ToRCH Profile IgM, Serum
Aids in the diagnosis of both congenital and acute acquired toxoplasmosis, cytomegalovirus, and herpes simplex virus
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Toxoplasma gondii is an obligate intracellular protozoan parasite that is capable of infecting a variety of intermediate hosts including humans. Infected definitive hosts (cats) shed oocysts in feces that rapidly mature in the soil and become infectious.(1) Toxoplasmosis is acquired by humans through ingestion of food or water contaminated with cat feces or through eating undercooked meat containing viable oocysts. Vertical transmission of the parasite through the placenta can also occur, leading to congenital toxoplasmosis. Following primary infection, Toxoplasma gondii can remain latent for the life of the host; the risk for reactivation is highest among immunosuppressed individuals.
Seroprevalence studies performed in the United States indicate that approximately 9% to 11% of individuals between the ages of 6 and 49 have antibodies to Toxoplasma gondii.(2) Infection of immunocompetent adults is typically asymptomatic. In symptomatic cases, patients most commonly present with lymphadenopathy and other nonspecific constitutional symptoms, making definitive diagnosis difficult to determine.
Severe-to-fatal infections can occur among patients with AIDS or individuals who are otherwise immunosuppressed. These infections are thought to be caused by reactivation of latent infections and commonly involved the central nervous system.(3)
Transplacental transmission of the parasites resulting in congenital toxoplasmosis can occur during the acute phase of acquired maternal infection. The risk of fetal infection is a function of the time at which acute maternal infection occurs during gestation.(4) The incidence of congenital toxoplasmosis increases as pregnancy progresses; conversely, the severity of congenital toxoplasmosis is greatest when maternal infection is acquired early during pregnancy. A majority of infants infected in utero are asymptomatic at birth, particularly if maternal infection occurs during the third trimester, with sequelae appearing later in life. Congenital toxoplasmosis results in severe generalized or neurologic disease in about 20% to 30% of the infants infected in utero; approximately 10% exhibit ocular involvement only and the remainder are asymptomatic at birth. Subclinical infection may result in premature delivery and subsequent neurologic, intellectual, and audiologic defects.
CMV is a member of the Herpesviridae family of viruses and usually causes asymptomatic infection after which it remains latent in patients, primarily within bone marrow derived cells.(5) Primary CMV infection in immunocompetent individuals may also manifest as a mononucleosis-type syndrome, similar to primary Epstein-Barr virus infection, with fever, malaise, and lymphadenopathy.
CMV is a significant cause of morbidity and mortality among bone marrow or solid organ transplant recipients, individuals with AIDS, and other immunosuppressed patients due to virus reactivation or from a newly acquired infection.(6,7) Infection in these patient populations can affect almost any organ and lead to multi-organ failure. CMV is also responsible for congenital disease among newborns and is 1 of the ToRCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and herpes simplex virus: HSV).
CMV seroprevalence increases with age. In the United States, the prevalence of CMV-specific antibodies increases from approximately 36% to over 91% in adolescents between the ages of 6 through 11 and adults over 80 years old, respectively.(8)
Herpes Simplex Virus (HSV):
HSV types 1 and 2 are members of the Herpesviridae family of viruses and produce infections that may range from mild stomatitis to disseminated and fatal disease. Clinical conditions associated with HSV infection include gingivostomatitis, keratitis, encephalitis, vesicular skin eruptions, aseptic meningitis, neonatal herpes, genital tract infections, and disseminated primary infection.
Infections with HSV types 1 and 2 can differ significantly in their clinical manifestations and severity. HSV type 2 primarily causes urogenital infections and is found almost exclusively in adults. HSV type 1 is closely associated with orolabial infection, although genital infection with this virus can be common in certain populations.
The diagnosis of HSV infections are routinely made based on clinical findings and supported by laboratory testing using PCR or viral culture. However, in instances of subclinical or unrecognized HSV infection, serologic testing for IgG-class antibodies to type-specific HSV glycoprotein G (gG) may be useful. There are several circumstances in which it may be important to distinguish between infection caused by HSV types 1 and 2.(9) For example, the risk for reactivation is highest for HSV type 2 and the method of antiviral therapy may differ depending on the specific type of HSV-causing disease. In addition, the results of HSV type-specific IgG testing is sometimes used during pregnancy to identify risks of congenital HSV disease and allow for focused counseling prior to delivery.(10,11)
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Toxoplasma Ab, IgM
Toxoplasma IgM Value
> or =0.65 (positive)
Negative (reported as positive, negative, or equivocal)
HERPES SIMPLEX VIRUS, IGM
Negative (reported as positive or negative)
Diagnosis of acute central nervous system, intrauterine, or congenital toxoplasmosis is difficult by routine serological methods. Active toxoplasmosis is suggested by the presence of IgM antibodies, but elevated anti-IgM titers are often absent in immunocompromised patients. In addition, elevated IgM can persist from an acute infection that may have occurred as long ago as 1 year.
A suspected diagnosis of acute toxoplasmosis should be confirmed by further testing at a toxoplasmosis reference laboratory or by detection of Toxoplasma gondii DNA by PCR analysis of cerebrospinal fluid or amniotic fluid specimens (PTOX / Toxoplasma gondii, Molecular Detection, PCR).
For confirmation of a diagnosis, the FDA issued a Public Health Advisory (7/25/1997) suggesting that sera found to be positive/equivocal for Toxoplasma gondii IgM antibody be sent to a Toxoplasma reference laboratory. The CDC or Jack Remington MD, Palo Alto Medical Foundation, 860 Bryant Street, Palo Alto, CA 94301 were recommended. (Reviewed 12/2011)
Specimens interpreted as equivocal may contain very low levels of IgM. A second specimen should be drawn and tested.
A negative CMV IgM result suggests that the patient is not experiencing a recent infection. However, a negative result does not rule-out primary CMV infection.
It has been reported that CMV-specific IgM antibodies were not detectable in 10% to 30% of cord blood sera from infants demonstrating infection in the first week of life. In addition, up to 23% (3/13) of pregnant women with primary CMV infection did not demonstrate detectable CMV IgM responses within 8 weeks postinfection. In cases of primary infection, where the time of seroconversion is not well defined, as high as 28% (10/36) of pregnant women did not demonstrate CMV IgM antibody.
Positive CMV IgM results indicate a recent infection (primary, reactivation, or reinfection). IgM antibody responses in secondary (reactivation) CMV infections have been demonstrated in some CMV mononucleosis patients, in a few pregnant women, and in renal and cardiac transplant patients. Levels of antibody may be lower in transplant patients with secondary rather than primary infections.
Equivocal CMV IgM or IgG results may occur during acute infection or may be due to nonspecific binding reactions. Submit an additional sample for testing if clinically indicated.
Herpes Simplex Virus (HSV):
The presence of IgM-class antibodies indicates recent infection
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Results must be used in conjunction with clinical symptoms and patient history.
Positive test results may not be valid in persons who have received blood transfusions or other blood products in the past several months.
Negative results do not preclude recent primary Toxoplasma gondii infection. A negative result could indicate either no previous exposure or also could be seen in cases of remote exposure with subsequent loss of detectable antibody. A second specimen drawn at a later point in time may be needed to rule out a recent infection.
Positive serologic results alone are not diagnostic of Toxoplasma gondii infection. For example, infections with Epstein-Barr virus (EBV) have been suspected to elicit antigen-specific IgM responses (eg, false-positive IgM Toxoplasma reactions) in individuals previously sensitized to a variety of non-EBV infectious agents.
Since persisting IgM levels may be detected long after the onset of acquired infection, the use of a single serological test result must be used with caution in those cases when it is critical to establish the time of infection. This applies to the diagnosis of acute Toxoplasma gondii infection acquired during pregnancy. Determination of the date of infection based solely on the results of detectable IgM antibody to Toxoplasma gondii is not recommended. That determination should include clinical history and previous serology, since low levels of IgM antibody may persist for a year or more. The use of a test to determine a rise in IgG antibody to Toxoplasma gondii (TOXGP / Toxoplasma gondii Antibody, IgG, Serum or TOXOP / Toxoplasma gondii Antibody, IgM and IgG (Separate Determinations), Serum) may provide additional information as to the date of infection. Therefore, the FDA has instructed commercial suppliers of Toxoplasma IgM kits to recommend Toxoplasma IgG testing also be performed.
Sera drawn very early during the acute stage of infection may have undetectable levels of CMV IgM.
Immunocompromised patients may have impaired immune responses, and nonreactive IgM results may be due to delayed seroconversion and do not rule-out current infection.
CMV IgM results should not be used alone to diagnose CMV infection. Results should be considered in conjunction with clinical presentation, patient history, and other laboratory findings. In cases of suspected disease, submit a second specimen for testing in 10 to 14 days.
The performance characteristics of these assays have not been evaluated in immunosuppressed or organ transplant recipients and have not been established for cord blood or for testing of neonates. These assays should not be used for screening blood or plasma donors.
Immune complexes or other immunoglobulin aggregates present in patient specimens may cause increased nonspecific binding and produce false-positive results.
Potential cross-reactivity for CMV IgM may occur with specimens positive for EBV viral capsid antigen IgM and parvovirus B19 IgM.
Herpes Simplex Virus (HSV):
Individuals infected with HSV may not exhibit detectable levels of IgM antibody in the early stages of infection. This assay does not discriminate between antibodies to HSV-1 and HSV-2.
The VIDAS TOXO IgM system was compared to an indirect immunofluorescence (IFA) IgM assay (GenBio, San Diego, CA). Of 125 specimens tested, 45 and 47 were IFA and VIDAS positive, respectively. Using the IFA IgM as the gold standard, the sensitivity and specificity of the VIDAS Toxo IgM assay was 98% and 96%, respectively.
Cytomegalovirus (CMV) IgM:
To evaluate the accuracy of the BioPlex CMV IgM multiplex flow immunoassay, 600 prospective serum specimens submitted for routine CMV IgM testing by the VIDAS enzyme-linked fluorescence immunoassay (ELFA; bioMerieux, Durham, NC) were also analyzed in a blinded fashion by the BioPlex assay within a 24-hour period. Specimens with discordant results after initial testing were repeated by both assays during the same freeze/thaw cycle. Further resolution of discrepant results was performed by using the DiaMedix (Miami, FL) EIA CMV IgM. The resolved results are summarized below:
CMV IgM (VIDAS ELFA)
BioPlex CMV IgM
a. These 15 samples tested negative by the DiaMedix EIA
Sensitivity: 93.7% (15/16); 95% Confidence Interval (95% CI): 69.7%-100%
Specificity: 96.7% (556/574); 95% CI: 95.1%-98.0%
Overall Percent Agreement: 95.7% (574/600); 95% CI: 93.7%-97.4%
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Tenter AM, Heckeroth AR, Weiss LM: Toxoplasma gondii: from animals to humans. Int J Parasitol 2000;30(12-13):1217-1258
2. Jones JL, Kruszon-Moran D, Sanders-Lewis K, Wilson M: Toxoplasma gondii infection in the United States, 1999-2004, decline from the prior decade. Am J Trop Med Hyg 2007;77(3):405-410
3. Luft BJ, Remington JS: Toxoplasmic encephalitis in AIDS. Clin Infect Dis 1992;15(2):211-222
4. Wong SY, Remington JS: Toxoplasmosis in pregnancy. Clin Infect Dis 1994;18(6):853-861
5. Soderberg-Naucler C, Fish KN, Nelson JA: Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 1997;91:119-126
6. Kusne S, Shapiro R, Fung J: Prevention and treatment of cytomegalovirus infection in organ transplant recipients. Transpl Infect Dis 1999;1(3):187-203
7. Rubin RH: Importance of CMV in the transplant population. Transpl Infect Dis 1999;1(1):3-7
8. Staras SA, Dollard SC, Radford KW, et al: Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis 2006;43(9):1143-1151
9. Ashley RL, Wald A: Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev 1999;12:1-8
10. Ashley RL, Wu L, Pickering JW, et al: Premarket evaluation of a commercial glycoprotein G-based enzyme immunoassay for herpes simplex virus type-specific antibodies. J Clin Microbiol 1998;36:294-295
11. Brown ZA, Selke S, Zeh J, et al: The acquisition of herpes simplex virus during pregnancy. N Engl J Med 1997;337:509-515
12. Binnicker MJ, Jespersen DJ, Harring JA: Comparative evaluation of three multiplex flow immunoassays to enzyme immunoassay for the detection and differentiation of IgG-class antibodies to herpes simplex virus types 1 and 2. Clin Vaccine Immunol 2010;17(2):253-257