The results of our retrospective analysis showed that the most common cause of classic FUO is infectious disease, which are followed by connective tissue disease. The results are consistent with most previous studies at home and abroad   . The causes of FUO are related to diseases, among which the incidence of connective tissue disease is higher in women than men, while the incidence of infectious disease is more common in men, and the incidence of neoplastic disease is not significantly correlated with gender. There is no significant difference in the incidence of infectious disease in all age groups, and connective tissue disease is more common in patients under 40 years of age, and the incidence of neoplastic disease in patients over 40 years old increases. The time from onset to final confirmation of the cause of FUO also varies. Through the retrospective study, we found that the diagnoses of infectious diseases in West China Hospital were not significantly associated with durations of fever, while foreign studies have shown that the time required for diagnosis of infectious disease is usually short . The lung infections and biliary tract infections involved in this study could not be diagnosed until more than 30 days after the onset of fever. This may be related to the fact that Chengdu is located in the western part of China, and the distribution of primary medical resources is uneven, resulting in some patients unable to seek medical treatment in time. Generally, after hospitalization, FUO patients will routinely undergo chest and abdominal radiographic, bone marrow needle biopsy, and immune function examinations. Therefore, most of the connective tissue diseases and neoplastic diseases involved in this study were diagnosed quickly.
Among the infectious diseases that cause FUO, tuberculosis is the most common, but a large number of tuberculosis patients were not diagnosed by pathogenic investigation, but were diagnosed based on the effectiveness of diagnostic anti-tuberculosis treatment. By reviewing the results of adjuvant examinations, we found that in most tuberculosis patients with long-term fever, the white blood cell count was normal or increased, the proportion of neutrophil was increased, the erythrocyte sedimentation rate and C - reactive protein were increased, and the increase of procalcitonin was lower than that in patients with common bacterial infections. Some other tuberculosis patients, through bone marrow biopsy, were found to have DNA fragments of mycobacterium tuberculosis, or that their bone marrow smears were positive for acid-fast staining, which further reminds clinicians of the importance of bone marrow biopsy for patients with FUO. In addition to tuberculosis, some infectious diseases such as kala-azar also require bone marrow biopsy to be effectively diagnosed.
Due to the popularity of radiographic examination methods such as CT and MRI, FUO caused by deep abscess has become rare, and only 19 cases were involved in our study. FUO caused by sepsis is still common, and there are some special pathogens like brucellosis. Therefore, patients with FUO should receive blood culture examination during fever. When deep abscess exists and is not easy to drain, positive blood cultures can also help reasonable selection of antibacterial drugs.
Among the connective tissue diseases that cause FUO, AOSD is the most common. By reviewing the results of adjuvant examination of cases diagnosed as AOSD, we found that, in most AOSD patients serum iron ferritin was significantly increased, and procalcitonin was also increased. Procalcitonin, as an indicator of serologic evaluation of the presence of bacterial infection, has attracted increasing attention from clinicians. However, exclusion of infection is necessary in diagnosis of AOSD, so the increase of procalcitonin brings some interference to the diagnosis. AOSD is characterized by increased white blood cell count and mainly neutrophil. It is sometimes difficult to distinguish AOSD from bacterial infection. Therefore, the typical signs of rash and the increase of ferritin should receive special attention. Compared with AOSD patients, ferritin in patients with bacterial infections tends to be normal or only slightly increased.
Some connective tissue diseases have positive autoantibodies, but they cannot be classified as a specific autoimmune disease. The diagnoses of undifferentiated connective tissue diseases in our hospital usually require diagnostic treatment of glucocorticoids or immunosuppressive agents to be confirmed.
Similar to FUO caused by deep abscesses, FUO caused by solid tumors has become rare due to the popularity of radiographic examination methods. Only 32 solid tumors were involved in our study, accounting for 1.95% of the causes of all the cases of FUO. Hematological tumors, especially lymphoma, were the most common neoplastic diseases causing FUO. In our retrospective study, many cases of diffuse large B-cell lymphoma and NK\T-cell lymphoma were found, and a large proportion of them were secondary to EB virus infection. The clinical manifestations of lymphoma are diverse. We found that a large proportion of the lymphoma patients had skin lesions and nasopharynx ulcers. The lymphoma patients were diagnosed by skin or mucosal biopsy. It should be noted that the bone marrow biopsy of such patients often has no positive results, so it is necessary to pay attention to physical examinations to understand whether there are skin and mucous membrane related lesions in order to facilitate timely biopsy. In addition to bone marrow biopsy, attention should be paid to the flow cytometry of bone marrow, serous membrane effusion, and peripheral blood. Some lymphoma and multiple myeloma’s bone marrow biopsies do not produce specific indications, but can be diagnosed by flow cytometry.
Sometimes, patients with hematological tumors cannot receive invasive examinations such as bone marrow puncture due to reasons such as thrombocytopenia and coagulation dysfunction, but they should actively receive routine blood tests and blood biochemical tests. In patients diagnosed with hematological malignancies, the probability of finding abnormal cells by routine blood tests is high; the detection of significant increase in lactate dehydrogenase and triglycerides through blood biochemical tests is suggestive. It has also been reported at home and abroad that 66.66% of patients with non-Hodgkin lymphoma have increased lactate dehydrogenase; the increase of lactate dehydrogenase in patients with highly malignant lymphoma is greater than that in patients with low-grade malignant lymphoma (P<0.05) . Some scholars even suggested that the level of lactate dehydrogenase could be used as an independent indicator  to judge the prognosis of patients with lymphoma. Our study also shows that lymphoma accounts for the highest proportion of neoplastic diseases causing FUO, so clinicians should pay more attention to markedly increased lactate dehydrogenase.
The clinical manifestations of lymphoma and tuberculosis causing FUO are not characteristic, and it is often difficult to distinguish between the two, but we failed to find the clinical features and routine laboratory investigation methods for distinguishing between lymphoma and tuberculosis. Diagnosis of lymphoma often needs to be confirmed by pathological examination, but serological and pathogenic examinations of tuberculosis are often suggestive, which reminds clinicians to complete specific examinations (such as tuberculosis infection T-cellγinterferon release test, PPD skin test, tuberculosis antibody test, etc.) related to tuberculosis for patients with FUO caused by diseases that are difficult to diagnose, so as to shorten the time required for diagnoses and reduce invasive examinations.
Of the 137 patients who were discharged from the hospital with unclear causes of their FUO, only a few were seriously ill and most were well. These patients are characterized by a long course of disease, non-suggestive adjuvant investigations, slightly increased inflammatory indicators such as blood sedimentation and C - reactive protein, and effective treatment with anti-inflammatory drugs such as glucocorticoids and non-steroidal anti-inflammatory drugs. PET-CT has been reported at home and abroad to be of great significance for the diagnoses of cases of classic FUO that are difficult to identify  . However, due to the constraints of economic development in western China, few FUO patients can receive PET-CT examination in our hospital, which needs further improvement in the future.