The purpose of this study is to determine whether two-step method of diagnostic strategy is effective in the diagnosis and treatment of fever of unknown origin (FUO). (TSMD research, a pilot study) Fever of unknown origin (FUO) is a fever in excess of 38.3◦C continued for more than 3 weeks, and its cause could not be identified by tests during hospitalization for more than 1 week [1]. As diagnostic techniques such as imaging technology and clinical tests have been developed and outpatient access to diagnostic tests have improved, the FUO is defined as a shortened period where the cause could not be revealed despite diagnostic tests during three visits to the outpatient department or during 3 days of hospitalization [2]. FUO can be caused by many diseases, and causes can vary depending on region and time period. FUO was first reported in the medical literature 80 years ago. Since then, the causative diseases have greatly changed with changes in the social environment and widespread use of diagnostic imaging. The causes of FUO, according to traditional diagnosis and treatment, could be divided into four principal groups: infections, non-infectious inflammatory diseases (NIID, including rheumatic diseases and vasculitic diseases), neoplasms, and other diseases. Despite the development of various diagnostic techniques, 34-51% of FUO patients remain undiagnosed [3,4]. In China, over-reliance on antibiotics for disease therapy and infection prevention are common phenomena in traditional treatment of FUO[5].

Two-step method of diagnostic strategy is a method to diagnose FUO disease. First step is to differentiate FUO according to the onset of disease and invasive pathogens. Second step is to further differentiate FUO according to trends of disease and inflammation scores. The diagnosis of FUO can be difficult for both patients and their physicians. Depending on the experience and qualifications of the treating physicians, time to reach a diagnosis can vary. Two-step method of diagnostic strategy would afford a standard method for physicians to diagnoses the FUO.

So many reports of FUO have also been published in China, but have been limited to single-facility or limited-region studies; no nationwide studies have yet been conducted. Moreover, few assessments of tests used in the diagnostic evaluation of FUO have been reported. In particular, few studies have assessed the clinical usefulness of tests such as serum procalcitonin or positron emission tomography (PET) in China, although these tests are now frequently used.

We therefore will conduct a multicenter collaborative retrospective and prospective （randomized and controlled ）study of patients with FUO at hospitals affiliated with China's Ministry of Health. This is the first nationwide study in China on diseases causing FUO and the diagnostic workup, and identified diseases that should be considered when evaluating FUO in China. In addition, we will investigate the rate of performing various tests in the current diagnostic workup of FUO.

Classical FUO was diagnosed based on the definition by Durack et al[6] in patients meeting all of criteria 1-4 below.

1. Fever with axillary temperature ≥38°C at least twice over a ≥3-week period. 2. Unknown cause after three outpatient visits or during 3 days of hospitalization.

3. Not diagnosed with immunodeficiency before fever onset. 4. No confirmed HIV infection before fever onset. The data described below were collected. No additional testing was performed in this study due to insufficient data.

1. Patient characteristics: sex, age, concomitant disease, medical history and medication history.
2. Clinical findings: subjective symptoms and objective physical findings.
3. Blood tests: blood count, biochemical examination and inflammatory markers (C reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin, etc.).
4. Results of blood cultures if performed.
5. Results of imaging studies and endoscopy if performed.
6. Results of cytology, histology, genetic testing or autopsy findings if performed.
7. Final diagnosis, day of diagnosis and outcome. This study is safety for no drug involved to determine the effectiveness of two-step method of diagnostic strategy in the diagnosis and treatment of fever of unknown origin.

Inclusion Criteria:

• Clinical diagnosis of FUO
• Agreed to take part in this study

Exclusion Criteria:

• Diagnosed with immunodeficiency before fever onset.
• Confirmed HIV infection before fever onset.
• Hospitalized patients and hospital acquired infection cannot be ruled out
• Medical history of serious mental illness
• Medical history of severe seizures or using anticonvulsants currently
• Confirmed with HIV infection before fever onset or organ transplant patients, using glucocorticoid or immunsuppression or any other patients who are not considered to be suitable for this study
• having evidence of drug abuse or treat with methadone in the previous year
• included in other clinical trials
• unable or unwilling to provide informed consent or follow the request.

patients meeting the definition of Classical FUO :

1. Fever with axillary temperature ≥38°C at least twice over a ≥3-week period.
2. Unknown cause after three outpatient visits or during one week of hospitalization.