Febrile agglutinins are serologic tests for a group of unrelated infectious diseases that are sometimes responsible for so-called fever of unknown origin. They include typhoid and enteric (Salmonella) fever, certain rickettsial diseases, brucellosis, and tularemia. Since organisms causing these diseases are potential causes of fever of unknown origin, and since relatively simple slide agglutination serologic techniques are available for each, most laboratories automatically include the same selection of tests when febrile agglutinins are ordered. Typhoid or enteric (paratyphoid) fever may be caused by certain serotypes of the Salmonella species. The more common salmonellae are separated into groups on the basis of antigens prepared from these organisms; these antigens are used to detect antibodies in the patient’s serum (Widal test). The groups are given a letter designation; for example, Salmonella typhi is included in Salmonella D (see Table 37-7). The Widal agglutination test involves antibodies produced to the somatic (O) and flagellar (H) antigens of Salmonella organisms. These antibodies appear approximately 7-10 days after onset of illness. Peak titers are reached between the 3rd and 4th weeks. In nonvaccinated individuals or most of those vaccinated more than 1 year previously, titers of 1:40 for the H antigen and 1:80 for the O antigen are suspicious, titers of 1:80 for the H antigen and 1:160 for the O antigen are definitely significant. However, recent (<1 year) vaccination may cause a greatly increased titer of either the O or the H antigen or both. The O antigen is more significant for diagnosis than the H antigen.

Most investigators today seriously question the usefulness of the Widal agglutination tests for typhoid or paratyphoid. Only about 65% (range, 58%-82%) of typhoid patients eventually reach a definitely abnormal titer of 1:160. False-positive elevations may occur due to cross-reaction with other Salmonella organisms in group D, are relatively frequent (20% in one series) in narcotic addicts, and possibly may occur due to cross-reaction in other conditions. Correlation of titers between laboratories on the same specimens have been rather poor. False negative results may be due to antibiotic therapy, inconsistent antibody formation in previously vaccinated persons, or specimens obtained before peak titer was reached.

Antibody-antigen agglutination tests for brucellosis and tularemia are also included. Again, titers of 1:80 are suspicious, and 1:160 are definitely abnormal. Antibodies appear 2-3 weeks after onset of the illness. Similar slide agglutination tests for rickettsia (Weil-Felix reaction) complete the febrile agglutinin battery. Interpretation of Weil-Felix results is discussed in Chapter 15.

It is necessary to emphasize that negative febrile agglutinin test results or low titers do not rule out the diagnosis in any of these diseases. On the other hand, a single titer of 1:160 or more raises the suspicion of infection but is not conclusive. Only a fourfold rising titer can definitely confirm the diagnosis and prove acute infection. Unfortunately, for a variety of reasons, the fourfold rising titer is not easy to obtain (only 22% of typhoid patients in one series). Also, serologic tests obviously are not helpful in the early stage of the disease.