Why is it necessary to test for both Toxoplasma and Cytomegalovirus (CMV) Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies in Human Immunodeficiency Virus (HIV) patients, rather than just IgG?

Why Both IgM and IgG Testing is Necessary for Toxoplasma and CMV in HIV Patients

In HIV patients, testing only IgG antibodies for Toxoplasma and CMV is insufficient because IgG merely indicates prior exposure or latent infection, not active disease, while IgM (along with IgA and antigen detection) can help identify acute infection or reactivation—though the primary reason for testing is actually to establish baseline IgG seropositivity for risk stratification and prophylaxis decisions, not to diagnose active disease through serology alone. 1

The Core Purpose: Risk Stratification, Not Active Disease Diagnosis

For Toxoplasma gondii

• All HIV-infected patients should be tested for anti-Toxoplasma IgG upon initiation of care to identify those with latent infection who are at risk for reactivation when CD4 counts drop below 100 cells/µL 1

• IgG-positive patients (indicating prior exposure) are at risk for toxoplasmic encephalitis when severely immunosuppressed, while IgG-negative patients have minimal risk and need counseling on exposure prevention 1

• Serologic tests for Toxoplasma can never be used to diagnose or exclude active toxoplasmosis—a seronegative patient with a CNS space-occupying lesion is less likely to have toxoplasmosis than a seropositive patient, but diagnosis requires imaging, clinical response to therapy, or biopsy 1

For CMV

• Patients at lower risk of CMV infection should be tested for anti-CMV IgG upon initiation of care to identify seronegativity, which would prompt use of CMV-negative or leukocyte-reduced blood products during transfusions 1

• CMV seropositivity (IgG positive) is extremely high among HIV-infected persons, particularly MSM and injection drug users, who may be assumed CMV-seropositive 1

Why IgM Testing Has Limited Clinical Utility

The IgM Problem in HIV Patients

• IgM antibodies have poor diagnostic value in HIV patients because approximately 60% of positive IgM results from commercial laboratories represent false-positives or chronic infections rather than acute infections 2

• In one study of 62 AIDS patients with active toxoplasmosis, only 3 patients (4.8%) had detectable IgM antibodies, while 61 had IgG antibodies, demonstrating that IgM is frequently absent even during active disease 3

• Thirteen patients (38%) with active toxoplasmosis showed rising IgG titers without any detectable IgM production, indicating that reactivation in immunocompromised patients often occurs without an IgM response 3

When IgM/IgA Testing May Be Considered

• Detection of IgM, IgA, and toxoplasma antigen in addition to IgG may improve diagnostic sensitivity from 37.3-68.6% (single tests) to 76.5-96.1% (combined testing) in patients with suspected cerebral toxoplasmosis 4

• Toxoplasma antigen detection showed 14% positivity in HIV patients, and in one patient with CNS symptoms and CD4 <50 cells/µL who lacked any specific immunoglobulin response, antigen detection was the only positive marker 5

• IgA antibodies were detected in 7% of HIV-infected patients and may provide additional diagnostic information when combined with other markers 5

The Critical Clinical Pitfall

Guidelines Recommend IgG Only for Baseline Screening

• Current IDSA/HIV Medicine Association guidelines (2009,2013,2014) recommend only anti-Toxoplasma IgG testing upon initiation of care, with no mention of routine IgM testing for screening purposes 1

• For CMV, only anti-CMV IgG testing is recommended for baseline screening in lower-risk populations 1

• The purpose is to identify latent infection (IgG-positive) versus susceptibility (IgG-negative), not to diagnose active disease 1

When to Repeat Toxoplasma Testing

• Serologic testing should be repeated for previously seronegative patients if CD4 count decreases to <100 cells/µL, especially if unable to receive prophylaxis against Pneumocystis pneumonia (which is active against toxoplasmosis) 1

• This repeat testing is to detect seroconversion (new IgG positivity) from recent exposure, not to detect IgM 1

Practical Algorithm for HIV Patients

At Initial HIV Diagnosis

1. Order anti-Toxoplasma IgG (not IgM) to establish baseline serostatus 1
2. Order anti-CMV IgG (not IgM) for lower-risk patients to identify seronegativity 1
3. If Toxoplasma IgG-negative: Counsel on exposure prevention (proper meat cooking, cat litter precautions, hand hygiene) 1
4. If CMV IgG-negative: Use CMV-negative or leukocyte-reduced blood products for transfusions; counsel on safer sex practices 1

During Follow-Up Care

1. If CD4 drops to <100 cells/µL and patient was initially Toxoplasma IgG-negative: Repeat IgG testing to detect seroconversion 1
2. If Toxoplasma IgG-positive and CD4 <100 cells/µL: Initiate prophylaxis with TMP-SMX (which also covers PCP) 1
3. Do not routinely order IgM or IgA for screening or monitoring purposes 1

When Suspecting Active Toxoplasmic Encephalitis

1. Diagnosis is based on clinical presentation, neuroimaging (ring-enhancing lesions), and therapeutic response, not serology 1
2. IgG seropositivity supports the diagnosis but does not confirm it 1
3. IgM testing is unreliable and frequently negative even in active disease 3
4. Consider combined testing (IgG, IgM, IgA, antigen detection) only in reference laboratories when diagnosis remains uncertain despite imaging and clinical evaluation 2, 4
5. All positive IgM results from commercial laboratories must be confirmed at a toxoplasmosis reference laboratory before interpretation as acute infection 2

Special Populations

HIV-Infected Pregnant Women

• Toxoplasma IgG-positive pregnant women have increased risk of maternal reactivation and congenital transmission, and infants born to seropositive women should be evaluated for congenital toxoplasmosis 1

• In this specific context, IgM testing may be warranted to distinguish chronic from acute infection, but positive IgM requires confirmation at a reference laboratory 2