_Harrison. in Atlanta (telephone number, 404-639-3670). The efficacy of benznidazole is similar or even superior to that of nifurtimox. A cure rate of >90% among congenitally infected infants treated before their first birthday has been reported. Adverse effects include rash, peripheral neuropathy, and rare instances of granulocytopenia. The recommended oral dosage is 5 mg/kg per day for 60 days for adults and 5–10 mg/kg per day for 60 days for children, with administration of two or three divided doses. Benznidazole is generally considered the drug of choice in Latin America. The question of whether adults in the indeterminate or chronic symptomatic phase of Chagas disease should be treated with nifurtimox or benznidazole has been debated for years. The fact that cure rates in persons with long-established chronic infection are notably inferior to those in patients with acute or recent chronic infection is central to this controversy. No convincing evidence from randomized controlled trials


InternalMed_Harrison

InternalMed_Harrison. chronic infection are notably inferior to those in patients with acute or recent chronic infection is central to this controversy. No convincing evidence from randomized controlled trials indicates that nifurtimox or benznidazole treatment of adults in the indeterminate or chronic symptomatic phase reduces either the appearance or progression of symptoms or mortality rates. On the basis of results of some observational studies, a panel of experts convened by the CDC in 2006 recommended that adults <50 years old with presumably long-standing indeterminate T. cruzi infections— or even with mild to moderate disease—be offered treatment. A large randomized clinical trial (the BENEFIT multicenter trial) designed to assess the parasitologic and clinical efficacy of benznidazole in 2856 adults (18–75 years old) with chronic Chagas heart disease (without advanced lesions) is being performed in Brazil, Argentina, Colombia, Bolivia, and El Salvador, but results will not be available until 2015.


InternalMed_Harrison

InternalMed_Harrison. years old) with chronic Chagas heart disease (without advanced lesions) is being performed in Brazil, Argentina, Colombia, Bolivia, and El Salvador, but results will not be available until 2015. In contrast, randomized studies have shown that treatment of children is useful, and the current consensus of Latin American authorities and the CDC panel of experts is that all


InternalMed_Harrison

InternalMed_Harrison. T. cruzi–infected persons up to 18 years old and all adults known to have become infected recently should be given benznidazole or nifurtimox. The usefulness of antifungal azoles for the treatment of Chagas disease has been studied in laboratory animals and to a lesser extent in humans. To date, none of these drugs has exhibited a level of anti–T. cruzi activity that would justify its use in humans. Several newer drugs in this class have shown promise in animal studies and are currently being evaluated in phase 2 clinical trials.


InternalMed_Harrison

InternalMed_Harrison. Patients who develop cardiac and/or gastrointestinal disease in association with T. cruzi infection should be referred to appropriate subspecialists for further evaluation and treatment. Pacemakers can be useful in patients with ominous arrhythmias. The usefulness of implantable cardioverter defibrillators in persons with Chagas heart disease has not been established and currently is being studied in a prospective randomized trial. Cardiac transplantation is an option for patients with end-stage chagasic cardiomyopathy; more than 150 such transplantations have been done in Brazil and the United States. The survival rate among Chagas disease cardiac transplant recipients seems to be higher than that among persons receiving cardiac transplants for other reasons. This better outcome may be due to the fact that lesions are limited to the heart in most patients with symptomatic chronic Chagas disease.


InternalMed_Harrison

InternalMed_Harrison. Because drug therapy has limitations and vaccines are not available, the control of T. cruzi transmission in endemic countries depends on the reduction of domiciliary vector populations by spraying of insecticides, improvements in housing, and education of at-risk persons. As noted above, these measures, coupled with serologic screening of blood donors, have markedly reduced transmission of the parasite in many endemic countries. Tourists would be wise to avoid sleeping in dilapidated houses in rural areas of endemic countries. Mosquito nets and insect repellent can provide additional protection.


InternalMed_Harrison

InternalMed_Harrison. In view of the possibly serious consequences of chronic T. cruzi infection, it would be prudent for all immigrants from endemic regions who are living in the United States to be tested for evidence of infection. Identification of persons harboring the parasite would permit periodic electrocardiographic monitoring, which is important to detect incipient heart disease and guide further diagnostic studies and treatment. The possibility of congenital transmission is yet another justification for screening. T. cruzi is classified as a Risk Group 2 agent in the United States and a Risk Group 3 agent in some European countries. Laboratory staff should work with the parasite or infected vectors and mammals at containment levels consistent with the risk group designation in their areas.


InternalMed_Harrison

InternalMed_Harrison. Sleeping sickness, or human African trypanosomiasis (HAT), is caused by flagellated protozoan parasites that belong to the T. brucei complex and are transmitted to humans by tsetse flies. In untreated patients, the trypanosomes first cause a febrile illness that is followed months or years later by progressive neurologic impairment and death.


InternalMed_Harrison

InternalMed_Harrison. The East African (rhodesiense) and the West African (gambiense) forms of sleeping sickness are caused, respectively, by two trypanosome subspecies: T. b. rhodesiense and T. b. gambiense. These subspecies are morphologically indistinguishable but cause illnesses that are epidemiologically and clinically distinct (Table 252-1). The parasites are transmitted by blood-sucking tsetse flies of the genus Glossina. The insects acquire the infection when they ingest blood from infected mammalian hosts. After many cycles of multiplication in the midgut of the vector, the parasites migrate to the salivary glands. Their transmission takes place when they are inoculated into a mammalian host during a subsequent blood meal. The injected trypanosomes multiply in the blood (Fig. 252-2) and other extracellular spaces and evade immune destruction for long periods by undergoing antigenic variation, a process driven by gene switching in which the antigenic structure of the organisms’ surface coat of


InternalMed_Harrison

InternalMed_Harrison. spaces and evade immune destruction for long periods by undergoing antigenic variation, a process driven by gene switching in which the antigenic structure of the organisms’ surface coat of glycoproteins changes periodically.


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InternalMed_Harrison. West African East African Point of Comparison (gambiense) (rhodesiense) Abbreviation: CNS, central nervous system. Source: Reprinted with permission from LV Kirchhoff, in GL Mandell et al (eds): Principles and Practice of Infectious Diseases, 7th ed. Philadelphia, Elsevier Churchill Livingstone, 2010. FIGuRE 252-2 Trypanosoma brucei rhodesiense parasites in rat blood. The slender parasite is thought to be the form that multiplies in mammalian hosts, whereas the stumpy forms are nondividing and are capable of infecting insect vectors (Giemsa, 1200 × ). (Courtesy of Dr. G. A. Cook, Madison, WI; with permission.)


InternalMed_Harrison

InternalMed_Harrison. A self-limited inflammatory lesion (trypanosomal chancre) may appear a week or so after the bite of an infected tsetse fly. A systemic febrile illness then evolves as the parasites are disseminated through the lymphatics and bloodstream. Systemic HAT without central nervous system (CNS) involvement is generally referred to as stage 1 disease. In this stage, widespread lymphadenopathy and splenomegaly reflect marked lymphocytic and histiocytic proliferation and invasion of morular cells, which are plasmacytes that may be involved in the production of IgM. Endarteritis, with perivascular infiltration of both parasites and lymphocytes, may develop in lymph nodes and the spleen. Myocarditis develops frequently in patients with stage 1 disease and is especially common in T. b. rhodesiense infections.


InternalMed_Harrison

InternalMed_Harrison. Hematologic manifestations that accompany stage 1 HAT include moderate leukocytosis, thrombocytopenia, and anemia. High levels of immunoglobulins, consisting primarily of polyclonal IgM, are a constant feature, and heterophile antibodies, antibodies to DNA, and rheumatoid factor are often detected. High levels of antigen–antibody complexes may play a role in the tissue damage and increased vascular permeability that facilitate dissemination of the parasites. Stage 2 disease involves invasion of the CNS. The presence of trypanosomes in perivascular areas is accompanied by intense infiltration of mononuclear cells. Abnormalities in cerebrospinal fluid (CSF) include increased pressure, elevated total protein concentration, and pleocytosis. In addition, trypanosomes are frequently found in CSF.


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InternalMed_Harrison. The trypanosomes that cause sleeping sickness are found only in sub-Saharan Africa. After its near-eradication in the mid 1960s, sleeping sickness underwent a resurgence in the 1990s, primarily in Uganda, Sudan, the Central African Republic, the Democratic Republic of the Congo, and Angola. A subsequent increase in control activities reduced the incidence in many endemic areas, however, and in 2009 fewer than 10,000 cases were reported to the World Health Organization. Although underreporting is a persistent problem, the level of control achieved to date was the basis for convening a panel of experts in 2009 to develop a vision for eradication of HAT.


InternalMed_Harrison

InternalMed_Harrison. Humans are the only reservoir of T. b. gambiense, which occurs in widely distributed foci in tropical rain forests of Central and West Africa. Gambiense trypanosomiasis is primarily a problem in rural populations; tourists rarely become infected. Trypanotolerant antelope species in savanna and woodland areas of Central and East Africa are the principal reservoir of T. b. rhodesiense. Cattle can also be infected with this and other trypanosome species but generally succumb to the infection. Because risk results from contact with tsetse flies that feed on wild animals, humans acquire T. b. rhodesiense infection only inciden-1397 tally, usually while visiting or working in areas where infected game and vectors are present. Roughly one or two imported cases of HAT acquired in East African parks are reported to the CDC each year.


InternalMed_Harrison

InternalMed_Harrison. A painful trypanosomal chancre appears in some patients at the site of inoculation of the parasite. Hematogenous and lymphatic dissemination (stage 1 disease) is marked by the onset of fever. Typically, bouts of high temperatures lasting several days are separated by afebrile periods. Lymphadenopathy is prominent in T. b. gambiense trypanosomiasis. The nodes are discrete, movable, rubbery, and nontender. Cervical nodes are often visible, and enlargement of the nodes of the posterior cervical triangle, or Winterbottom’s sign, is a classic finding. Pruritus and maculopapular rashes are common. Inconstant findings include malaise, headache, arthralgias, weight loss, edema, hepatosplenomegaly, and tachycardia. The differential diagnosis of stage 1 HAT includes many diseases that are common in the tropics and are associated with fevers. HIV infection, malaria, and typhoid fever are common in populations at risk for HAT and need to be considered.


InternalMed_Harrison

InternalMed_Harrison. CNS invasion (stage 2 disease) is characterized by the insidious development of protean neurologic manifestations that are accompanied by progressive abnormalities in the CSF. A picture of progressive indifference and daytime somnolence develops (hence the designation “sleeping sickness”), sometimes alternating with restlessness and insomnia at night. A listless gaze accompanies a loss of spontaneity, and speech may become halting and indistinct. Extrapyramidal signs may include choreiform movements, tremors, and fasciculations. Ataxia is frequent, and the patient may appear to have Parkinson’s disease, with a shuffling gait, hypertonia, and tremors. In the final phase, progressive neurologic impairment ends in coma and death.


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InternalMed_Harrison. The most striking difference between the gambiense and rhodesiense forms of HAT is that the latter illness tends to follow a more acute course. Typically, in tourists with T. b. rhodesiense disease, systemic signs of infection, such as fever, malaise, and headache, appear before the end of the trip or shortly after the return home. Persistent tachycar dia unrelated to fever is common early in the course of T. b. rhodesiense trypanosomiasis, and death may result from arrhythmias and congestive heart failure before CNS disease develops. In general, untreated T. b. rhodesiense trypanosomiasis leads to death in a matter of weeks to months, often without a clear distinction between the hemolymphatic and CNS stages. In contrast, T. b. gambiense disease can smolder for many months or even for years.


InternalMed_Harrison

InternalMed_Harrison. A definitive diagnosis of HAT requires detection of the parasite. If a chancre is present, fluid should be expressed and examined directly by light microscopy for the highly motile trypanosomes. The fluid also should be fixed and stained with Giemsa. Material obtained by needle aspiration of lymph nodes early in the illness should be examined similarly. Examination of wet preparations and Giemsa-stained thin and thick films of serial blood samples is also useful. If parasites are not seen initially in blood, efforts should be made to concentrate the organisms, which can be done in microhematocrit tubes containing acridine orange. Alternatively, the buffy coat from 10–15 mL of anti-coagulated blood can be examined directly under a microscope. The likelihood of finding parasites in blood is higher in stage 1 than in stage 2 disease and in patients infected with T. b. rhodesiense rather than T. b. gambiense. Trypanosomes may also be seen in material aspirated from the bone marrow; the


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InternalMed_Harrison. is higher in stage 1 than in stage 2 disease and in patients infected with T. b. rhodesiense rather than T. b. gambiense. Trypanosomes may also be seen in material aspirated from the bone marrow; the aspirate can be inoculated into liquid culture medium, as can blood, buffy coat, lymph node aspirates, and CSF. It is essential to examine CSF from all patients in whom HAT is suspected. Abnormalities in the CSF that may be associated with stage 2 disease include an increase in the CSF cell count as well as increases in opening pressure and in levels of total protein and IgM. Trypanosomes may be seen in the sediment of centrifuged CSF. Any CSF abnormality in a patient in whom trypanosomes have been found at other sites must be viewed as pathognomonic for CNS involvement and thus must prompt specific treatment for CNS disease. In patients 1398 with CSF pleocytosis in whom parasites are not found, tuberculous meningitis and HIV-associated CNS infections such as cryptococcosis should be


InternalMed_Harrison

InternalMed_Harrison. specific treatment for CNS disease. In patients 1398 with CSF pleocytosis in whom parasites are not found, tuberculous meningitis and HIV-associated CNS infections such as cryptococcosis should be considered in the differential diagnosis. A number of serologic assays, such as the card agglutination test for trypanosomes (CATT) for T. b. gambiense, are available to aid in the diagnosis of HAT. Their ease of use makes them valuable for epidemiologic surveys, but their variable sensitivity and specificity mandate that decisions about treatment be based on demonstration of the parasite. Accurate PCR assays for detecting African trypanosomes in humans have been developed, but the lack of the necessary technical and human resources in most endemic areas stands in the way of their widespread use.


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InternalMed_Harrison. The drugs used for treatment of HAT are suramin, pentamidine, eflornithine, and the organic arsenical melarsoprol. In the United States, these drugs can be obtained from the CDC. Therapy for HAT must be individualized on the basis of the infecting subspecies, the presence or absence of CNS disease, adverse reactions, and occasionally drug resistance. The choices of drugs for the treatment of HAT are summarized in Table 252-2.


InternalMed_Harrison

InternalMed_Harrison. Suramin is highly effective against stage 1 rhodesiense HAT. However, it can cause serious adverse effects and must be administered under the close supervision of a physician. A 100to 200-mg IV test dose should be given to detect hypersensitivity. The dosage for adults is 20 mg/kg on days 1, 5, 12, 18, and 26. The drug is given by slow IV infusion of a freshly prepared 10% aqueous solution. Approximately 1 patient in 20,000 has an immediate, severe, and potentially fatal reaction to the drug, developing nausea, vomiting, shock, and seizures. Less severe reactions include fever, photo-phobia, pruritus, arthralgias, and skin eruptions. Renal damage is the most common important adverse effect of suramin. Transient proteinuria often appears during treatment. A urinalysis should be done before each dose, and treatment should be discontinued if proteinuria increases or if casts and red cells appear in the sediment. Suramin should not be given to patients with renal insufficiency.


InternalMed_Harrison

InternalMed_Harrison. Pentamidine is the first-line drug for treatment of stage 1 gambiense HAT. The dose for both adults and children is 4 mg/kg per day, given IM or IV for 7–10 days. Frequent, immediate adverse reactions include nausea, vomiting, tachycardia, and hypotension. These reactions are usually transient and do not warrant cessation of therapy. Other adverse reactions include nephrotoxicity, abnormal liver function tests, neutropenia, rashes, hypoglycemia, and sterile abscesses. Suramin is an alternative agent for stage 1 T. b. gambiense disease.


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InternalMed_Harrison. Eflornithine is highly effective for treatment of both stages of gambiense sleeping sickness. In the trials on which the FDA based its approval, this agent cured >90% of 600 patients with stage 2 disease. The recommended treatment schedule is 400 mg/kg per day, given IV in four divided doses, for 2 weeks. Adverse reactions include diarrhea, anemia, thrombocytopenia, seizures, and hearing loss. The high dosage and duration of therapy required are disadvantages that make widespread use of eflornithine difficult. A randomized trial Abbreviations: CSF, cerebrospinal fluid; NECT, nifurtimox-eflornithine combination therapy.


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InternalMed_Harrison. Abbreviations: CSF, cerebrospinal fluid; NECT, nifurtimox-eflornithine combination therapy. comparing the standard eflornithine regimen (400 mg/kg per day infused over 6 h for 14 days) with nifurtimox-eflornithine combination therapy (NECT; oral nifurtimox, 15 mg/kg per day in three divided doses, plus IV eflornithine, 200 mg/kg per day in two divided doses, both for 7 days) in adults with stage 2 gambiense HAT showed improved efficacy and reduced adverse effects with combination therapy, making this drug suitable for first-line use.


InternalMed_Harrison

InternalMed_Harrison. The arsenical melarsoprol is the drug of choice for the treatment of rhodesiense HAT with CNS involvement and is an alternative agent for stage 2 gambiense disease. The “short course” of melarsoprol that is currently recommended has been shown to be noninferior to the decades-old treatment course for T. b. rhodesiense, which was administered over several weeks and was much more toxic. The short-course regimen consists of 10 daily doses of 2.2 mg/kg IV, each given with prednisolone (1 mg/kg).


InternalMed_Harrison

InternalMed_Harrison. Melarsoprol is highly toxic and should be administered with great care. As noted, all patients receiving melarsoprol should be given prednisolone to reduce the likelihood of drug-induced encephalopathy. Without prednisolone prophylaxis, the incidence of reactive encephalopathy has been as high as 18% in some series. Clinical manifestations of reactive encephalopathy include high fever, headache, tremor, impaired speech, seizures, and even coma and death. Treatment with melarsoprol should be discontinued at the first sign of encephalopathy but may be restarted cautiously at lower doses a few days after signs have resolved. Extravasation of the drug results in intense local reactions. Vomiting, abdominal pain, nephrotoxicity, and myocardial damage can occur.


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InternalMed_Harrison. HAT poses complex public-health and epizootic problems in Africa. Considerable progress has been made in many areas through control programs that focus on eradication of vectors and drug treatment of infected humans. People can reduce their risk of acquiring trypanosomiasis by avoiding areas known to harbor infected insects, by wearing protective clothing, and by using insect repellent. Chemoprophylaxis is not recommended, and no vaccine is available to prevent transmission of the parasites. Kami Kim, Lloyd H. Kasper


InternalMed_Harrison

InternalMed_Harrison. Kami Kim, Lloyd H. Kasper Toxoplasmosis is caused by infection with the obligate intracellular parasite Toxoplasma gondii. Acute infection acquired after birth may be asymptomatic but is thought to result in the lifelong chronic persistence of cysts in the host’s tissues. In both acute and chronic toxoplasmosis, the parasite is responsible for clinically evident disease, including lymphadenopathy, encephalitis, myocarditis, and pneumonitis. Congenital toxoplasmosis is an infection of newborns that results from the transplacental passage of parasites from an infected mother to the fetus. These infants may be asymptomatic at birth, but most later manifest a wide range of signs and symptoms, including chorioretinitis, strabismus, epilepsy, and psychomotor retardation. In immunocompetent individuals, toxoplasmosis can also present as acute disease (typically chorioretinitis) associated with foodor waterborne sources.


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InternalMed_Harrison. T. gondii is an intracellular coccidian that infects both birds and mammals. There are two distinct stages in the life cycle of T. gondii that yield transmissible forms of the parasite (Fig. 253-1). In the asexual stages, tissue cysts that contain bradyzoites or sporulated oocysts that contain sporozoites are ingested by an intermediate host (e.g., a human, mouse, sheep, pig, or bird). The cyst is rapidly digested by the Intermediate host: birds, mammals, humans Bradyzoites encyst within the CNS and muscle of the infected host. Oocysts are excreted in cat feces. Contaminated soil is ingested by birds, mammals, and humans.


InternalMed_Harrison

InternalMed_Harrison. Oocysts are excreted in cat feces. Contaminated soil is ingested by birds, mammals, and humans. T. gondii infects a wide range of mammals and birds. Its seroprevalence depends on the locale and the age of the population. Generally, hot arid climatic conditions are associated with a low prevalence of infection. In the United States and most European countries, the seroprevalence increases with age and exposure. For example, in the United States, 5–30% of individuals 10–19 years old and 10–67% of those >50 years old have serologic evidence of expo- the host, replicate, and cause tissue sure. In Central America, France, Turkey, damage. and Brazil, the seroprevalence is higher. Because of increased awareness of food-borne infections, the prevalence of seropositivity has decreased worldwide.


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InternalMed_Harrison. TRANSMISSION Toxoplasmic Oral Transmission Most cases of human encephalitis Toxoplasma infection are thought to be acquired by the oral route. Transmission can be attributable to ingestion of FIGuRE 253-1 Life cycle ofToxoplasma gondii. The cat is the definitive host in which the sexual sporulated oocysts from contaminated phase of the cycle is completed. Oocysts shed in cat feces can infect a wide range of animals, soil, food, or water. During acute feline including birds, rodents, grazing domestic animals, and humans. The bradyzoites found in the infection, a cat may excrete as many as muscle of food animals may infect humans who eat insufficiently cooked meat products, particularly 100 million parasites per day. These very lamb and pork. Although human disease can take many forms, congenital infection and encepha-stable sporozoite-containing oocysts are litis from reactivation of latent infection in the brains of immunosuppressed persons are the most highly infectious and may


InternalMed_Harrison

InternalMed_Harrison. congenital infection and encepha-stable sporozoite-containing oocysts are litis from reactivation of latent infection in the brains of immunosuppressed persons are the most highly infectious and may remain viable important manifestations. CNS, central nervous system. (Courtesy of Dominique Buzoni-Gatel, Institut for many years in soil or water. Humans


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InternalMed_Harrison. Pasteur, Paris; with permission.) acidic-pH gastric secretions. Bradyzoites or sporozoites are released, enter the small-intestinal epithelium, and transform into rapidly dividing tachyzoites. The tachyzoites can infect and replicate in all mammalian cells except red blood cells. The parasite actively penetrates the cell and forms a parasitophorous vacuole. Parasite replication continues within the vacuole. After the parasites reach a critical mass, intracellular signaling within the host and the parasite, including calcium fluxes, result in parasite egress from the vacuole. The host cell is destroyed, and the released tachyzoites infect adjoining cells. The tachyzoite replication cycle within an infected organ causes cytopathology. Most tachyzoites are eliminated by the host’s humoral and cell-mediated immune responses. Tissue cysts containing many bradyzoites develop 7–10 days after systemic tachyzoite infection. These tissue cysts occur in various host organs but persist


InternalMed_Harrison

InternalMed_Harrison. humoral and cell-mediated immune responses. Tissue cysts containing many bradyzoites develop 7–10 days after systemic tachyzoite infection. These tissue cysts occur in various host organs but persist principally within the central nervous system (CNS) and muscle. The development of this chronic stage completes the asexual portion of the life cycle. Active infection in the immunocompromised host is most likely to be due to the spontaneous release of encysted parasites that undergo rapid transformation into tachyzoites within the CNS and are not contained by the immune system.


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InternalMed_Harrison. The sexual stage in the life cycle takes place in the cat (the definitive host). The parasite’s sexual phase is defined by the formation of oocysts within the feline host. This enteroepithelial cycle begins with the ingestion of the bradyzoite tissue cysts and, after several intermediate stages, culminates in the production of gametes. Gamete fusion produces a zygote, which envelops itself in a rigid wall and is secreted in the feces as an unsporulated oocyst. After 2–3 days of exposure to air at ambient temperature, the noninfectious oocyst sporulates to produce eight sporozoite progeny. The sporulated oocyst can be ingested by an intermediate host, such as a person emptying a cat’s litter box or a pig rummaging in a barnyard. It is in the intermediate host that


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InternalMed_Harrison. T. gondii completes its life cycle. Sporulated oocysts are environmentally hardy and very infectious; they are thought to be sources of waterborne outbreaks such as those reported in Victoria (British Columbia, Canada) and in South America. ies to the oocyst/sporozoite. Children and adults also can acquire infection from tissue cysts containing bradyzoites. The ingestion of a single cyst is all that is required for human infection. Undercooking or insufficient freezing of meat is an important source of infection in the developed world. In the United States, lamb products and pork products may yield evidence of cysts that contain bradyzoites, but the overall prevalence of T. gondii has been gradually decreasing. The incidence in beef is much lower— perhaps as low as 1%. Direct ingestion of bradyzoite cysts in these various meat products leads to acute infection.


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InternalMed_Harrison. Transmission via Blood or Organs In addition to being transmitted orally, T. gondii can be transmitted directly from a seropositive donor to a seronegative recipient in a transplanted heart, heart-lung, kidney, liver, or pancreas. Viable parasites can be cultured from refrigerated anticoagulated blood, which may be a source of infection in individuals receiving blood transfusions. T. gondii reactivation has been reported in bone marrow, hematopoietic stem cell, and liver transplant recipients as well as in individuals with AIDS. Although antibody titers generally are not useful in monitoring T. gondii infection, individuals with higher antibody titers may be at relatively high risk for reactivation after hematopoietic stem cell transplantation; thus routine polymerase chain reaction (PCR) screening of blood from these patients may be in order. Finally, laboratory personnel can be infected after contact with contaminated needles or glassware or with infected tissue.


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InternalMed_Harrison. Transplacental Transmission On average, about one-third of all women who acquire infection with T. gondii during pregnancy transmit the parasite to the fetus; the remainder give birth to normal, uninfected babies. Of the various factors that influence fetal outcome, gestational age at the time of infection is the most critical (see below). Few data support a role for recrudescent maternal infection as the source of congenital disease, although rare cases of transmission by immunocompromised women (e.g., those infected with HIV or those receiving high-dose glucocorticoids) have been reported. Thus, women who are seropositive before pregnancy usually are protected against acute infection and do not give birth to congenitally infected neonates.


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InternalMed_Harrison. 1400 The following general guidelines can be used to evaluate congenital infection. There is essentially no risk if the mother becomes infected ≥6 months before conception. If infection is acquired <6 months before conception, the likelihood of transplacental infection increases as the interval between infection and conception decreases. Women with documented acute toxoplasmosis should be counseled to use appropriate measures to prevent pregnancy for 6 months after infection. In pregnancy, if the mother becomes infected during the first trimester, the incidence of transplacental infection is lowest (~15%), but the disease in the neonate is most severe. If maternal infection occurs during the third trimester, the incidence of transplacental infection is greatest (65%), but the infant is usually asymptomatic at birth. Infected infants who are normal at birth may have a higher incidence of learning disabilities and chronic neurologic sequelae than uninfected children. Only a small


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InternalMed_Harrison. is usually asymptomatic at birth. Infected infants who are normal at birth may have a higher incidence of learning disabilities and chronic neurologic sequelae than uninfected children. Only a small proportion (20%) of women infected with T. gondii develop clinical signs of infection. Often the diagnosis is first appreciated when routine postconception serologic tests show evidence of specific antibody.


InternalMed_Harrison

InternalMed_Harrison. Upon the host’s ingestion of either tissue cysts containing bradyzoites or oocysts containing sporozoites, the parasites are released from the cysts by the digestive process. Bradyzoites are resistant to the effect of pepsin and invade the host’s gastrointestinal tract. Within enterocytes (or other gut-associated cells), the parasites undergo morphologic transformation, giving rise to invasive tachyzoites. These tachyzoites induce a parasite-specific secretory IgA response. From the gastrointestinal tract, parasites disseminate to a variety of organs, particularly lymphatic tissue, skeletal muscle, myocardium, retina, placenta, and the CNS. At these sites, the parasite infects host cells, replicates, and invades the adjoining cells. In this fashion, the hallmarks of the infection develop: cell death and focal necrosis surrounded by an acute inflammatory response.


InternalMed_Harrison

InternalMed_Harrison. In the immunocompetent host, both the humoral and the cellular immune responses control infection; parasite virulence and tissue tropism may be strain specific. Tachyzoites are sequestered by a variety of immune mechanisms, including induction of parasiticidal antibody, activation of macrophages with radical intermediates, production of interferon γ (IFN-γ), and stimulation of CD8+ cytotoxic T lymphocytes. These antigen-specific lymphocytes are capable of killing both extracellular parasites and target cells infected with parasites. As tachyzoites are cleared from the acutely infected host, tissue cysts containing bradyzoites begin to appear, usually within the CNS and the retina. Studies indicate that Toxoplasma secretes signaling molecules into infected host cells and that these molecules modulate host gene expression, host metabolism, and host immune response. While it was initially thought that cysts with bradyzoites are not eliminated by the immune system, recent studies in the


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InternalMed_Harrison. modulate host gene expression, host metabolism, and host immune response. While it was initially thought that cysts with bradyzoites are not eliminated by the immune system, recent studies in the murine model indicate that both CD8+ T cells and alternatively activated macrophages are able to kill cysts in vivo; some cysts persist, however, and the ability to eliminate cysts may depend on the genetic background of the infected host.


InternalMed_Harrison

InternalMed_Harrison. In the immunocompromised or fetal host, the immune factors necessary to control the spread of tachyzoite infection are lacking. This altered immune state allows the persistence of tachyzoites and gives rise to progressive focal destruction that results in organ failure (i.e., necrotizing encephalitis, pneumonia, and myocarditis).


InternalMed_Harrison

InternalMed_Harrison. It is thought that all infected individuals have persistent infection with cysts containing bradyzoites, but this lifelong infection usually remains subclinical. Although bradyzoites are in a slow metabolic phase, cysts do degenerate and rupture within the CNS. This degenerative process, with the development of new bradyzoite-containing cysts, is the most probable source of recrudescent infection in immunocompromised individuals and the most likely stimulus for the persistence of antibody titers in the immunocompetent host. Although the concept is controversial, the persistence of toxoplasmosis has been hypothesized to be a contributing factor to a variety of neuropsychiatric conditions, including schizophrenia and bipolar disease. In rodents, infection clearly has significant effects on behavior, increasing predation.


InternalMed_Harrison

InternalMed_Harrison. Cell death and focal necrosis due to replicating tachyzoites induce an intense mononuclear inflammatory response in any tissue or cell type infected. Tachyzoites rarely can be visualized by routine histopathologic staining of these inflammatory lesions. However, immunofluorescent staining with parasitic antigen–specific antibodies can reveal either the organism itself or evidence of antigen. In contrast to this inflammatory process caused by tachyzoites, bradyzoite-containing cysts cause inflammation only at the early stages of development, and even this inflammation may be a response to the presence of tachyzoite antigens. Once the cysts reach maturity, the inflammatory process can no longer be detected, and the cysts remain immunologically quiescent within the brain matrix until they rupture.


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InternalMed_Harrison. Lymph Nodes During acute infection, lymph node biopsy demonstrates characteristic findings, including follicular hyperplasia and irregular clusters of tissue macrophages with eosinophilic cytoplasm. Granulomas rarely are evident in these specimens. Although tachyzoites are not usually visible, they can be sought either by subinoculation of infected tissue into mice, with resultant disease, or by PCR. PCR amplification of DNA fragments of Toxoplasma genes is effective and sensitive in establishing lymph node infection by tachyzoites. Eyes In the eye, infiltrates of monocytes, lymphocytes, and plasma cells may produce unior multifocal lesions. Granulomatous lesions and chorioretinitis can be observed in the posterior chamber after acute necrotizing retinitis. Other ocular complications include iridocyclitis, cataracts, and glaucoma.


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InternalMed_Harrison. Central Nervous System During CNS involvement, both focal and diffuse meningoencephalitis can be documented, with evidence of necrosis and microglial nodules. Necrotizing encephalitis in patients without AIDS is characterized by small diffuse lesions with perivascular cuffing in contiguous areas. In the AIDS population, polymorphonuclear leukocytes may be present in addition to monocytes, lymphocytes, and plasma cells. Cysts containing bradyzoites frequently are found contiguous with the necrotic tissue border. As a consequence of combined antiretroviral therapy (cART) for AIDS, the incidence of toxoplasmosis has decreased in the developed world. Its incidence in under-resourced settings is not known.


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InternalMed_Harrison. Lungs and Heart Among patients with AIDS who die of toxoplasmosis, 40–70% have involvement of the lungs and heart. Interstitial pneumonitis can develop in neonates and immunocompromised patients. Thickened and edematous alveolar septa infiltrated with mononuclear and plasma cells are apparent. This inflammation may extend to the endothelial walls. Tachyzoites and bradyzoite-containing cysts have been observed within the alveolar membrane. Superimposed bronchopneumonia can be caused by other microbial agents. Cysts and aggregates of parasites in cardiac muscle tissue are evident in patients with AIDS who die of toxoplasmosis. Focal necrosis surrounded by inflammatory cells is associated with hyaline necrosis and disrupted myocardial cells. Pericarditis is associated with toxoplasmosis in some patients.


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InternalMed_Harrison. Gastrointestinal Tract Rare cases of human gastrointestinal tract infection with T. gondii have presented as ulcerations in the mucosa. Acute infection in certain strains of inbred mice (C57BL/6) results in lethal ileitis within 7–9 days. This inflammatory bowel disease has been recognized in several other mammalian species, including pigs and nonhuman primates. Although the association between human inflammatory bowel disease and either acute or recurrent Toxoplasma infection has not been established, studies have demonstrated recognition of the infection by human intestinal epithelial cells, as evidenced by mitogen-activated protein kinase phosphorylation, nuclear factor κB translocation, and interleukin (IL) 8 secretion.


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InternalMed_Harrison. Other Sites Pathologic changes during disseminated infection are similar to those described for the lymph nodes, eyes, and CNS. In patients with AIDS, the skeletal muscle, pancreas, stomach, and kidneys can be involved, with necrosis, invasion by inflammatory cells, and (rarely) tachyzoites detectable by routine staining. Large necrotic lesions may cause direct tissue destruction. In addition, secondary effects from acute infection of these various organs, including pancreatitis, myositis, and glomerulonephritis, have been reported.


InternalMed_Harrison

InternalMed_Harrison. Acute Toxoplasma infection evokes a cascade of protective immune responses in the immunocompetent host. Toxoplasma enters the host at the gut mucosal level and evokes a mucosal immune response that includes the production of antigen-specific secretory IgA. Titers of serum IgA antibody directed at p30 (SAG1) are a useful marker for congenital and acute toxoplasmosis. Milk-whey IgA from acutely infected mothers contains a high titer of antibody to T. gondii and can block infection of enterocytes in vitro. In mice, IgA intestinal secretions directed at the parasite are abundant and are associated with the induction of mucosal T cells.


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InternalMed_Harrison. Within the host, T. gondii rapidly induces detectable levels of both IgM and IgG serum antibodies. Monoclonal gammopathy of the IgG class can occur in congenitally infected infants. IgM levels may be increased in newborns with congenital infection. The polyclonal IgG antibodies evoked by infection are parasiticidal in vitro in the presence of serum complement and are the basis for the Sabin-Feldman dye test. However, cell-mediated immunity is the major protective response evoked by the parasite during host infection. Macrophages are activated after phagocytosis of antibody-opsonized parasites. This activation can lead to death of the parasite by either an oxygen-dependent or an oxygen-independent process. If the parasite is not phagocytosed and enters the macrophage by active penetration, it continues to replicate, and this replication may represent the mechanism for transport and dissemination to distant organs. Toxoplasma stimulates a robust IL-12 response by human dendritic cells.


InternalMed_Harrison

InternalMed_Harrison. it continues to replicate, and this replication may represent the mechanism for transport and dissemination to distant organs. Toxoplasma stimulates a robust IL-12 response by human dendritic cells. The requirement for costimulation via CD40/154 has been established. The CD4+ and CD8+ T cell responses are antigen-specific and further stimulate the production of a variety of important lymphokines that expand the T cell and natural killer cell repertoire. T. gondii is a potent inducer of a TH1 phenotype, with IL-12 and IFN-γ playing an essential role in the control of the parasites’ growth in the host. Regulation of the inflammatory response is at least partially under the control of a TH2 response that includes the production of IL-4 and IL-10 in seropositive individuals. Both asymptomatic patients and those with active infection may have a depressed CD4+-to-CD8+ ratio. This shift may be correlated with a disease syndrome but is not necessarily correlated with disease outcome. Human T


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InternalMed_Harrison. patients and those with active infection may have a depressed CD4+-to-CD8+ ratio. This shift may be correlated with a disease syndrome but is not necessarily correlated with disease outcome. Human T cell clones of both the CD4+ and the CD8+ phenotypes are cytolytic against parasite-infected macrophages. These T cell clones produce cytokines that are “microbistatic.” IL-18, IL-7, and IL-15 upregulate the production of IFN-γ and may be important during acute and chronic infection. The effect of IFN-γ may be paradoxical, with stimulation of a host down-regulatory response as well.


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InternalMed_Harrison. Although T. gondii infection is believed to be recrudescent in patients with AIDS or other immunocompromised states, antibody titers are not useful in establishing reactivation or in following the activity of infection. An absence of positive serologies suggests an alternative diagnosis, although AIDS patients may have borderline positive or low serologies. T cells from AIDS patients with reactivation of toxoplasmosis fail to secrete both IFN-γ and IL-2. This alteration in the production of these critical immune cytokines contributes to the persistence of infection. Toxoplasma infection frequently develops late in the course of AIDS, when the loss of T cell–dependent protective mechanisms, particularly CD8+ T cells, becomes most pronounced.


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InternalMed_Harrison. In persons whose immune systems are intact, acute toxoplasmosis is usually asymptomatic and self-limited. This condition can go unrecognized in 80–90% of adults and children with acquired infection. The asymptomatic nature of this infection makes diagnosis difficult in mothers infected during pregnancy. In contrast, the wide range of clinical manifestations in congenitally infected children includes severe neurologic complications such as hydrocephalus, microcephaly, mental retardation, and chorioretinitis. If prenatal infection is severe, multiorgan failure and subsequent intrauterine fetal death can occur. In children and adults, chronic infection can persist throughout life, 1401 with little consequence to the immunocompetent host.


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InternalMed_Harrison. Toxoplasmosis in Immunocompetent Patients The most common manifestation of acute toxoplasmosis is cervical lymphadenopathy. The nodes may be single or multiple, are usually nontender, are discrete, and vary in firmness. Lymphadenopathy also may be found in suboccipital, supraclavicular, inguinal, and mediastinal areas. Generalized lymphadenopathy occurs in 20–30% of symptomatic patients. Between 20% and 40% of patients with lymphadenopathy also have headache, malaise, fatigue, and fever (usually with a temperature of <40°C [<104°F]). A smaller proportion of symptomatic individuals have myalgia, sore throat, abdominal pain, maculopapular rash, meningoencephalitis, and confusion. Rare complications associated with infection in the normal immune host include pneumonia, myocarditis, encephalopathy, pericarditis, and polymyositis. Signs and symptoms associated with acute infection usually resolve within several weeks, although the lymphadenopathy may persist for some months. In one


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InternalMed_Harrison. pericarditis, and polymyositis. Signs and symptoms associated with acute infection usually resolve within several weeks, although the lymphadenopathy may persist for some months. In one epidemic, toxoplasmosis was diagnosed correctly in only 3 of the 25 patients who consulted physicians. If toxoplasmosis is considered in the differential diagnosis, routine laboratory and serologic screening should precede node biopsy.


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InternalMed_Harrison. It is now appreciated that genotypes of T. gondii prevalent in in North America or Europe. These genotypes may be associated with acute or recurrent ocular disease in immunocompetent individuals and have also been associated with pneumonitis and a fulminant sepsis picture in immunologically normal individuals. Thus a detailed history is critical for establishing a diagnosis.


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InternalMed_Harrison. The results of routine laboratory studies are usually unremarkable except for minimal lymphocytosis, an elevated erythrocyte sedimentation rate, and a nominal increase in serum aminotransferase levels. Evaluation of cerebrospinal fluid (CSF) in cases with evidence of encephalopathy or meningoencephalitis shows an elevation of intra-cranial pressure, mononuclear pleocytosis (10–50 cells/mL), a slight increase in protein concentration, and (occasionally) an increase in the gamma globulin level. PCR amplification of the Toxoplasma DNA target sequence in CSF may be beneficial. The CSF of chronically infected individuals is normal.


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InternalMed_Harrison. Infection of Immunocompromised Patients Patients with AIDS and those receiving immunosuppressive therapy for lymphoproliferative disorders are at greatest risk for developing acute toxoplasmosis. Toxoplasmosis has also been reported after treatment with antibodies to tumor necrosis factor. The infection may be due either to reactivation of latent infection or to acquisition of parasites from exogenous sources such as blood or transplanted organs. In individuals with AIDS, >95% of cases of Toxoplasma encephalitis (TE) are believed to be due to recrudescent infection. In most of these cases, encephalitis develops when the CD4+ T cell count falls below 100/µL. In immunocompromised hosts, the disease may be rapidly fatal if untreated. Thus, accurate diagnosis and initiation of appropriate therapy are necessary to prevent fulminant infection.


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InternalMed_Harrison. Toxoplasmosis is a principal opportunistic infection of the CNS in persons with AIDS. Although geographic origin may be related to frequency of infection, it has no correlation with the severity of disease in immunocompromised hosts. Individuals with AIDS who are seropositive for T. gondii are at high risk for encephalitis. Before the advent of current cART, about one-third of the 15–40% of adult AIDS patients in the United States who were latently infected with T. gondii developed TE. TE may still be a presenting infection in individuals who are unaware of their positive HIV status.


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InternalMed_Harrison. The signs and symptoms of acute toxoplasmosis in immunocompromised patients principally involve the CNS (Fig. 253-2). More than 50% of patients with clinical manifestations have intracerebral involvement. Clinical findings at presentation range from nonfocal to focal dysfunction. CNS findings include encephalopathy, meningoencephalitis, and mass lesions. Patients may present with altered mental status (75%), fever (10–72%), seizures (33%), headaches (56%), and focal neurologic findings (60%), including motor deficits, cranial nerve


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InternalMed_Harrison. FIGuRE 253-2 Toxoplasmic encephalitis in a 36-year-old patient with AIDS. The mul-tiple lesions are demonstrated by MRI scanning (T1-weighted with gadolinium enhance-ment). (Courtesy of Clifford Eskey, Dartmouth Hitchcock Medical Center, Hanover, NH; with permission.) palsies, movement disorders, dysmetria, visual-field loss, and aphasia. Patients who present with evidence of diffuse cortical dysfunction develop evidence of focal neurologic disease as infection progresses. This altered condition is due not only to the necrotizing encephalitis caused by direct invasion by the parasite but also to secondary effects, including vasculitis, edema, and hemorrhage. The onset of infection can range from an insidious process over several weeks to an acute presentation with fulminant focal deficits, including hemiparesis, hemiplegia, visual-field defects, localized headache, and focal seizures.


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InternalMed_Harrison. Although lesions can occur anywhere in the CNS, the areas most often involved appear to be the brainstem, basal ganglia, pituitary gland, and corticomedullary junction. Brainstem involvement gives rise to a variety of neurologic dysfunctions, including cranial nerve palsy, dysmetria, and ataxia. With basal ganglionic infection, patients may develop hydrocephalus, choreiform movements, and choreoathetosis. Toxoplasma usually causes encephalitis, and meningeal involvement is uncommon. CSF findings may be unremarkable or may include a modest increase in cell count and in protein—but not glucose—concentration. Nonetheless, the parasite may be detected by PCR in CSF from many patients with TE.


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InternalMed_Harrison. Cerebral toxoplasmosis must be differentiated from other opportunistic infections or tumors in the CNS of AIDS patients. The differential diagnosis includes herpes simplex encephalitis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma. Involvement of the pituitary gland can give rise to panhypopituitarism and hyponatremia from inappropriate secretion of vasopressin (antidiuretic hormone). HIV-associated neurocognitive disorder (HAND) may present as cognitive impairment, attention loss, and altered memory. Brain biopsy in patients who have been treated for TE but who continue to exhibit neurologic dysfunction often fails to identify organisms.


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InternalMed_Harrison. Autopsies of Toxoplasma-infected patients have demonstrated the involvement of multiple organs, including the lungs, gastrointestinal tract, pancreas, skin, eyes, heart, and liver. Toxoplasma pneumonia can be confused with Pneumocystis pneumonia (PcP). Respiratory involvement usually presents as dyspnea, fever, and a nonproductive cough and may rapidly progress to acute respiratory failure with hemoptysis, metabolic acidosis, hypotension, and (occasionally) disseminated intravascular coagulation. Histopathologic studies demonstrate necrosis and a mixed cellular infiltrate. The presence of organisms is a helpful diagnostic indicator, but organisms can also be found in healthy tissue. Infection of the heart is usually asymptomatic but can be associated with cardiac tamponade or biventricular failure. Infections of the gastrointestinal tract and the liver have been documented.


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InternalMed_Harrison. Congenital Toxoplasmosis Between 400 and 4000 infants born each year in the United States are affected by congenital toxoplasmosis. Acute infection in mothers acquiring T. gondii during pregnancy is usually asymptomatic; most such women are diagnosed via prenatal serologic screening. Infection of the placenta leads to hematogenous infection of the fetus. As gestation proceeds, the proportion of fetuses that become infected increases, but the clinical severity of the infection declines. Although infected children may initially be asymptomatic, the persistence of


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InternalMed_Harrison. T. gondii can result in reactivation and clinical disease—most frequently chorioretinitis—decades later. Factors associated with relatively severe disabilities include delays in diagnosis and in initiation of therapy, neonatal hypoxia and hypoglycemia, profound visual impairment (see “Ocular Infection,” below), uncorrected hydrocephalus, and increased intracranial pressure. If treated appropriately, upwards of 70% of children have normal developmental, neurologic, and ophthalmologic findings at follow-up evaluations. Treatment for 1 year with pyrimethamine, a sulfonamide, and folinic acid is tolerated with minimal toxicity (see “Treatment,” below). Ocular Infection Infection with T. gondii is estimated to cause 35% of all cases of chorioretinitis in the United States and


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InternalMed_Harrison. Europe. It was formerly thought that the majority of cases of ocular disease were due to congenital infection. New ocular toxoplasmosis in immunocompetent individuals occurs more commonly than was previously appreciated and has been associated with outbreaks in Victoria (British Columbia) and in South America. A variety of ocular manifestations are documented, including blurred vision, scotoma, photophobia, and eye pain. Macular involvement occurs, with loss of central vision, and nystagmus is secondary to poor fixation. Involvement of the extraocular muscles may lead to disorders of convergence and to strabismus. Ophthalmologic examination should be undertaken in newborns with suspected congenital infection. As the inflammation resolves, vision improves, but episodic flare-ups of chorioretinitis, which progressively destroy retinal tissue and lead to glaucoma, are common. The ophthalmologic examination reveals yellow-white, cotton-like patches with indistinct margins of hyperemia. As


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InternalMed_Harrison. which progressively destroy retinal tissue and lead to glaucoma, are common. The ophthalmologic examination reveals yellow-white, cotton-like patches with indistinct margins of hyperemia. As the lesions age, white plaques with distinct borders and black spots within the retinal pigment become more apparent. Lesions usually are located near the posterior pole of the retina; they may be single but are more commonly multiple. Congenital lesions may be unilateral or bilateral and show evidence of massive chorioretinal degeneration with extensive fibrosis. Surrounding these areas of involvement are a normal retina and vasculature. In patients with AIDS, retinal lesions are often large, with diffuse retinal necrosis, and include both free tachyzoites and cysts containing bradyzoites. Toxoplasmic chorioretinitis may be a prodrome to the development of encephalitis.


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InternalMed_Harrison. DIAGNOSIS Tissue and Body Fluids The differential diagnosis of acute toxoplasmosis can be made by appropriate culture, serologic testing, and PCR (Table 253-1). Although available only at specialized laboratories, the isolation of T. gondii from blood or other body fluids can be accomplished after subinoculation of the sample into the peritoneal cavity of mice. If no parasites are found in the mouse’s peritoneal fluid 6–10 days after inoculation, its anti-Toxoplasma serum titer can be evaluated 4–6 weeks after inoculation. Isolation of T. gondii from the patient’s body fluids reflects acute infection, whereas isolation from biopsied tissue is an indication only of the presence of tissue cysts and should not be misinterpreted as evidence of acute toxoplasmosis. Persistent parasitemia in patients with latent, asymptomatic infection is rare. Histologic examination of lymph nodes may suggest the characteristic changes described above. Demonstration of tachyzoites in lymph nodes


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InternalMed_Harrison. in patients with latent, asymptomatic infection is rare. Histologic examination of lymph nodes may suggest the characteristic changes described above. Demonstration of tachyzoites in lymph nodes establishes the diagnosis of acute toxoplasmosis. Like subinoculation into mice, histologic demonstration of cysts containing bradyzoites confirms prior infection with T. gondii but is nondiagnostic for acute infection.


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InternalMed_Harrison. Serology The procedures mentioned above have great diagnostic value but are limited by difficulties encountered either in the growth Abbreviations: CNS, central nervous system; PCR, polymerase chain reaction. Source: Adapted from JD Schwartzman: Toxoplasmosis, in Principles and Practice of Clinical Parasitology. Hoboken, Wiley, 2001. of parasites in vivo or in the identification of tachyzoites by histochemical methods. Serologic testing has become the routine method of diagnosis.


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InternalMed_Harrison. Diagnosis of acute infection with T. gondii can be established by detection of the simultaneous presence of IgG and IgM antibodies to Toxoplasma in serum. The presence of circulating IgA favors the diagnosis of an acute infection. The Sabin-Feldman dye test, the indirect fluorescent antibody test, and the enzyme-linked immunosorbent assay (ELISA) all satisfactorily measure circulating IgG antibody to Toxoplasma. Positive IgG titers (>1:10) can be detected as early as 2–3 weeks after infection. These titers usually peak at 6–8 weeks and decline slowly to a new baseline level that persists for life. Antibody avidity increases with time and can be useful in difficult cases during pregnancy for establishing when infection may have occurred. The serum IgM titer should be measured in concert with the IgG titer to better establish the time of infection; either the double-sandwich IgM-ELISA or the IgM-immunosorbent assay (IgM-ISAGA) should be used. Both assays are specific and sensitive, with


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InternalMed_Harrison. the IgG titer to better establish the time of infection; either the double-sandwich IgM-ELISA or the IgM-immunosorbent assay (IgM-ISAGA) should be used. Both assays are specific and sensitive, with fewer false-positive results than other commercial tests. The double-sandwich IgA-ELISA is more sensitive than the IgM-ELISA for detecting congenital infection in the fetus and newborn. Although a negative IgM result with a positive IgG titer indicates distant infection, IgM can persist for >1 year and should not necessarily be considered a reflection of acute disease. If acute toxoplasmosis is suspected, a more extensive panel of serologic tests can be performed. In the United States, testing is available at the Toxoplasma Serology Laboratory at Palo Alto Medical 1403 Foundation (http://www.pamf.org/serology/clinicianguide.html).


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InternalMed_Harrison. T. gondii in biologic samples independent of the serologic response. Results obtained with PCR have suggested high sensitivity, specificity, and clinical utility in the diagnosis of TE, and PCR technology may be becoming more readily available in resource-poor settings. Real-time PCR is a promising technique that can provide quantitative results. Isolates can be genotyped and polymorphic sequences can be obtained, with consequent identification of the precise strain. Molecular epidemiologic studies with polymorphic markers have been useful in correlating clinical signs and symptoms of disease with different T. gondii genotypes.


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InternalMed_Harrison. The Immunocompetent Adult or Child For the patient who presents with lymphadenopathy only, a positive IgM titer is an indication of acute infection—and an indication for therapy, if clinically warranted (see “Treatment,” below). The serum IgM titer should be determined again in 3 weeks. An elevation in the IgG titer without an increase in the IgM titer suggests that infection is present but is not acute. If there is a borderline increase in either IgG or IgM, the titers should be reassessed in 3–4 weeks.


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InternalMed_Harrison. The Immunocompromised Host A presumptive clinical diagnosis of TE in patients with AIDS is based on clinical presentation, history of exposure (as evidenced by positive serology), and radiologic evaluation. To detect latent infection with T. gondii, HIV-infected persons should be tested for IgG antibody to Toxoplasma soon after HIV infection is diagnosed. When these criteria are used, the predictive value is as high as 80%. More than 97% of patients with AIDS and toxoplasmosis have IgG antibody to T. gondii in serum. IgM serum antibody usually is not detectable. Although IgG titers do not correlate with active infection, serologic evidence of infection virtually always precedes the development of TE. It is therefore important to determine the Toxoplasma antibody status of all patients infected with HIV. Antibody titers may range from negative to 1:1024 in patients with AIDS and TE. Fewer than 3% of patients have no demonstrable antibody to Toxoplasma at diagnosis of TE.


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InternalMed_Harrison. Patients with TE have focal or multifocal abnormalities demonstrable by CT or MRI. Neuroradiologic evaluation should include double-dose contrast CT of the head. By this test, single and frequently multiple contrast-enhancing lesions (<2 cm) may be identified. MRI usually demonstrates multiple lesions located in both hemispheres, with the basal ganglia and corticomedullary junction most commonly involved; MRI provides a more sensitive evaluation of the efficacy of therapy than does CT (Fig. 253-2). These findings are not pathognomonic of Toxoplasma infection, because 40% of CNS lymphomas are multifocal and 50% are ring-enhancing. For both MRI and CT scans, the rate of false-negative results is ~10%. The finding of a single lesion on an MRI scan increases the likelihood of primary CNS lymphoma (in which solitary lesions are four times more likely than in TE) and strengthens the argument for the performance of a brain biopsy. A therapeutic trial of anti-Toxoplasma medications is


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InternalMed_Harrison. lymphoma (in which solitary lesions are four times more likely than in TE) and strengthens the argument for the performance of a brain biopsy. A therapeutic trial of anti-Toxoplasma medications is frequently used to assess the diagnosis. Treatment of presumptive TE with pyrimethamine plus sulfadiazine or clindamycin results in quantifiable clinical improvement in >50% of patients by day 3. Leucovorin is administered to prevent bone marrow toxicity. By day 7, >90% of treated patients show evidence of improvement. In contrast, if patients fail to respond or have lymphoma, clinical signs and symptoms worsen by day 7. Patients in this category require brain biopsy with or without a change in therapy. This procedure can now be performed by a stereotactic CT-guided method that reduces the potential for complications. Brain biopsy for T. gondii identifies organisms in 50–75% of cases. PCR amplification of CSF may also confirm toxoplasmosis or suggest alternative diagnoses (Table 253-1), such


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InternalMed_Harrison. for complications. Brain biopsy for T. gondii identifies organisms in 50–75% of cases. PCR amplification of CSF may also confirm toxoplasmosis or suggest alternative diagnoses (Table 253-1), such as progressive multifocal leukoencephalopathy (JC virus positive) or primary CNS lymphoma (Epstein-Barr virus positive).


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InternalMed_Harrison. CT and MRI with contrast are currently the standard diagnostic imaging tests for TE. As in other conditions, the radiologic response may lag behind the clinical response. Resolution of lesions may take 1404 from 3 weeks to 6 months. Some patients show clinical improvement despite worsening radiographic findings. Congenital Infection The issue of concern when a pregnant woman has evidence of recent T. gondii infection is whether the fetus is infected. PCR analysis of the amniotic fluid for the B1 gene of


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InternalMed_Harrison. Congenital Infection The issue of concern when a pregnant woman has evidence of recent T. gondii infection is whether the fetus is infected. PCR analysis of the amniotic fluid for the B1 gene of T. gondii has replaced fetal blood sampling. Serologic diagnosis is based on the persistence of IgG antibody or a positive IgM titer after the first week of life (a time frame that excludes placental leak). The IgG determination should be repeated every 2 months. An increase in IgM beyond the first week of life is indicative of acute infection. Up to 25% of infected newborns may be seronegative and have normal routine physical examinations. Thus assessment of the eye and the brain, with ophthalmologic testing, CSF evaluation, and radiologic studies, is important in establishing the diagnosis.


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InternalMed_Harrison. Ocular Toxoplasmosis The serum antibody titer may not correlate with the presence of active lesions in the fundus, particularly in cases of congenital toxoplasmosis. In general, a positive IgG titer (measured in undiluted serum if necessary) in conjunction with typical lesions establishes the diagnosis. Antibody production in ocular fluids, expressed in terms of the Goldmann-Witmer coefficient, has been described for diagnosis of ocular disease but does not always correlate with PCR results. If lesions are atypical and the serum antibody titer is in the low-positive range, the diagnosis is presumptive. The parasitic antigen–specific polyclonal IgG assay as well as parasite-specific PCR may facilitate the diagnosis. Accordingly, the clinical diagnosis of ocular toxoplasmosis can be supported in 60–90% of cases by laboratory tests, depending on the time of anterior chamber puncture and the panel of antibody analyses used. In the remaining cases, the possibility of a falsely negative


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InternalMed_Harrison. in 60–90% of cases by laboratory tests, depending on the time of anterior chamber puncture and the panel of antibody analyses used. In the remaining cases, the possibility of a falsely negative laboratory diagnosis or of an incorrect clinical diagnosis cannot be clarified further.


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InternalMed_Harrison. Congenitally infected neonates are treated with daily oral pyrimethamine (1 mg/kg) and sulfadiazine (100 mg/kg) with folinic acid for 1 year. Depending on the signs and symptoms, prednisone (1 mg/kg per day) may be used for congenital infection. Some U.S. states and some countries routinely screen pregnant women (France, Austria) and/or newborns (Denmark, Massachusetts). Management and treatment regimens vary with the country and the treatment center. Most experts use spiramycin to treat pregnant women who have acute toxoplasmosis early in pregnancy and use pyrimethamine/ sulfadiazine/folinic acid to treat women who seroconvert after 18 weeks of pregnancy or in cases of documented fetal infection. This treatment is somewhat controversial: clinical studies, which have included few untreated women, have not proven the efficacy of such therapy in preventing congenital toxoplasmosis. However, studies do suggest that treatment during pregnancy decreases the severity of infection. Many


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InternalMed_Harrison. women, have not proven the efficacy of such therapy in preventing congenital toxoplasmosis. However, studies do suggest that treatment during pregnancy decreases the severity of infection. Many women who are infected in the first trimester elect termination of pregnancy. Those who do not terminate pregnancy are offered prenatal antibiotic therapy to reduce the frequency and severity of Toxoplasma infection in the infant. The optimal duration of treatment for a child with asymptomatic congenital toxoplasmosis is not clear, although most clinicians in the United States would treat the child for 1 year in light of cohort investigations conducted by the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study.