For many years, series of patients who fit the definition of fever of unknown origin have been reported. The causes of fever of unknown origin (NBA) are sometimes rare diseases and sometimes common diseases that differ from the expected manifestations.
Prolonged and unknown fever was first reported by Petersdorf and Beeson in 1961. It is defined as a fever above 38.3°C that lasts for at least 3 weeks and whose cause cannot be determined despite a 1-week examination in the hospital. This definition is still valid.
Infections appear to be the leading cause in the large-scale fever series of unknown cause reported in the literature, and their frequency varies between 22.6-36%. In our study (Erten and Saka et al.Int. J. Clin. Pract2005) infections constituted the majority (42%). Infection is the most common cause in NBA series reported in our country (42-65%). While tuberculosis ranks first in the infection group in our country, infective endocarditis, abscesses and other infections are mentioned first in publications from Western countries. There was no significant difference between other causes of fever of unknown origin.
The most common cause in our country is tuberculosis, which is among the infectious diseases group, with a frequency of 50% and above. Pulmonary tuberculosis with a miliary (diffuse) distribution was generally encountered in these series. In our series, extrapulmonary tuberculosis was diagnosed in 9 of 12 cases, while pulmonary tuberculosis with miliary distribution was detected in two cases. In all tuberculosis cases, there were complaints such as fatigue, weight loss and sweating, as well as fever rising at night, and it was determined that the average time until diagnosis was 2 months. PPD (skin test) test was positive in all cases. Although the frequency of tuberculosis has decreased over the years in series in developed countries, new tuberculosis cases are increasing with the increase in HIV infection.
In our study, brucellosis was diagnosed in 5 of 24 infection cases. Although it is quite rare in foreign series, it is not rare in the series in our country. Wright agglutination test, hemoculture and, if necessary, Diagnosis can be made with emic marrow culture. In these patients, the diagnosis was made with the agglutination test being positive at high titers.
Infective endocarditis was detected in two cases. In both cases, there were attacks of fever (39-400C) with widespread body pain and chills, a systolic murmur in the precordial area on physical examination, and splenomegaly in one case. In one case, methicillin-resistant staphylococcus and in the other case, alpha hemolytic streptococcus grew in the second blood cultures. In both cases, vegetations located on the mitral valve were detected in transthoracic echocardiography, and in the second case, rheumatic heart valve disease was present.
In one case, monoarthritis and polyserositis were detected from the beginning, and in further examinations, thick drops, serological methods were detected. and Leptospirosis was diagnosed with culture. When the literature was scanned, it was seen that the coexistence of leptospirosis and polyserositis was quite rare.
In our study, various tumors were detected in 18% of the cases and inflammatory rheumatic diseases were detected in 30%. When compared with previous studies, it was understood that they were at similar frequencies. Adult Still's disease was diagnosed in six patients (10%). Classic disease symptoms are high fever, skin rash and arthritis/arthralgia. Oligo/polyarthritis findings were detected in all of our patients, maculopapular skin rashes in two, and hepatosplenomegaly in one. Neutrophilic leukocytosis, high sedimentation and increased ferritin values were found in all patients. There were no degenerative changes in the joint spaces on plain radiographs. The fact that adult Still's disease comes first in the group of inflammatory rheumatic diseases is attributed to the fact that the diagnosis is made by eliminating other possible causes in the differential diagnosis as well as clinical findings, and other group diseases can be detected in a short time thanks to advanced techniques. Among the most likely diseases included in the differential diagnosis in our country, tuberculosis, acute rheumatic fever, infective endocarditis, viral hepatitis, inflammatory rheumatic diseases (systemic lupus erythematosus, mixed connective tissue diseases), vasculitides, tumors and, more rarely, HIV infection and sarcoidosis should be considered.
Fever cases of unknown cause in foreign series� In 9-25% of cases, etiology could not be determined despite detailed examinations. In patients for whom a definitive diagnosis could not be reached, empirical treatments were selected considering the possible diagnosis. As revealed in this study, the diagnosis could be made by biopsy in only three of the 12 tuberculosis cases and by culture in one, while in the other cases the diagnosis was confirmed by clinical findings, PPD positivity, family anemnesis and response to treatment. Similarly, primary splenic lymphoma was suspected in one of our patients in the light of fever, splenomegaly and other biochemical values. The patient's general condition and platelet count did not allow splenectomy, and the patient's general condition improved in a short time as a result of the treatment initiated with the clinical diagnosis.
Imaging methods have played a major role in reducing the frequency of fever of unknown origin in recent years. Although it is not definitively diagnostic, diagnosis can be made in a short time with invasive radiological examinations performed with these methods. During the examinations, we also used various imaging methods in many of our patients (computed tomography, magnetic resonance imaging, PET-CT and scintigraphic methods were used in the diagnosis of solid and hematological malignancies).
In all cases 11 patients were in the geriatric age group (≥ 65 years). In this group, malignancies came first in 5 patients (metastatic adenocarcinoma of unknown primary in two patients, primary splenic lymphoma in one patient, non-Hodgkin lymphoma in one patient, and mesothelioma in one patient). Inflammatory rheumatic disease (Crohn's disease, temporal arteritis and necrotizing vasculitis) was detected in three patients and infection (infective endocarditis and granulomatous hepatitis due to tuberculosis) was detected in two patients. In one patient, no cause was found. It should not be forgotten that infections may occur with atypical findings in geriatric patients. Fever may not occur in 20-30% of patients or may be detected later. Delay in diagnosis can significantly increase the risk of morbidity and mortality.
There is no specified algorithm for fever cases of unknown cause. Routine examinations following detailed anamnesis and physical examination can give insight and point in the direction of further laboratory examination. As revealed in our study NBA cases should be investigated within three main groups. These are primarily infections, inflammatory rheumatic diseases and tumors. When suspected, HIV infection and rare infections (one of our patients was diagnosed with leptospirosis) should be investigated. Relevant serological examinations should be performed for inflammatory rheumatic diseases and necessary imaging methods and interventional techniques should be applied for tumors.
In our country, infections rank first among the causes of fever of unknown origin. As in our study, tuberculosis and brucellosis constitute the majority of this group. In the group of inflammatory diseases, the number of adult Still's disease is noteworthy. As laboratory techniques develop and accelerate, it is possible that the number of patients included in the definition of fever of unknown origin in clinics will decrease and some changes will be made in this definition. It is very important to be meticulous in anamnesis and physical examination before differential diagnosis.
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