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Toxoplasmosis
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Epidemiology

The major mode of transmission of Toxoplasma gondii infection among infants and young children is congenital, occurring almost exclusively among neonates born to women who sustain primary Toxoplasma infection during pregnancy. The estimated incidence of congenital toxoplasmosis in the United States is one case per 1,000-12,000 live-born infants (534Guerina NG, Hsu HW, Meissner HC, et al. Neonatal serologic screening and early treatment for congenital Toxoplasma gondii infection. The New England Regional Toxoplasma Working Group. N Engl J Med 1994;330:1858-63., 535Jara M, Hsu HW, Eaton RB, et al. Epidemiology of congenital toxoplasmosis identified by population-based newborn screening in Massachusetts. Pediatr Infect Dis J 2001;20:1132-5.). The seroprevalence of T. gondii in U.S.-born persons aged 12-49 years declined from 14.1% in the National Health and Nutrition Examination Survey 1988-1994 to 9.0% in 1999-2004 (536Smith KL, Wilson M, Hightower AW, et al. Prevalence of Toxoplasma gondii antibodies in US military recruits in 1989: comparison with data published in 1965. Clin Infect Dis 1996;23:1182-3.). Older children, adolescents, and adults typically acquire Toxoplasma infection by eating poorly cooked meat that contains parasitic cysts or by unintentionally ingesting sporulated oocysts in soil or contaminated food or water (537Jones JL, Kruszon-Moran D, Wilson M, et al. Toxoplasma gondii infection in the United States: seroprevalence and risk factors. Am J Epidemiol 2001;154:357-65.) Cats are the only definitive host for T. gondii . However, cats excrete sporulated oocysts in their feces only transiently after initial infection, and studies have failed to show a correlation between cat ownership and Toxoplasma infection in humans. Indeed, Toxoplasma infection in humans in the United States has declined despite increased cat ownership (537Jones JL, Kruszon-Moran D, Wilson M, et al. Toxoplasma gondii infection in the United States: seroprevalence and risk factors. Am J Epidemiol 2001;154:357-65.).

The overall risk for maternal-fetal transmission in HIV-uninfected women who acquire primary Toxoplasma infection during pregnancy is 29% (95% confidence interval [CI]: 25%-33%) (538Dunn D, Wallon M, Peyron F, et al. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling Lancet 1999;353:1829-33.). The risk for congenital infection is low among infants born to women who become infected during the first trimester (range: 2%-6%) but increases sharply thereafter, with a risk as high as 81% for women acquiring infection during the last few weeks of pregnancy (538Dunn D, Wallon M, Peyron F, et al. Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counselling Lancet 1999;353:1829-33., 539Montoya JG. Laboratory diagnosis of Toxoplasma gondii infection and toxoplasmosis. J Infect Dis 2002;185(Suppl 1):S73-82.). Infection of the fetus in early gestation usually results in more severe disease than does infection late in gestation.

The prevalence of latent Toxoplasma infection among women with and without HIV infection in the United States was assessed in a cross-sectional study of 2525 nonpregnant women enrolled in the Women's Interagency Health Study (540Falusi O, French AL, Seaberg EC, et al. Prevalence and predictors of Toxoplasma seropositivity in women with and at risk for human immunodeficiency virus infection. Clin Infect Dis 2002;35:1414-7.). The prevalence of Toxoplasma seropositivity was 15% and did not differ by HIV infection status. A few cases of mother-to-infant transmission of Toxoplasma in HIV-infected women have been reported (541Minkoff H, Remington JS, Holman S, et al. Vertical transmission of Toxoplasma by human immunodeficiency virus-infected women. Am J Obstet Gynecol 1997;176:555-9., 542Dunn D, Newell ML, Gilbert R. Low risk of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus. Pediatr Infect Dis J 1997;16:84., 543Dunn DT, Newell ML, Gilbert R, et al. Low incidence of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus. European Collaborative Study and Research Network on Congenital Toxoplasmosis. Eur J Obstet Gynecol Reprod Biol 1996;68:93-6., 544Mitchell CD, Erlich SS, Mastrucci MT, et al. Congenital toxoplasmosis occurring in infants perinatally infected with human immunodeficiency virus 1. Pediatr Infect Dis J 1990;9:512-8., 545D'Offizi G, Topino S, Anzidei G, et al. Primary Toxoplasma gondii infection in a pregnant human immunodeficiency virus-infected woman. Pediatr Infect Dis J 2002;21:981-2.). Prenatal transmission of T. gondii from women without HIV infection who have chronic Toxoplasma infection acquired before pregnancy is rare (546Vogel N, Kirisits M, Michael E, et al. Congenital toxoplasmosis transmitted from an immunologically competent mother infected before conception. Clin Infect Dis 1996;23:1055-60.). However, with HIV coinfection, perinatal transmission of Toxoplasma has been observed among women with chronic Toxoplasma infection (transmission rate:<4%), presumably because of reactivation of replication of the organism among women with severe immune suppression (541Minkoff H, Remington JS, Holman S, et al. Vertical transmission of Toxoplasma by human immunodeficiency virus-infected women. Am J Obstet Gynecol 1997;176:555-9., 542Dunn D, Newell ML, Gilbert R. Low risk of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus. Pediatr Infect Dis J 1997;16:84., 543Dunn DT, Newell ML, Gilbert R, et al. Low incidence of congenital toxoplasmosis in children born to women infected with human immunodeficiency virus. European Collaborative Study and Research Network on Congenital Toxoplasmosis. Eur J Obstet Gynecol Reprod Biol 1996;68:93-6., 544Mitchell CD, Erlich SS, Mastrucci MT, et al. Congenital toxoplasmosis occurring in infants perinatally infected with human immunodeficiency virus 1. Pediatr Infect Dis J 1990;9:512-8.).

CNS infection with T. gondii was reported as an AIDS-indicator condition in <1% of pediatric AIDS cases before the advent of HAART (547CDC. HIV/AIDS surveillance report. 1996:8(2):1-18.). During the HAART era, this condition is rarely encountered in U.S. children with HIV infection. Development of CNS toxoplasmosis in HIV-infected children during the HAART era occurred in 0.2% (five of 2767) of those enrolled in the long-term follow-up study PACTG 219c (3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.). In most cases of Toxoplasma encephalitis (TE) among HIV-infected children, infection is considered to have occurred in utero. More rarely, it has been reported among older HIV-infected children, who presumably had primary acquired toxoplasmosis (548Sobanjo A, Ferguson DJ, Gross U. Primary acquired toxoplasmosis in a five-year-old child with perinatal human immunodeficiency virus type 1 infection. Pediatr Infect Dis J 1999;18:476-8., 549Wahn V, Kramer HH, Voit T, et al. Horizontal transmission of HIV infection between two siblings. Lancet 1986;2:694., 550King SM, Matlow A, Al-Hajjar S, et al. Toxoplasmic encephalitis in a child with HIV infection-United States. Pediatr AIDS and HIV Infect. Fetus to Adolesc 1992: 3:242-4.). As in adults, the greatest risk is among severely immunosuppressed children (e.g., CD4 count <50 cells/mm3).

Clinical Manifestations

In studies of nonimmunocompromised infants with congenital toxoplasmosis, most infants (70%-90%) are asymptomatic at birth.However, most asymptomatic children develop late sequelae (e.g., retinitis, visual impairment, and intellectual or neurologic impairment),with onset of symptoms ranging from several months to years after birth. Symptoms in newborns take either of two presentations: generalized disease or predominantly neurologic disease. Symptoms might include maculopapular rash; generalized lymphadenopathy; hepatosplenomegaly; jaundice; hematologic abnormalities, including anemia, thrombocytopenia, and neutropenia; and substantial CNS disease, including hydrocephalus, intracerebral calcification, microcephaly, chorioretinitis, and seizures (551McAuley J, Boyer KM, Patel D, et al. Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial. Clin Infect Dis 1994;18:38-72.).

Similarly, toxoplasmosis acquired after birth is most often initially asymptomatic. When symptoms occur, they are frequently nonspecific and can include malaise, fever, sore throat, myalgia, lymphadenopathy (cervical), and a mononucleosis- like syndrome featuring a maculopapular rash and hepatosplenomegaly.

TE should be considered among all HIV-infected children with new neurologic findings. Although focal findings are more typical, the initial presentation can vary and reflect diffuse CNS disease. Other symptoms include fever, reduced alertness, and seizures.

Isolated ocular toxoplasmosis is rare and usually occurs in association with CNS infection. As a result, a neurologic examination is indicated for children in whom Toxoplasma chorioretinitis is diagnosed. Ocular toxoplasmosis appears as white retinal lesions with little associated hemorrhage; visual loss might occur initially.

Less frequent presentations among HIV-infected children with reactivated chronic toxoplasmosis include systemic toxoplasmosis, pneumonitis, hepatitis, and cardiomyopathy/ myocarditis (544Mitchell CD, Erlich SS, Mastrucci MT, et al. Congenital toxoplasmosis occurring in infants perinatally infected with human immunodeficiency virus 1. Pediatr Infect Dis J 1990;9:512-8., 552Medlock MD, Tilleli JT, Pearl GS. Congenital cardiac toxoplasmosis in a newborn with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1990;9:129-32.).

Diagnosis

HIV-infected women might be at increased risk for transmitting T. gondii to their fetuses, and serologic testing for Toxoplasma should be performed for all HIV-infected pregnant women. All infants whose mothers are both HIV-infected and seropositive for Toxoplasma should be evaluated for congenital toxoplasmosis (90American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006.). Congenital toxoplasmosis can be diagnosed by EIA or an immunosorbent assay to detect Toxoplasma -specific IgM, IgA, or IgE in neonatal serum within the first 6 months of life or persistence of specific IgG antibody beyond age 12 months (553Pinon JM, Dumon H, Chemla C, et al. Strategy for diagnosis of congenital toxoplasmosis: evaluation of methods comparing mothers and newborns and standard methods for postnatal detection of immunoglobulin G, M, and A antibodies. J Clin Microbiol 2001;39:2267-71., 554Wilson M, Jones JL, McAuley JB. Toxoplasma. In: Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA, eds. Manual of clinical microbiology, 9th ed. St. Louis, MO: ASM Press; 2007:2070-81., 555Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;363:1965-76., 556Wong SY, Hajdu MP, Ramirez R, et al. Role of specific immunoglobulin E in diagnosis of acute Toxoplasma infection and toxoplasmosis. J Clin Microbiol 1993;31:2952-9.). IgA might be more sensitive for detecting congenital infection than IgM or IgE (554Wilson M, Jones JL, McAuley JB. Toxoplasma. In: Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA, eds. Manual of clinical microbiology, 9th ed. St. Louis, MO: ASM Press; 2007:2070-81.). However, approximately 20%-30% of infants with congenital toxoplasmosis will not be identified during the neonatal period with IgA or IgM assays (555Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;363:1965-76.).

Serologic testing is the major method of diagnosis, but interpretation of assays often is confusing and difficult. Using the services of a specialized reference laboratory that can perform serology, isolation of organisms, and PCR and offers assistance in interpreting results, especially when attempting to diagnose congenital toxoplasmosis, can be helpful (554Wilson M, Jones JL, McAuley JB. Toxoplasma. In: Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA, eds. Manual of clinical microbiology, 9th ed. St. Louis, MO: ASM Press; 2007:2070-81.).

Additional methods that can be used to diagnose infection in the newborn include isolation of the Toxoplasma parasite by mouse inoculation or inoculation in tissue cultures of CSF, urine, placental tissue, amniotic fluid, or infant blood. T. gondii DNA can be detected by PCR performed on clinical specimens (e.g., white blood cells, CSF, amniotic fluid, or tissue) in a reference laboratory (554Wilson M, Jones JL, McAuley JB. Toxoplasma. In: Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA, eds. Manual of clinical microbiology, 9th ed. St. Louis, MO: ASM Press; 2007:2070-81., 555Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;363:1965-76.). If a possible diagnosis of congenital toxoplasmosis at delivery is uncertain, the neonate should be evaluated, including ophthalmologic, auditory, and neurologic examinations; lumbar puncture; and imaging of the head (either CT or magnetic resonance imaging [MRI] scans) to determine whether hydrocephalus or calcifications are present.

In the United States, routine Toxoplasma serologic screening of HIV-infected children whose mothers do not have toxoplasmosis is not recommended because of its low prevalence. However, in regions with high incidence of Toxoplasma infection (≥1% per year), serologic testing might be selectively considered for HIV-infected children aged >12 months. HIV-infected adolescents without previous Toxoplasma infection should undergo serologic testing.

CNS toxoplasmosis is presumptively diagnosed on the basis of clinical symptoms, serologic evidence of infection, and presence of a space-occupying lesion on imaging studies of the brain (557Portegies P, Solod L, Cinque P, et al. Guidelines for the diagnosis and management of neurological complications of HIV infection. Eur J Neurol 2004;11:297-304.). TE rarely has been reported in persons without Toxoplasma -specific IgG antibodies; therefore, negative serology does not definitively exclude that diagnosis. CT of the brain might indicate multiple, bilateral, ring-enhancing lesions in CNS toxoplasmosis, especially in the basal ganglia and cerebral corticomedullary junction. MRI is more sensitive and will confirm basal ganglia lesions in most patients (558Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clin Radiol 2006;61:393-401.). F-fluoro- 2-deoxyglucose-positive emission tomography reportedly is helpful in adults in distinguishing Toxoplasma abscesses from primary CNS lymphoma, but the accuracy is not high, and this test is not widely available.

Definitive diagnosis of TE requires histologic or cytologic confirmation by brain biopsy, which might demonstrate leptomeningeal inflammation, microglial nodules, gliosis, and Toxoplasma cysts. Brain biopsy is reserved by some experts for patients who do not respond to specific therapy.

Prevention Recommendations
Preventing Exposure

All HIV-infected children and adolescents and their caregivers should be counseled about sources of T. gondii infection. They should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison (BIII). All meat (lamb, beef, pork, and chicken) should be cooked to an internal temperature of 165ºF-170ºF (559U.S. Department of Agriculture. FoodSafety.gov: gateway to government food safety information. Washington, DC: US Departent of Agriculture, 2002. Available at http://www.foodsafety.gov.) until it is no longer pink inside. Hands should be washed after contact with raw meat and after gardening or other contact with soil; in addition, fruits and vegetables should be washed well before being eaten raw (BIII). Stray cats should not be handled or adopted; a cat already in the household should be kept inside and the litter box changed daily, preferably by an HIV-negative, nonpregnant person (BIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII). Patients need not be advised to part with their cats or to have their cats tested for toxoplasmosis (EII).

Preventing First Episode of Disease

Toxoplasma -seropositive adolescents and adults who have a CD4 count of <100 cells/mm3 should be administered prophylaxis against TE (AII) (435Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim- sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992;117:106-11.). Specific levels of immunosuppression that increase the risk for TE in children are less well defined. Toxoplasma -seropositive children with CD4 <15% should be administered prophylaxis against TE (AIII). For children aged ≥6 years, the same absolute CD4 cell count level used for HIV-infected adults can be used (AIII).

In HIV-infected adolescents and adults, the double-strength tablet daily dose of TMP-SMX recommended as the preferred regimen for PCP prophylaxis is effective TE prophylaxis (AII) (435Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim- sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992;117:106-11.). TMP-SMX, one double-strength tablet three times weekly (or 3 consecutive days a week), is an alternative (BIII). Data are limited on the efficacy of TMP-SMX as a primary preventive agent for TE in children. However, data on adults suggest it also is the regimen of choice in children (BIII) (Table 1). If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine, which also is effective against PCP (BI) (560Podzamczer D, Salazar A, Jimenez J, et al. Intermittent trimethoprim- sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med 1995; 122:755-61., 561Opravil M, Hirschel B, Lazzarin A, et al. Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clin Infect Dis 1995;20:531-41.). Atovaquone with or without pyrimethamine also can be considered (CIII). Singledrug prophylaxis with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI) (435Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim- sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med 1992;117:106-11., 436Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med 1995;332:693-9.). Toxoplasma-seronegative adults and adolescents who are not taking a PCP-prophylactic regimen known to be active against TE should be retested for IgG antibody to Toxoplasma when their CD4 count declines to <100 cells/mm3 to determine whether they have seroconverted and are therefore at risk for TE (CIII). Severely immunosuppressed children who are not receiving TMP-SMX or atovaquone who are seropositive for Toxoplasma should be administered prophylaxis for both PCP and toxoplasmosis (i.e., dapsone plus pyrimethamine) (BIII).

Discontinuing Primary Prophylaxis

Prophylaxis against TE should be discontinued among HIVinfected adults and adolescents who have responded to HAART with an increase in CD4 count to >200 cells/mm3 for >3 months (AI). Multiple observational studies (447Dworkin MS, Hanson DL, Kaplan JE, et al. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis 2000;182:611-5., 562Kirk O, Lundgren JD, Pedersen C, et al. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS 1999;13:1647-51., 563Furrer H, Opravil M, Bernasconi E, et al. Stopping primary prophylaxis in HIV-1-infected patients at high risk of Toxoplasma,/i> encephalitis. Swiss HIV Cohort Study. Lancet 2000;355:2217-8.) and two randomized trials (564Mussini C, Pezzotti P, Govoni A, et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis 2000;181:1635-42., 565Miro JM, Lopez JC, Podzamczer D, et al. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006;43:79-89.) have reported that primary prophylaxis can be discontinued with minimal risk for TE recrudescence among patients who have responded to HAART with an increase in CD4 count from <200 cells/mm3 to ≥200 cells/mm3 for >3 months. Although patients with CD4 counts of <100 cells/ mm3 are at greatest risk for TE, the risk for TE when CD4 count increases to 100-200 cells/mm3 has not been studied as rigorously as an increase to >200 cells/mm3. Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/mm3. Discontinuing primary TE prophylaxis is recommended because prophylaxis adds limited disease prevention for toxoplasmosis and because discontinuing drugs reduces pill burden, the potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost. Data do not exist on the safety of discontinuing primary TE prophylaxis for HIVinfected children whose CD4 percentage rises above 15%. Data on adults suggest discontinuation of TMP-SMX may be safe once a child responds to HAART with a sustained rise in CD4 percentage above 15%; for children aged ≥6 years, the same CD4 count used for HIV-infected adults can be used (CIII).

Prophylaxis should be reintroduced in HIV-infected adults and adolescents if the CD4 count decreases to <100-200 cells/ mm3 (AIII) or the CD4 percentage falls below 15% for HIVinfected children (BIII).

Treatment Recommendations
Treatment of Disease

Pregnant women with suspected or confirmed primary toxoplasmosis and newborns with possible or documented congenital toxoplasmosis should be managed in consultation with an appropriate specialist. Although controversy exists about the efficacy of treating pregnant women who have acute toxoplasmosis in an attempt to prevent infection of the fetus (566SYROCOT (Systematic Review on Congenital Toxoplasmosis) Study Group, Thiébaut R, Leproust S, et al. Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data. Lancet 2007;369:115-22.), most experts would recommend such therapy (BII) (90American Academy of Pediatrics. Red book: 2006 report of the Committee on Infectious Diseases. 27th ed. Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Elk Grove Village, IL;2006.). For an HIV-infected woman with a symptomatic Toxoplasma infection during pregnancy, empiric therapy of the newborn should be strongly considered, regardless of whether the mother was treated during pregnancy (BIII).

The preferred treatment for congenital toxoplasmosis is pyrimethamine combined with sulfadiazine, with supplementary leucovorin (folinic acid) to minimize pyrimethamine-associated hematologic toxicity (AII) (551McAuley J, Boyer KM, Patel D, et al. Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial. Clin Infect Dis 1994;18:38-72., 567McLeod R, Boyer K, Karrison T, et al. Outcome of treatment for congenital toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based Congenital Toxoplasmosis Study. Clin Infect Dis 2006;42:1383-94.). Although the optimal duration of therapy is undefined, the recommended duration of treatment of congenital toxoplasmosis for infants without HIV infection is 12 months (AII) (567McLeod R, Boyer K, Karrison T, et al. Outcome of treatment for congenital toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based Congenital Toxoplasmosis Study. Clin Infect Dis 2006;42:1383-94.).

For HIV-uninfected children who have mild congenital toxoplasmosis, certain experts alternate pyrimethamine/sulfadiazine/ folinic acid monthly with spiramycin during months 7-12 of treatment (CIII). However, for children with moderate to severe disease and children with HIV infection, the full 12-month regimen of pyrimethamine/sulfadiazine should be administered (AII).

HIV-infected children with acquired CNS, ocular, or systemic toxoplasmosis should be treated with pyrimethamine and leucovorin plus sulfadiazine (AI). Acute therapy should be continued for 6 weeks, assuming clinical and radiologic improvement (BII). Longer courses of treatment might be required for extensive disease or poor response after 6 weeks. The primary alternative for sulfadiazine in patients who develop sulfonamide hypersensitivity is clindamycin, administered with pyrimethamine and leucovorin (AI). Azithromycin instead of clindamycin also has been used with pyrimethamine and leucovorin among sulfa-allergic adults, but this regimen has not been studied among children (CIII).

Another alternative in adults is atovaquone plus pyrimethamine and leucovorin, or atovaquone with sulfadiazine alone, or atovaquone as a single agent among patients intolerant to both pyrimethamine and sulfadiazine (BII); however, these regimens have not been studied in children (CIII). TMP-SMX alone has been used as an alternative to pyrimethamine-sulfadiazine in adults but not in children (CIII).

For isolated ocular toxoplasmosis in nonimmunocompromised hosts, TMP-SMX alone is as effective as pyrimethamine-sulfadiazine (568Soheilian M, Sadoughi MM, Ghajarnia M, et al. Prospective randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis. Ophthalmology 2005;112:1876-82.). However, these data have not been duplicated in HIV-infected persons; therefore, this regimen cannot be recommended for this group of patients (DIII).

Corticosteroids (e.g., dexamethasone or prednisone) are recommended for children with CNS disease when CSF protein is highly elevated (i.e., >1000 mg/dL) or with focal lesions with substantial mass effects (BIII). Because of the potential immunosuppressive effects of steroids, they should be discontinued as soon as possible.

Anticonvulsants should be administered to children with TE who have a history of seizures (AIII) but should not be administered prophylactically to children without a history of seizures (DIII). Anticonvulsants, if administered, should be continued at least through acute therapy.

Monitoring and Adverse Events, Including IRIS

Children with TE should be routinely monitored for clinical and radiologic improvement and for adverse effects of treatment; changes in antibody titers are not useful for monitoring responses to therapy.

Toxoplasmosis-associated IRIS has been described rarely in HIV-infected adults and has not been described in HIVinfected children (569Lawn SD. Immune reconstitution disease associated with parasitic infections following initiation of antiretroviral therapy. Curr Opin Infect Dis 2007;20:482-8.).

Pyrimethamine can be associated with rash (including Stevens-Johnson syndrome) and nausea. The primary toxicity of pyrimethamine is reversible bone marrow suppression (i.e., neutropenia, anemia, and thrombocytopenia). A complete blood count should be performed at least weekly while the child is on daily pyrimethamine and at least monthly while on less-than-daily dosing (AIII). Leucovorin (folinic acid) always should be administered with pyrimethamine; increased doses of leucovorin might be required in the event of marrow suppression. Because of the long half-life of pyrimethamine, leucovorin should be continued 1 week after pyrimethamine has been discontinued.

Adverse effects of sulfadiazine include rash, fever, leukopenia, hepatitis, GI symptoms (e.g., nausea, vomiting, and diarrhea), and crystalluria. Clindamycin can be associated with fever, rash, and GI symptoms (e.g., nausea; vomiting; and diarrhea, including pseudomembranous colitis) and hepatotoxicity. Drug interactions between anticonvulsants and antiretrovirals should be evaluated. Patients receiving corticosteroids should be closely monitored for development of other OIs.

Management of Treatment Failure

Brain biopsy should be considered in the event of early clinical or radiologic neurologic deterioration despite adequate empiric treatment or in children who do not clinically respond to anti-Toxoplasma therapy after 10-14 days. For children who undergo brain biopsy and have confirmed histopathologic evidence of TE despite treatment, a switch to an alternative regimen as previously described should be considered (BIII).

Prevention of Recurrence

Patients who have completed initial therapy for acquired TE should be administered lifelong suppressive therapy (i.e., secondary prophylaxis or chronic maintenance therapy) (AI) (570Katlama C, De Wit S, O'Doherty E, et al. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996;22:268-75., 571Dannemann B, McCutchan JA, Israelski D, et al. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group. Ann Intern Med 1992;116:33-43.) unless immune reconstitution occurs with antiretroviral therapy (Table 3). The combination of pyrimethamine plus sulfadiazine plus leucovorin is highly effective for this purpose (AI). A commonly used regimen for patients who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin (BI); however, only the combination of pyrimethamine plus sulfadiazine provides protection against PCP as well (AII). Data on adults indicate atovaquone with or without pyrimethamine also can be considered for children (CIII). Limited data support the use of TMP-SMX for secondary prophylaxis (572Duval X, Pajot O, Le Moing V, et al. Maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy. AIDS 2004;18:1342-4.); this regimen should be used only for persons who do not tolerate pyrimethamine plus sulfadiazine or pyrimethamine plus clindamycin (CII).

Discontinuing Secondary Prophylaxis

Adults and adolescents receiving secondary prophylaxis for acquired TE are at low risk for recurrence of TE when they have successfully completed their initial therapy, continue to have no signs or symptoms of TE, and have a sustained increase in CD4 count of >200 cells/mm3 after HAART (e.g., >6 months) (562Kirk O, Lundgren JD, Pedersen C, et al. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS 1999;13:1647-51., 563Furrer H, Opravil M, Bernasconi E, et al. Stopping primary prophylaxis in HIV-1-infected patients at high risk of Toxoplasma,/i> encephalitis. Swiss HIV Cohort Study. Lancet 2000;355:2217-8., 565Miro JM, Lopez JC, Podzamczer D, et al. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006;43:79-89., 573Soriano V, Dona C, Rodriguez-Rosado R, et al. Discontinuation of secondary prophylaxis for opportunistic infections in HIVinfected patients receiving highly active antiretroviral therapy. AIDS 2000;14:383-6., 574Bertschy S, Opravil M, Cavassini M, et al. Discontinuation of maintenance therapy against Toxoplasma encephalitis in AIDS patients with sustained response to anti-retroviral therapy. Clin Microbiol Infect 2006;12:666-71.). Discontinuing chronic maintenance therapy in HIV-infected adolescents and adults who meet these criteria is a reasonable consideration (BI). Highest risk for relapse appears to occur within the first 6 months after stopping secondary prophylaxis. Certain specialists would obtain an MRI of the brain as part of their evaluation to determine whether discontinuing therapy is appropriate. The safety of discontinuing secondary prophylaxis after immune reconstitution with HAART among children has not been studied extensively. However, given the data in adults, clinicians caring for HIV-infected children aged 1-5 years can consider discontinuing secondary prophylaxis against T. gondii after they have completed TE therapy and ≥6 months of stable HAART and are asymptomatic and once the CD4 percentage has risen to ≥15% for >3 consecutive months. For children aged ≥6 years, the same CD4 count used in adults (CD4 >200 cells/mm3) also can be used (BIII). Prophylaxis should be reinstituted if these parameters are not met.

Prophylaxis to prevent first episode of opportunistic infections among HIV-exposed and HIV-infected infants and children, United States*†
Preventive regimen

Excerpted from Table 1

* Abbreviations: HIV = human immunodeficiency virus; PCP = Pneumocystis pneumonia; TMP-SMX = trimethoprim-sulfamethoxazole; TST = tuberculin skin test; TB = tuberculosis; IM = intramuscularly; IVIG = intravenous immune globulin; IgG = immunoglobulin G; CMV = cytomegalovirus; VZV = varicella-zoster virus; FDA = Food and Drug Administration.

† Information in these guidelines might not represent FDA approval or FDA-approved labeling for products or indications. Specifically, the terms “safe” and “effective” might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendation and the quality of the evidence supporting it (see Box).

§§ Daily trimethoprim-sulfamethoxazole (TMP-SMX) reduces the frequency of certain bacterial infections. TMP-SMX, dapsone-pyrimethamine, and possibly atovaquone (with or without pyrimethamine) protect against toxoplasmosis; however, data have not been prospectively collected. Compared with weekly dapsone, daily dapsone is associated with lower incidence of PCP but higher hematologic toxicity and mortality. Patients receiving therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected against PCP and do not need TMP-SMX.

¶ Substantial drug interactions can occur between rifamycins (i.e., rifampin and rifabutin) and protease inhibitors and non-nucleoside reverse transcriptase inhibitors. A specialist should be consulted.

** Children routinely being administered intravenous immune globulin (IVIG) should receive VariZIG if the last dose of IVIG was administered >21 days before exposure.

†† As of 2007, VariZIG can be obtained only under a treatment Investigational New Drug protocol (1-800-843-7477, FFF Enterprises, Temecula, California.)

§§ Protection against toxoplasmosis is provided by the preferred anti-Pneumocystis regimens and possibly by atovaquone.

PathogenIndicationFirst choiceAlternative
Usually recommended
Toxoplasma gondii§§

Immunoglobulin G (Ig>G) antibody to Toxoplasma and severe immunosuppression: HIV-infected children aged <6 yrs with CD4 <15%; HIV-infected children aged ≥6 yrs with CD4 <100 cells/mm3 (BIII)

transparent gifgrey bulletTMP-SMX, 150/750 mg/m2 body surface area daily orally in 2 divided doses (BIII)
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transparent gifgrey bulletAcceptable alternative dosage schedules for same dosage (AI): single dose orally 3 times weekly on consecutive days; 2 divided doses orally daily; or 2 divided doses orally 3 times weekly on alternate days
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transparent gifgrey bulletDapsone (children aged ≥1 mos), 2 mg/kg body weight or 15 mg/m2 body surface area (max 25 mg) orally daily, PLUS pyrimethamine, 1 mg/kg body weight (max 25 mg) orally daily; PLUS leucovorin, 5 mg orally every 3 days (BI)
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transparent gifgrey bulletAtovaquone (children aged 1-3 mos and >24 mos,30 mg/kg body weight orally daily; children aged 4-24 mos, 45 mg/kg body weight orally daily) with or without pyrimethamine, 1 mg/kg body weight or 15 g/m2 body surface area (max 25 mg) orally daily; PLUS leucovorin, 5 mg orally every 3 days (CIII)
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Not recommended for most children; indicated for use only in unusual circumstances
Invasive bacterial infections

Hypogammaglobulinemia (i.e., IgG <400 mg/dL)

transparent gifgrey bulletIVIG (400 mg/kg body weight every 2-4 wks) (AI)
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Cytomegalovirus

CMV antibody positivity and severe immunosuppression (CD4 <50 cells/mm3)

transparent gifgrey bulletValganciclovir, 900 mg orally 1 time daily with food for older children who can receive adult dosing (CIII)
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Prophylaxis to prevent recurrence of opportunistic infections, after chemotherapy for acute disease, among HIV-exposed and HIV-infected infants and children, United States*†:Toxoplasma gondii
Preventive regimen

Excerpted from Table 2

* Information in these guidelines might not represent FDA approval or FDA-approved labeling for products or indications. Specifically, the terms “safe”and “effective” might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box).

† Abbreviations: HIV—human immunodeficiency virus; FDA—Food and Drug Administration; PCP—Pneumocystis pneumonia; TMP-SMX—trimethoprim-sulfamethoxazole; HAART—highly active antiretroviral treatment; IV—intravenous; IVIG—intravenous immune globulin.

§§ Pyrimethamine plus sulfadiazine, and possibly atovaquone, confers protection against PCP as well as against toxoplasmosis. Although the clindamycin-plus-pyrimethamine or atovaquone-with/without-pyrimethamine regimens are recommended for adults, they have not been tested in children. However, these drugs are safe and are used for other infections in children.

¶ Substantial drug interactions might occur between rifabutin and protease inhibitors and non-nucleoside reverse transcriptase inhibitors. A specialist should be consulted.

** Antimicrobial prophylaxis should be chosen on the basis of microorganism identification and antibiotic susceptibility testing. TMP-SMX, if used, should be administered daily. Health-care providers should be cautious about using antibiotics solely for this purpose because of the potential for development of drug-resistant microorganisms. IVIG might not provide additional benefit to children receiving daily TMP/SMX but might be considered for children who have recurrent bacterial infections despite TMP-SMX prophylaxis. Choice of antibiotic prophylaxis versus IVIG also should involve consideration of adherence, ease of IV access, and cost. If IVIG is used, respiratory syncytial virus (RSV) IVIG (750 mg/kg body weight), not monoclonal RSV antibody, can be substituted for IVIG during the RSV season to provide broad anti-infective protection, if this product is available.

IndicationFirst choiceAlternative
Recommended as standard of care after completion of initial therapy
Before Toxoplasma encephalitis

Sulfadiazine, 85-120 mg/kg body weight (max 2-4 g) daily orally divided into in 2-4 doses; PLUS pyrimethamine, 1 mg/kg body weight or 15 mg/m2 body surface area (max 25 mg) orally daily; PLUS leucovorin, 5 mg orally every 3 days (AI)

Clindamycin, 20-30 mg/kg body weight daily orally divided into 3-4 doses; PLUS pyrimethamine, 1 mg/kg body weight or 15 mg/m2 body surface area (max 25 mg) orally daily; PLUS leucovorin, 5 mg orally every 3 days (BI)

Atovaquone (children aged 1-3 mos and >24 mos, 30 mg/kg body weight orally daily; children aged 4-24 mos, 45 mg/kg body weight orally daily) with or without pyrimethamine, 1 mg/kg body weight or 15 mg/m2 body surface area (max 25 mg) orally daily; PLUS leucovorin, 5 mg orally every 3 days (CIII)

Criteria for discontinuing and restarting prophylaxis for opportunistic infections among HIV-exposed and HIV-infected infants and children, United States*: Toxoplasma gondii encephalitis
Criteria for discontinuing primary prophylaxisCriteria for restarting primary prophylaxisCriteria for discontinuing secondary prophylaxisCriteria for restarting secondary prophylaxis

Excerpted from Table 3

* Abbreviations: HIV=human immunodeficiency virus; PCP=Pneumocystis pneumonia; HAART: highly active antiretroviral treatment; TE=Toxoplasma encephalitis; MAC=Mycobacterium avium complex.

Do not discontinue in children aged <1 yr

After ≥6 mos of HAART and

transparent gifgrey bullet Age 1-5 yrs: CD4 percentage ≥15% for >3 consecutive mos (CIII)
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transparent gifgrey bullet Age ≥6 yrs: CD4 percentage ≥15% or count >100-200 cells/mm3 for >3 consecutive mos (CIII)
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Age 1-5 yrs: CD4 percentage <15% (CIII)

Age ≥6 yrs: CD4 percentage <15% or count <100-200 cells/mm3 (CIII)

If all of the following criteria fulfilled (CIII):

transparent gifgrey bulletCompleted ≥6 mos of HAART
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transparent gifgrey bulletCompleted initial therapy for TE
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transparent gifgrey bulletAsymptomatic for TE
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transparent gifgrey bulletAge 1-5 yrs: CD4 percentage ≥15% or count>500 cells/mm3 for >3 consecutive mos (CIII)
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transparent gifgrey bulletAge ≥6 yrs: CD4 percentage ≥15% or count >200 cells/mm3 for >3 consecutive mos (CIII)
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Age 1-5 yrs: CD4 percentage <15% or count <500 cells/mm3 (CIII)

Age ≥6 yrs: CD4 percentage <15% or count <200 cells/mm3 (BIII)

Recommendations for treatment of opportunistic infections in HIV-exposed and HIV-infected infants and children, United States*†: Toxoplasma gondii
Preferred therapies and durationAlternative therapiesOther options or issues

Excerpted from Table 4

* HIV=human immunodeficiency virus; PCP=Pneumocystis pneumonia; TB=tuberculosis; IV=intravenous; IV=intravenous; IM=intramuscularly; CSF=cerebrospinal fluid;CNS=central nervous system; TMP/SMX=trimethoprim-sulfamethoxazole; HAART=highly active antiretroviral therapy; CMV=cytomegalovirus. HBV=hepatitis B virus; HBeAg=hepatitis B e antigen; HCV=hepatitis C virus; IRIS=immune reconstitution inflammatory syndrome; PCR=polymerase chain reaction; HSV=herpes simplex virus; HPV=human papillomavirus

† Information in these guidelines might not represent Food and Drug Administration (FDA) approval or approved labeling for products or indications. Specifically, the terms safe and effective might not be synonymous with the FDA-defined legal standards for product approval. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box).

Congenital toxoplasmosis (AII):

transparent gifgrey bulletPyrimethamine: loading dose, 2 mg/kg body weight orally once daily for 2 days, then 1 mg/kg body weight orally once daily for 2-6 mos, then 1 mg/kg body weight orally 3 times weekly; PLUS leucovorin (folinic acid), 10 mg orally or IM with each dose of pyrimethamine; PLUS sulfadiazine, 50 mg/kg body weight orally twice daily
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Treatment duration: 12 mos (AII)

Acquired toxoplasmosis, acute induction therapy (followed by chronic suppressive therapy) (AI):

transparent gifgrey bulletPyrimethamine: loading dose, 2 mg/kg body weight (max 50 mg) orally once daily for 3 days, then 1 mg/kg body weight (max 25 mg) orally once daily; PLUS sulfadiazine, 25-50 mg/kg body weight (max 1.0- 1.5 g/dose) orally per dose 4 times daily; PLUS leucovorin, 10-25 mg orally daily, followed by chronic suppressive therapy.

Treatment duration (followed by chronic suppressive therapy): ≥6 wks (longer if clinical or radiologic disease is extensive or response in incomplete at 6 wks) (BII)
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For sulfonamide-intolerant patients:

transparent gifgrey bulletClindamycin, 5-7.5 mg/kg body weight (max 600 mg/dose) orally or IV per dose 4 times a day can be substituted for sulfadiazine combined with pyrimethamine and leukovorin (AI)
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Congenital toxoplasmosis:

• For infants born to mothers with symptomatic Toxoplasma infection during pregnancy, empiric therapy of the newborn should be strongly considered irrespective of the mothers treatment during pregnancy (BIII).


Acquired toxoplasmosis:

transparent gifgrey bulletPyrimethamine use requires complete blood count monitoring at least weekly while patient is on daily dosing and at least monthly while on less than daily dosing (AIII)
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transparent gifgrey bulletTMP-SMX (5 mg/kg body weight TMP PLUS 25 mg/kg body weight SMX per dose IV or orally twice daily) has been used as an alternative to pyrimethamine-sulfadiazine in adults (BI) but has not been studied in children (CIII).
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transparent gifgrey bulletAtovaquone /(adults: 1.5 g orally twice daily with food) in regimens combined with pyrimethamine/ leukovorin; with sulfadiazine alone; or as a single agent in patients intolerant to both pyrimethamine and sulfadiazine has been used in adults (BII), but these regimens have not been studied in children (CIII).
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transparent gifgrey bulletAzithromycin (adults: 900-1200 mg/day) also has been used in adults combined with pyrimethaminesulfadiazine (BII) but has not been studied in children (CIII).
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transparent gifgrey bulletCorticosteriods (e.g., prednisone or dexamethasone) have been used in children with CNS disease when CSF protein is very elevated (>1000 mg/dL) or when the child has focal lesions with significant mass effects, with discontinuation as soon as clinically feasible (BIII).
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transparent gifgrey bulletAnticonvulsants should be administered to patients with a history of seizures (AIII) and continue through the acute treatment, but they should not be used prophylactically (DIII).
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transparent gifgrey bullet Chronic suppressive therapy (secondary prophylaxis) is recommended for adults and children after initial therapy (AI).
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