Febrile Reactions: Types, Examination, Analysis And Interpretation

The  febrile reactions  are a group of laboratory tests specially designed to diagnose certain diseases that are clinically febrile almost indistinguishable. The basis of these tests is the antigen-antibody reaction.

To carry out these tests, specific antigens of the causative agent to be investigated are added to a serum sample from the sick patient. If the patient has been exposed to this causative agent, the antibodies present in his blood will react with the antibodies producing agglutination and therefore a positive test. Otherwise, the result is negative.

Importantly, a single febrile reaction is not sufficient to establish the diagnosis. On the contrary, this is based on the comparison of the evolution of antibody titers over time, being necessary to carry out the test at least 2 times with a separation of 3 to 4 weeks.

Since it is intended to investigate a set of febrile diseases and not a specific disease, the febrile reactions are assembled together; that is, the patient’s serum sample is fractionated by reacting with different antigens in order to determine precisely which is the causative agent.

Types of febrile reactions 

As its name suggests, febrile reactions are designed to identify the causative agent of febrile infectious diseases whose symptoms are very similar, making it almost impossible to establish the differential diagnosis based exclusively on traditional clinical practice.

Febrile reactions are not a single test. On the contrary, it is a battery of tests where the blood taken from the patient is divided and then antigens from each of the causal agents to be studied are added.

If agglutination occurs, the test is positive, while if it does not appear, it is negative. It is necessary to do the test in a serial way and with enough time between the samples (at least 4 weeks), in order to establish the behavior of the antibodies over time and make an accurate diagnosis.

Illnesses that can be diagnosed by febrile reactions include:

– Typhoid fever.

– Paratyphoid fever.

– Brucellosis.

– Rickettsiosis.

Typhoid fever

Produced by Salmonella Typhi , it is characterized by a constant fever pattern accompanied in some cases by profuse sweating, associated with general malaise, diarrhea and nonspecific gastrointestinal symptoms.

The disease develops in four phases. During the first, the symptoms are usually mild to moderate, with fever, general malaise and gastrointestinal symptoms being observed more frequently as indicated above.

During the second week, far from improving, the symptoms worsen, making the patient prostrate. The fever reaches 40ºC, delirium and sometimes small red spots on the skin (petechiae) may occur.

If left untreated and allowed to evolve, life-threatening complications can occur in the third week, ranging from endocarditis and meningitis to internal bleeding. The clinical picture of the patient at this point is serious.

In the absence of death or any serious complication, the progressive recovery of the patient begins during the fourth week; the temperature decreases and little by little normal body functions are restored.

Paratyphoid fever

Clinically, paratyphoid fever is practically indistinguishable from typhoid fever; in fact, the only thing they differ is that the incubation period is usually slightly shorter and the intensity of the symptoms somewhat milder in paratyphoid fever.

Classified among enteric fevers, paratyphoid fever is caused by Salmonella Paratyphi (serotypes A, B and C), being necessary to perform laboratory tests to establish the specific causative agent. Its most severe complications include jaundice and liver abscesses.

Treatment is basically the same as that used for typhoid fever. Therefore, the identification of the etiological agent is useful more for statistical purposes and the design of public health policies than for the decision of the patient’s treatment.

Brucellosis

Brucellosis is an infectious disease, which is acquired by consuming contaminated dairy products. In its acute form, it is characterized by high fever with a wavy pattern, predominantly in the evening, associated with general malaise and headache.

When it becomes chronic, it can present various clinical pictures that can compromise various systems and systems (hematological, osteoarticular, respiratory, digestive).

The causative agent is a bacteria of the genus Brucella , with cases being particularly abundant in rural areas of developing countries where milk is not pasteurized before consumption.

Clinically, the diagnosis of this entity is very difficult, being necessary to have epidemiological data and laboratory tests to be able to find the definitive diagnosis.

Rickettsiosis

It is a disease transmitted by lice, fleas and ticks accidentally from animals to man. Therefore, it is considered a zoonosis.

With a variable incubation period ranging from 7 to 10 days, rickettsiosis is caused by strict intracellular coccobacilli, with the exception of Coxiella Burnetii,  the causative agent of Q Fever, which can live outside the cell and in fact be transmitted by airway. These are transmitted by the bite of insects (fleas, lice, ticks, mites) that previously bit a sick host.

Clinically, rickettsial infection is characterized by high fever, enlarged liver and spleen (hepatosplenomegaly), cough, and rash.

Rickettsioses are divided into three groups: typhus group, spotted fever group, and scrub typhus group.

Typhus group

Within this group we find endemic typhus ( Rickettsia typha ) and epidemic typhus ( Rickettsia prowazekii ). Diseases in this category are often confused with typhoid fever, but they are distinct conditions.

Spotted fever group

The causative agent is Rickettsia rickettsii , the classic clinical picture being Rocky Mountain fever. It is a disease transmitted mainly by ticks.

Typhus scrub

The latter disease is transmitted by mites. The causal agent that causes it is the Orientia tsutsugamushi .

Although the causative agents and transmission vectors of each of these diseases are clearly defined, the clinical picture is usually very similar, so it is necessary to carry out complementary studies in order to establish the etiological agent. This is where feverish reactions come into play.

Exam 

The test of choice to confirm the diagnosis is usually the isolation of the causative agent in cultures. The exception to this occurs with rickettsiae, since this requires specialized culture media that are not available in any laboratory.

On the other hand, molecular diagnostic tests, which tend to be much more accurate than febrile reactions, are gaining more value every day. However, its costs do not allow its widespread use, especially in endemic areas of underdeveloped countries.

In light of this, febrile reactions, despite being somewhat nonspecific and somewhat outdated, are still used as a diagnostic tool in many developing countries. This is especially true when examining for epidemiological purposes.

Analysis and testing

The analysis of febrile reactions is carried out in the laboratory, where a sample of blood from the affected patient is centrifuged to separate the plasma from the red blood cells. Once this is done, specific antigens are added to determine whether or not there is agglutination in the sample.

Each of the febrile diseases mentioned previously corresponds to a specific type of antigen. Next we will see how the specific tests are performed for each of the pathologies described above.

Typhoid fever

Agglutination tests are performed with the O antigen (somatic antigen) and the H antigen (flagellar antigen).

Originally, this was done using the Widal technique. However, when evaluating both antigens simultaneously this procedure has the disadvantage of many false positives due to cross reaction.

That is why more precise and specific techniques were developed to separately determine the presence of anti-O and anti-H agglutinins.

Paratyphoid fever

Paratyphoid agglutinins A and B are used for the diagnosis of paratyphoid fever. Each of these agglutinins contains specific antigens of the serotypes of S. paratyphi A and B, which makes it possible to know the causative agent involved with considerable precision.

Brucellosis

In this case the Huddleson reaction is used. This reaction consists of adding decreasing concentrations of Brucella abortus antigens to the studied serum, in order to determine in which range agglutination occurs.

Rickettsiosis

Specific antibodies against rickettsiae cannot be used to prepare agglutination tests, due to the complexity and cost of working with these bacteria. Therefore, there are no specific antigens available.

However, it has been determined that rickettsia antigens are cross- reactive with Proteus OX 19 antigens, so proteus antigen preparations are used to react with the serum under study.

Although in the correct clinical-epidemiological context the test can guide the diagnosis, the truth is that since it is a cross reaction, its sensitivity and specificity are very low, so it is always possible to obtain a false positive result.

Interpretation 

The interpretation of the results of febrile reactions should be carried out with caution, and always adequately correlating the symptoms, the epidemiological history and the other laboratory findings of the patient.

In general, these tests are for informational and epidemiological purposes, since due to the time it takes for the results, it is not possible to wait for the results to start treatment.

Typhoid fever

The results of this test are considered positive when the antibody titers against O antigen are greater than 1: 320, and those for H antigen greater than 1:80.

It is extremely important to note that for the diagnosis of typhoid fever through febrile reactions, the antibody titers must quadruple between the first and second feeding.

Paratyphoid fever

Dilution greater than 1: 320 for O antigen and greater than 1:80 for paratypic antigen A or B.

Rickettsiosis

Titles greater than 1: 320 for Proteus 0X-19.

Brucellosis

Any positive titer in the Huddleson reaction.

References 

  1. Kerr, WR, Coghlan, J., Payne, DJH, & Robertson, L. (1966). The Laboratory Diagnosis of Chronic Brucellosis. Lancet , 1181-3.
  2. Sanchez-Sousa, A., Torres, C., Campello, MG, Garcia, C., Parras, F., Cercenado, E., & Baquero, F. (1990). Serological diagnosis of neurobrucellosis. Journal of clinical pathology43 (1), 79-81.
  3. Olsen, SJ, Pruckler, J., Bibb, W., Thanh, NTM, Trinh, TM, Minh, NT,… & Chau, NV (2004). Evaluation of rapid diagnostic tests for typhoid fever. Journal of clinical microbiology42 (5), 1885-1889.
  4. Levine, MM, Grados, O., Gilman, RH, Woodward, WE, Solis-Plaza, R., & Waldman, W. (1978). Diagnostic value of the Widal test in areas endemic for typhoid fever. The American journal of tropical medicine and hygiene27 (4), 795-800.
  5. La Scola, B., & Raoult, D. (1997). Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. Journal of clinical microbiology35 (11), 2715.

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