toxoplasmosis

Etiology

• ingestion infective oocysts
  • inadequately cooked meat, especially pork & lamb
  • material contaminated by cat feces
  • drinking contaminated water
  • unpasteurized goat milk
• inhalation of contaminated dusts
• transmission via blood transfusion
• transmission via organ transplantation
• active disease may result from reactivation of latent infection

Epidemiology

• most common central nervous system infection in patients with AIDS
• most toxoplasmosis is due to reactivation of previous infection
• one of top 5 neglected parasitic infections in the U.S.
  • chronically infection in 60 million Americans

Pathology

• primary infection in immunocompetent persons is usually asymptomatic, but latent infection may persist & reactivation may occur if a person becomes immunocompromised

Clinical manifestations

• infections in immunocompetent individuals
  • generally asymptomatic or mild
  • fever
  • lymphadenopathy
• infection in utero
  • 1st 1/2 of pregnancy
    • stillbirth
    • hydrocephalus
    • microcephalus
    • intracranial calcifications
    • unrelated to symptoms (or lack of symptoms) in mother
  • 2nd 1/2 of pregnancy
    • infants generally asymptomatic at birth
    • fever, hepatomegaly & jaundice may be develop
    • chorioretinitis, psychomotor retardation & seizures may occur months to years later
• immunosuppressed individuals (especially patients with AIDS)
  • central nervous system involvement (encephalitis)
    • fever, headache, disorientation
    • hemiparesis, speech impairment, visual disturbances, cranial nerve palsies, tremor
    • seizures
  • pneumonitis
  • myocarditis
  • chorioretinitis
  • pancreatitis
  • orchitis
  • mononucleosis-like syndrome

Laboratory

• CD4 count:
  • encephalitis in patients with CD4 count < 100 cells/uL
• Toxoplasma serology: Toxoplasma gondii serology
  • tests
    • Sabin-Feldman dye test
    • immunofluorescence antibody (IFA)
    • enzyme immunoassay (EIA)
  • antibodies appear in 2 weeks after infection
  • titers peak at 6-8 weeks
  • Toxoplasma IgM antibodies indicate acute infection
    • IgM antibodies may persist for more than a year
    • false positives
  • Toxoplasma IgG antibodies suggest chronic infection
    • low IgG titers may indicate remote infection
    • IgG present in nearly all patients with encephalitis
• Toxoplasma gondii in isolate
  • Toxoplasma gondii in CSF
  • Toxoplasma gondii in stool
  • direct examination of tissues, blood or body fluids
    • stains
      • giemsa stain
      • immunoperoxidase stain
      • fluorescent stain
        • hematoxylin & eosin (H & E) does not reveal organisms well
  • isolation from blood or body fluid is evidence of active disease
  • recovery from tissues may reflect chronic infection
• tissue culture
• PCR for Toxoplasma gondii DNA
• complete blood count (CBC) shows atypical lymphocytosis
• sterotactic brain biopsy if definitive diagnosis is needed
  • no response to 7-14 days of empiric therapy
  • solitary lesion
  • non-diagnostic imaging studies
• see ARUP consult

Radiology

• magnetic resonance imaging (MRI) of brain (encephalitis)
  • multiple bilateral lesions:
    • ring-enhancing lesions of toxoplasma abscesses
    • solitary lesion suggests another diagnosis (lymphoma)
  • lesions most abundant in basal ganglia & corticomedullary junction
  • deep lesions may show patterns of high & low signal intensity
  • lesions are enhanced with contrast
• computed tomography (CT) of brain (encephalitis)
  • less sensitive than MRI

Differential diagnosis

immunocompromised patients

• lymphoma (primary CNS lymphoma, B-cell lymphoma)
  • often a solitary lesion in the periventricular or subependymal area or in the corpus callosum
  • neither clinical nor MRI reliable distinguishes lymphoma from toxoplasmosis
  • brain biopsy diagnostic
• progressive multifocal leukoencephalopathy (PML)
  • dementia is often presenting symptom
  • non-enhancing white matter hyointensities without mass effect
  • CSF PCR for JC virus may be positive
  • CD4 counts generally < 50/uL
  • brain biopsy diagnostic
• Cryptococcus neoformans
  • headache, fever, altered mental status
  • serum & CSF cryptococcus serology is diagnostic
• tuberculosis
  • basilar meningitis with cranial nerve palsy
  • CD4 count is generally > 300/uL
  • CSF culture & PCR diagnostic
• cytomegalovirus (CMV)
  • diffuse encephalitis with fever
  • CD4 counts < 50/uL
  • CSF PCR is positive
  • brain biopsy is diagnostic
• syphilis
  • atypical & accelerated neurosyphilis is seen in HIV infection
  • CSF VDRL is diagnostic
  • serum serologic test for syphilis also positive
• cysticercosis
  • multiple enhancing cystic lesions
  • a central area of enhancement is due to a scolex of T solium

Management

• immunocompetent individuals with lymphadenopathy do not require therapy
• pharmacologic agents
  • indications
    • multiple ring-enhancing lesions
    • positive Toxoplasma gondii serology
    • CD4 count < 200/uL
  • folate antagonists (give with folic acid)
    • pyrimethamine
    • sulfadiazine
  • inhibitors of protein synthesis
    • clindamycin
    • chlortetracycline
    • azithromycin
  • inhibition of pyrimidine salvage
    • arprinocid
  • dapsone may be alternative to sulfadiazine
  • spiramycin used in Europe to treat pregnant women
    • reduces transplacental transmission
  • macrolides may be useful adjunctive agents
  • glucocorticoids may be useful to treat intracerebral edema
  • anticonvulsants for treatment of seizures
    • interaction between sulfadiazine & phenytoin
  • combination therapy
    • pyrimethamine plus sulfadiazine
      • initial therapy
        • pyrimethamine 200 mg PO loading dose, then 50-75 mg PO QD
        • sulfadiazine 4-6 g PO QD divided QID
        • leucovorin 10-20 mg QD
        • treatment with for 6 weeks or until radiographic improvement
      • lifelong suppressive therapy
        • pyrimethamine 25-50 mg QD
        • sulfadiazine 2-4 g QD
      • crosses blood brain barrier
      • 40% incidence of toxicity
        • bone marrow suppression
        • rash
        • crystalluria
        • hematuria
        • nephrotoxicity
    • pyrimethamine plus clindamycin
      • pyrimethamine 75 mg QD
      • clindamycin 450-600 mg PO/IV TID-QID
    • congenitally affected neonates
      • pyrimethamine 0.5-1.0 mg/kg QD
      • sulfadiazine 100 mg/kg QD
      • therapy for 1 year
      • additional agents which may be helpful
        • spiramycin 100 mg/kg QD
        • prednisone 1 mg/kg QD
    • pyrimethamine plus clarithromycin 1 g every 12 hours
    • pyrimethamine plus azithromycin 1 g QD
    • pyrimethamine plus atovaquone 750 mg PO every 6 hours
    • pyrimethamine plus dapsone 100 mg PO every 6 hours
  • 70-90% of HIV patients respond to therapy
    • response is seen with 7 days in 86% of responders
    • baseline status is reached in 14 days
  • biopsy lesions that fail to respond to 2 weeks of empiric therapy
  • maintenance therapy or secondary prophylaxis
    • all HIV patients: 95% relapse rate
    • same agents used for acute therapy at lower doses
    • Fansidar 3 times/week
    • discontinue after all signs & symptoms of disease have resolved & CD4 count > 200/mm3 for 6 months
    • indefinite treatment in persistent immunosuppression
  • primary prophylaxis
    • CD4 count < 200/mm3 & positive Toxoplasma serology
    • Bactrim for PCP prophylaxis will provide protection against activation of toxoplasmosis
    • dapsone 100 mg QD plus pyrimethamine 50 mg & folinic acid 10-20 mg weekly
    • discontinue prophylaxis when CD4 count > 200/mm3 for 3 months
• prevention
  • heating of meat to 60 C
  • freezing meat to kill cysts
  • avoiding oocyst-contaminated material (cat litter box)

More general terms

• coccidiosis

Additional terms

• Toxoplasma gondii