A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol

We conducted a prospective study to update our knowledge of fever of unknown origin (FUO) and to explore the utility of a structured diagnostic protocol. From December 2003 to July 2005, 73 patients with FUO were recruited from 1 university hospital (n = 40) and 5 community hospitals (n = 33) in the same region in The Netherlands. FUO was defined as a febrile illness of >3 weeks' duration, a temperature of >38.3 degrees C on several occasions, without a diagnosis after standardized history-taking, physical examination, and certain obligatory investigations. Immunocompromised patients were excluded. A structured diagnostic protocol was used. Patients from the university hospital were characterized by more secondary referrals and a higher percentage of periodic fever than those referred to community hospitals. Infection was the cause in 16%, a neoplasm in 7%, noninfectious inflammatory diseases in 22%, miscellaneous causes in 4%, and in 51%, the cause of fever was not found (no differences between university and community hospitals). There were no differences regarding the number and type of investigations between university and community hospitals. Significant predictors for reaching a diagnosis included continuous fever; fever present for <180 days; elevated erythrocyte sedimentation rate, C-reactive protein, or lactate dehydrogenase; leukopenia; thrombocytosis; abnormal chest computed tomography (CT); and abnormal F-fluorodeoxyglucose positron emission tomography (FDG-PET). For future FUO studies, inclusion of outpatients and the use of a set of obligated investigations instead of a time-related criterion are recommended. Except for tests from the obligatory part of our protocol and cryoglobulins in an early stage, followed by FDG-PET, and in a later stage by abdominal and chest CT, temporal artery biopsy in patients aged 55 years or older, and possibly bone marrow biopsy, other tests should not be used as screening investigations.     

Inflammation of unknown origin versus fever of unknown origin: Two of a kind

ObjectivesA vast literature exists on fever of unknown origin (FUO), characterized by prolonged and perplexing fevers > 38.3 °C. In contrast, no studies are available to guide the approach to inflammation of unknown origin (IUO), defined as prolonged and perplexing inflammation with temperatures < 38.3 °C. We aimed to determine the diagnostic yield, the case-mix, and the outcome of patients with IUO, relative to patients with FUO.MethodsWe matched 57 patients with IUO to 57 patients with FUO of the same gender (54% male) and a similar age (median: 67 years).ResultsA diagnosis was established in 35 patients with IUO (61%) and in 33 patients with FUO (58%) (p = .70). The case-mix did not differ significantly (p = .43). Non-infectious inflammatory disorders were the dominant diagnostic category in the IUO group (16 patients), while in the FUO group, similar numbers of malignancies [10], infections [9], and non-infectious inflammatory diseases [9] were diagnosed. ¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan contributed comparably to the diagnosis in both groups (in 18 of 50, 36%, patients with IUO and in 13 of 40, 33%, patients with FUO) (p = .83). In both groups, 7 patients (12%) died during an average follow-up of 1 year.ConclusionDiagnostic yield, case-mix, contribution of FDG-PET scan and vital outcome were similar in patients with IUO and FUO. These data suggest that the 38.3 °C boundary may be arbitrary and that the diagnostic approaches used in FUO can be applied to IUO.     

Rheumatologic diseases as the cause of fever of unknown origin

In 30% of patients with fever or inflammation of unknown origin (FUO/IUO), the cause is eventually found to be a rheumatologic disease such as autoimmune or granulomatous disease or vasculitis. Most of these patients suffer from an uncommon presentation of a common disease, instead of an uncommon disease. We demonstrate the diagnostic challenge with several cases. The workup of FUO is based on the identification of potential diagnostic clues (PDCs). In the absence of PDCs, a standardized diagnostic protocol should be followed, including early FDG–PET/CT. Other imaging techniques or invasive diagnostic techniques should be reserved for those in whom PDCs are present.     

感染性疾病是不明原因长期发热的重要病因

不明原因长期发热(fever of unknown origin,FUO),其定义为发热持续2～3周以上,体温≥38.5℃,经详细询问病史、体检和常规实验室检查仍未能明确诊断者.FUO的原因复杂,但可概括为感染、结缔组织病、血液病及恶性肿瘤四大类.     

人巨细胞病毒感染所致不明原因发热临床分析

目的提高人巨细胞病毒(HCMV)所致不明原因发热(FUO)的重视。方法对确诊的36例HCMV所致FUO患者病例资料进行临床分析。结果发病以年轻人为主,女性多于男性,主要表现为FUO;血清学检测巨细胞病毒IgG、IgM(CM-VIgG、IgM)均明显升高,而此项检查在发病早期均被医生忽视,致使延误诊断。结论 HCMV所致的FUO是容易被忽视的病因;FUO引发患者的焦虑大于疾病本身的痛苦;HCMV相关项目检测是诊断该病重要客观指标。     

Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study

Familial Mediterranean fever (FMF) is an autosomal recessive disease that is prevalent among eastern Mediterranean populations, mainly non-Ashkenazi Jews, Armenians, Turks, and Arabs. Since a large proportion of all the FMF patients in the world live in Turkey, the Turkish FMF Study Group (FMF-TR) was founded to develop a patient registry database and analyze demographic, clinical, and genetic features. The cohort was composed of 2838 patients (mean age, 23.0 +/- 13.33 yr; range, 2-87 yr), with a male:female ratio of 1.2:1. There was a mean period of 6.9 +/- 7.65 years from disease onset to diagnosis; the period was about 2 years shorter for each decade since 1981. Ninety-four percent of patients were living in the central-western parts of the country; however, their familial origins (70% from the central-eastern and Black Sea regions) reflected not only the ongoing east to west migration, but also the historical roots of FMF in Turkey. Patients' clinical features included peritonitis (93.7%), fever (92.5%), arthritis (47.4%), pleuritis (31.2%), myalgia (39.6%), and erysipelas-like erythema (20.9%). Arthritis, arthralgia, myalgia, and erysipelas-like erythema were significantly more frequent (p < 0.001) among patients with disease onset before the age of 18 years. Genetic analysis of 1090 patients revealed that M694V was the most frequent mutation (51.4%), followed by M680I (14.4%) and V726A (8.6%). Patients with the M694V/M694V genotype were found to have an earlier age of onset and higher frequencies of arthritis and arthralgia compared with the other groups (both p < 0.001). In contrast to other reported studies, there was no correlation between amyloidosis and M694V homozygosity in this cohort. However, amyloidosis was still remarkably frequent in our patients (12.9%), and it was prevalent (27.8%) even among the 18 patients with a disease onset after age 40 years. Twenty-two patients (0.8%) had nonamyloid glomerular diseases. The high prevalence of vasculitides (0.9% for polyarteritis nodosa and 2.7% for Henoch-Schonlein purpura) and high frequency of pericarditis (1.4%) were striking findings in the cohort. Phenotype II cases (those patients with amyloidosis as the presenting or only manifestation of disease) were rare (0.3% or less). There was a high rate of a past diagnosis of acute rheumatic fever, which suggested a possible misdiagnosis in children with FMF presenting with recurrent arthritis. To our knowledge, this is the largest series of patients with FMF reported from 1 country. We describe the features of the disease in the Turkish population and show that amyloidosis is still a substantial problem.     

脾脏切除在长期发热伴脾脏肿大中的诊断价值

目的 探讨发热待查在临床上公有脾肿大供组织学诊断中行脾切除术的价值。方法 回顾分析了我院血液科1996年来以发热待查收住院,除发热、脾肿大外无其它阳性体征,且辅助检查也为阴性的14例患者的临床资料,行脾切除术后取脾脏作病理学检查。结果 14例患者中,霍奇金淋巴瘤3例,非霍奇金淋巴瘤5例,结缔组织病3例,恶性组织细胞病2例,脾陈旧性梗死1例。随访15－54个月,3例结缔组织病完全缓解;1例脾陈旧性梗死痊愈;淋巴瘤3例完全缓解,1例部分缓解。结论 发热待查而临床上仅有脾肿大时,应动员患者尽早地作诊断性脾切除术并送病理学检查,以免延误诊断和治疗。     

Clinically benign fever of unknown origin: a personal retrospective

The purpose of this discussion has been to bring to the attention of physicians the fact that all instances of etiologically undefined persistent fever are not associated with potentially serious or life-threatening organic disease, regardless of the height of the temperature. As has been pointed out, many patients with FUO clearly have disorders that are clinically benign, and the cause of these disorders is defined much more frequently on the basis of information obtained from a detailed historic inquiry than on the basis of findings made during the most meticulous physical examination and extensive laboratory studies. These individuals are usually seen first in an outpatient setting and seldom, if ever, require hospitalization because the cause of their FUO can, with uncommon exceptions, be identified as a physiologic or emotional dysfunction, a reaction to a drug or a chemical, or a disorder that is genetically determined. Failure to recognize that even a high elevation of the temperature can represent a clinically benign situation may lead to unnecessary hospitalization, during which the many investigations that are usually carried out may serve only to reinforce the patient's concern about a serious disease. It is most important for both patients and physicians to be aware that temperature, like all other physiologic and chemical measurements in humans, is expressed by a range of values and that a temperature of 98.6 degrees F is not normal for all persons. It must also be appreciated that "normal" temperature varies with age. The newborn infant may develop high-grade fever in the absence of disease because of marked instability of the vasomotor system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fever of unknown origin in Turkey: evaluation of 87 cases during a nine-year-period of study

OBJECTIVES: To investigate fever of unknown origin (FUO) in 87 patients. METHODS: We investigated 87 (61 male) patients with FUO using the criteria of Petersdorf and Beeson [Medicine 40 (1961) 1] hospitalized between January 1994 and August 2002 at Cukurova University Hospital. RESULTS: The median age of the patients was 38.5 years (range: 14-80 years). Eleven patients (12.6%) were over 65. The mean duration of hospitalization was 22.5+/-13 days. Infectious diseases were the most common causes of FUO. Tuberculosis (n=15, 17.2%), infective endocarditis (n=6), abdominal abscess (n=6), brucellosis (n=5), urinary tract infection (n=5), visceral leishmaniasis (n=4), salmonellosis (n=3), rhinocerebral mucormycosis (n=4), atypical pneumonia, cerebral toxoplasmosis, Cytomegalovirus infection or encephalitis were diagnosed in 51 (58.6%) patients. The second most common causes of FUO were collagen vascular diseases (n=16, 18.3%) determined as vasculitis syndrome, adult Still's disease (n=4), systemic lupus erythematosus, Beh?et's disease, juvenile ankylosing spondylitis. Neoplasm was found in 12 (13.7%) patients; (non-Hodgkin lymphoma, Hodgkin lymphoma, chronic myeloid leukemia, gastrointestinal tract carcinoma, glioma). Miscellaneous diseases thyroiditis, granulomatous hepatitis were diagnosed in two (2.2%) patients. On admission, six patients (6.8%) were neutropenic. CONCLUSIONS: Infectious diseases, especially tuberculosis, were the leading diagnostic category of FUO in this study. Adult Still's disease was more common than expected. An aetiological diagnosis could not be reached in six (7%) patients who were followed for 1 year. Five of these patients completely recovered, and one patient died.     

Differential diagnosis in fever of unknown origin

Fever is one of the most frequent and important symptoms in pediatrics. Most cases are caused by self-limiting viral or easily treatable bacterial infections. If after 5-7 days no cause of the ongoing fever has been found, the condition is termed fever of unknown origin, a working diagnosis which often poses a diagnostic challenge. The ultimate cause may be an infectious disease, a chronic inflammatory disorder, a malignancy, or another rare disease. The cause may also remain obscure or the fever can finally disappear. Here we elaborate the diagnostic work-up and symptomatic treatment.     

Primary antiphospholipid syndrome: a cause of fever of unknown origin

Antiphospholipid syndrome (APS) is defined as the occurrence of thrombosis, recurrent miscarriage, or both in association with laboratory evidence of persistent antiphospholipid antibodies. Owing to protean manifestations and laboratory studies, the diagnosis may be difficult. Because the other signs and symptoms of thrombosis are predominant, prolonged fever is not usually the main clinical finding. We describe a patient who presented with fever of unknown origin (FUO) and was found to have thromboses of the splenic vein, the superior mesenteric vein, and the portal vein due to the primary antiphospholipid syndrome. We also reviewed the medical literature (Medline 1966-2001), including the main FUO series of the previous 40 years, and laparotomy series for FUO. We conclude that although very rare, primary APS and thrombosis may present with FUO. APS should be considered in the differential diagnosis of prolonged fever associated with thrombosis.     

Granulomatous hepatitis caused by Q fever: a differential diagnosis of fever of unknown origin

The differential diagnosis of fever of unknown origin (FUO) includes infectious, neoplastic, rheumatic-inflammatory and miscellaneous diseases. We report the case of a 35-year-old man with FUO caused by Q fever. A liver biopsy showed the characteristic fibrin-ring lipogranulomas compatible with Q fever. The serologic tests confirmed the diagnosis of acute infection by Coxiella burnetii. The therapeutic response was excellent. In conclusion, we described a patient with acute Q fever and granulomatous hepatitis.