One may not be able to readily obtain a sample or be able to easily grow an organism in culture, but one may be able to use the body's own immune response specific to an organism for diagnosis.
Serologic diagnosis is based upon a humoral immune response, with production of antibodies to a micro-organism. The initial antibody response is primarily production of IgM antibodies, followed by an increasing high titer of IgG antibodies. One can distinguish acute infection by finding IgM antibodies, such as finding hepatitis A IgM antibodies. Past exposure or past infection may just have IgG antibodies. Avidity assays provide the same information (antibody avidity increases with duration of infection). Presence of any antibodies may help in establishing that infection has occurred. The use of "paired sera" may help distinguish recent infection when a fourfold rise in titer (IgG antibodies) occurs in 1 to 3 weeks between the two specimens.
Just serologic positivity, such as presence of hepatitis B surface antibody, is useful to determine immune status for the purpose of vaccination.
There may be antibody cross-reactivity among species, or even among genera. Other non-infectious diseases, such as chronic inflammatory conditions and autoimmune diseases, may produce false positive serologic results. Persons who are immunocompromised, particularly by diseases affecting humoral immunity, may have no antibody response or minimal response.
If cross-reactivity and false positives are frequent, or the diagnosis carries a grave prognosis or treatment with significant morbidity and mortality, then confirmation is needed by another test. Hence, a serologic test for syphilis (STS) for initial screening may be performed with a rapid plasma reagin (RPR) test or a venereal disease research laboratory (VDRL) test. The former is cheaper and more often used for screening, but false positives occur. The fluorescent treponemal antigen (FTA) test is the most specific test that may be used to verify a true positive test.
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