Fever of Unknown Origin in Taiwan

Abstract Background: Fever of unknown origin (FUO) is a challenging problem worldwide. There was no prospective study of FUO in the past two decades in Taiwan. A prospective study was conducted. Materials and Methods: The prospective study was undertaken from March 2001 to May 2002. All patients fulfilling the modified criteria for FUO, either admitted, referred or consulted in a medical center in southern Taiwan, were enrolled for analysis. Results: A total of 94 cases met the criteria of FUO. The final diagnoses of FUO consisted of 54 infectious diseases (57.4%), 8 hematologic/neoplastic (8.5%), 7 noninfectious inflammatory (7.4%), 8 miscellaneous (8.5%) and 17 undiagnosed (18.1%) cases. The single most common cause of FUO was tuberculosis. Some infectious diseases, such as rickettsiosis and melioidosis, were rarely reported in western countries. Three patients with hemophagocytotic syndrome without ascertainable etiologies were present with FUO in this study. Between the patients with and those without a final diagnosis, the short-term survival (3 months) was compared by the Kaplan–Meier analysis, which revealed no difference. Conclusions: Mycobacteriosis is still the leading cause of FUO in Taiwan and it is important to identify this treatable disease from all causes of FUO. This study has showed geographical variation among the studies of FUO.     

Crohn’s disease complicated by adult-onset Still’s disease

A 31-year-old man with Crohns disease developed arthritis, spiking fever, and skin rash indistinguishable from that of adult-onset Stills disease. He was admitted to our hospital because of a periumbilical intestinal skin fistula. Crohns disease had been diagnosed in 1991, and had required intestinal resection twice, and schizophrenia had been diagnosed in 1993. He developed polyarthritis and spiking fever, accompanied by a macular skin rash on both forearms. Marked hepatosplenomegaly and bilateral pleural effusion were detected on computed tomography examination. These findings are indistinguishable from those of adult-onset Stills disease. Because his mental status had deteriorated following high-dose prednisolone on a previous admission, he was treated with an immunosuppressive agent on this occasion, with the treatment being successful. This is the first report of adult-onset Stills disease complicating Crohns disease. In patients with Crohns disease, polyarthritis and skin rash can easily be misdiagnosed as enteropathic arthritis with erythema nodosum associated with the Crohns disease. Although adult-onset Stills disease may not be fatal, early diagnosis is important because it can, in rare cases, result in life-threatening complications.     

Fever of unknown origin: analysis of 71 consecutive cases

BACKGROUND: Fever of unknown origin (FUO) is still an important problem in clinical practice. Evaluation of patient characteristics may clarify the utility of diagnostic tests and etiologies of FUO. METHODS: Fever of unknown origin in 71 patients was investigated at Ankara Numune Education and Research Hospital in Turkey between February 2001 and December 2004. RESULTS: Mean hospital stay and fever duration was 20.5 days and 44 days, respectively. Etiologies of FUO were as follows: infections 32 (45.1%), collagen vascular disease 19 (26.8%), neoplasm 10 (14.1%), and miscellaneous diseases 4 (5.6%). Diagnosis remained obscure in 6 patients (8.5 %). Tuberculosis was found to be 40% of the infectious causes of FUO. Mean hospital stay and fever duration were prolonged in infectious cases. Female predominance was observed in collagen vascular diseases (P = 0.047). Splenomegaly and lymphadenopathy were common in the neoplasm group (P = 0.017, P = 0.017, respectively). Erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase and lactate hydrogenase levels were elevated in patients with collagen vascular diseases. Nine (12.7%) patients died during the follow-up period. CONCLUSIONS: Hospital stay and fever duration were prolonged in the infectious group of FUO patients. Infectious diseases, particularly tuberculosis, were the most important cause of FUO in our series. Tuberculosis should be kept in mind as an important etiology of FUO countries where tuberculosis is endemic.     

发热待查75例临床分析

目的探讨不明原因发热(FUO)的病因和临床特征。方法回顾性分析2005年1月～2012年1月在我科住院且符合FUO诊断标准的75例患者的临床资料,总结了病因、诊断方法和临床表现。结果 75例患者中,68例(90.7%)最终确诊,感染性疾病22例(32.4%),其中结核病9例(40.9%)、传染性单核细胞增多症5例(22.7%);结缔组织病29例(42.6%),其中成人Still病17例(58.6%)、系统性红斑狼疮6例(20.7%);恶性肿瘤10例(14.7%),其中淋巴瘤6例(60.0%);其他疾病7例(10.3%),其中组织细胞坏死性淋巴结炎4例(57.1%)。结论 FUO涉及的病因众多,发病机制复杂,感染性疾病、结缔组织病仍是发热待查的主要原因,肿瘤性疾病在发热待查中也占相当的比例,临床工作中要开阔思路,全面搜集资料,以利于明确诊断。     

长期不明原因发热388例临床分析

目的 探讨不明原因长期发热患者的病因.方法 分析在我院住院诊治且符合不明原因发热诊断标准的388例患者的临床资料.结果 388例患者中经各种检查或诊断性治疗最终明确诊断者253例,确诊率为65.2%.病因：感染性疾病131例,占51.8%,其中结核病55例,占感染性疾病的42.0%（55/131）;结缔组织病69例,占27.3%,成人still病占结缔组织病的30.3%（20/69）;肿瘤37例,占14.6%,其中淋巴瘤占86.4%（32/37）;其他疾病16例,占6.3%;原因未明者135例,占34.8%.结论 感染性疾病仍然是不明原因发热的主要病因,结核病尤其是肺外结核占较大比例.肿瘤性疾病和结缔组织病在发热待查中也占有相当比例,淋巴瘤和成人still疾病是这两类疾病的主要病种.     

Utility of polymerase chain reaction in diagnosis of tuberculosis from samples of bone marrow aspirate

Fever of unknown origin (FUO) poses a diagnostic challenge to the clinicians, with a differential diagnosis as varied as neoplastic and infectious diseases. In developing countries, the infectious causes are responsible for more cases of FUO, with tuberculosis as one of the main causes of classic FUO. Disseminated tuberculosis with negative pulmonary findings is a diagnostic problem. This study examines the diagnostic utility of the polymerase chain reaction (PCR) in samples of bone marrow aspirate in 85 patients presenting with diverse clinical symptoms. Using primers specific for Mycobacterium tuberculosis, tubercular etiology was detected in 33% of patients clinically suspected of tuberculosis while culture on Lowenstein-Jensen medium grew M. tuberculosis in only one patient (2.5%). None of these patients had been diagnosed by microscopy. Clinical improvement with ATT was observed in 85% of the patients with positive PCR. PCR demonstrated much higher sensitivity and specificity, thereby facilitating early therapeutic decisions for suspected extrapulmonary tuberculosis.     

不明原因长期发热110例临床分析

目的探讨我国不明原因长期发热的病因。方法回顾性地总结分析１９９５年１月至１９９６年１２月间在我科住院且符合不明原因长期发热（ＦＵＯ）诊断标准的患者１１０例。结果１１０例患者经各种检查或特异性治疗最后明确诊断者有１０２例，确诊率为９２７％。病因：感染性疾病５８例，占５２７％，其中结核病２７例，占感染性疾病的４６６％（２７／５８）；自身免疫性疾病２１例，占１９１％，Ｓｔｉｌ病占自身免疫性疾病的４２９％（９／２１）；肿瘤性疾病７例，占６４％；其他疾病１６例，占１４５％；原因仍未明者８例，占７３％。结论感染性疾病仍然是ＦＵＯ的主要病因，结核病尤其是肺外结核的发病率有增高趋势，本组肺外结核占３１０％（１８／５８）；其次自身免疫性疾病和肿瘤性疾病在ＦＵＯ中也占有相当比例，Ｓｔｉｌ病和不典型淋巴瘤诊断比较困难，但大多数ＦＵＯ通过仔细检查和分析最终可明确诊断     

老年人发热病因及临床特征分析

目的分析老年人发热性疾病的病因与临床特征。方法收集温州医学院附属第一医院2001-01~2004-04以发热为首发临床表现住院、资料完整且符合发热诊断标准的患者87例,进行回顾性分析。结果87例患者中,感染性疾病44例,结缔组织病4例,恶性肿瘤9例,其他疾病5例,诊断不明25例。感染性疾病中结核病占6例(13·6%)。B超、X线胸片、CT、MRI、骨髓穿刺、组织活检检查的确诊率分别为21·1%、16·9%、63·0%、0、16·7%、57·1%。结论老年人发热性疾病由于症状不典型,诊断较困难。感染性疾病仍然是老年人主要的发热原因。详细的有针对性的病史询问、查体及常规实验室检查(特别是血沉)对发热性疾病的诊断很重要,早期、合理使用影像学检查技术及必要的侵入性检查对疾病诊断有一定帮助。     

Diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with fever of unknown origin

Background

While fever of unknown origin (FUO) remains a challenging problem in clinical practice, fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) has been considered helpful in diagnosing its cause. The present study is set to evaluate the diagnostic value of PET/CT for patients with FUO.

Methods

We analyzed the records of 48 patients with FUO (34 men and 14 women; mean age of 57-year-old with a range between 24- and 82-year-old). The patients were examined by ¹⁸F-FDG PET/CT and the results were compared to a final diagnosis that was established by additional procedures.

Results

A final diagnosis was established for 36 patients (75%). Among them, 15 patients had infectious diseases, 12 patients had malignancies, and 9 patients had non-infectious inflammatory diseases. Thirty-two abnormal PET/CT results correctly revealed the source of fever (true-positives). Abnormal PET/CT results were considered false-positives for 8 patients without diagnoses. Normal PET/CT results in 4 patients with no diagnoses were classified as true-negatives. Four patients with normal PET/CT results with diagnosed cause for FUO were considered false-negatives. Therefore, PET/CT had a positive predictive value of 80%, a negative predictive value of 50%, a sensitivity of 89%, and a specificity of 33% in patients with FUO.

Conclusions

Our study demonstrated that FDG-PET/CT is a valuable imaging tool for the identification of the etiology in patients with FUO. The results suggest that this procedure may be considered as a second-line test, especially when conventional structural imaging was normal or unable to distinguish lesions from benign and malignant.     

不明原因发热449例临床分析

目的探讨不明原因发热(FUO)的原因。方法回顾性分析2000年1月∽2003年12月间在我院住院诊治的符合不明原因发热诊断标准的患者449例。结果449例患者中经各种检查或诊断性治疗最终明确诊断者387例,确诊率为86．2％。病因包括：感染性疾病220例(56．8％),其中结核病96例,占43．6％(96／220);结缔组织病76例(19．6％),其中Still病占34．2％(26／76),系统性红斑狼疮占18．4％(14／76),血管炎占13．2％(10／76);肿瘤性疾病64例(16．5％),其中淋巴瘤占39．1％(25／64);其他疾病27例(7．0％),其中坏死性淋巴结炎占33．3％(9／27),伪热占22．2％(6／27),药物热占26％(7／27);出院时仍未确诊的62例(13．8％)。结论感染性疾病是本组FUO患者的主要病因,结核病是其中的主要病种,结缔组织病和肿瘤性疾病在本组FUO病因中也占重要地位;大多数FUO经仔细的临床检查和分析是可以得到确诊的。     

Pure red cell aplasia and adult-onset Still’s disease

Pure red cell aplasia (PRCA) associated with adult-onset Stills disease (AOSD) is very rare. In this report a 28-year-old woman was admitted with fever, skin rash, jaundice and anemia. She was diagnosed as having AOSD with PRCA by bone marrow examination. Treatment with high-dose prednisolone and intravenous immunoglobulin resulted in remission of the PRCA and a good response of the AOSD.Abbreviations ANA Antinuclear antibodies - AOSD Adult-onset Stills disease - PRCA Pure red cell aplasia - RF Rheumatoid factor     

Fever of unknown origin in uremic patients: a controlled prospective study.

Twenty-nine uremic patients with fever of unknown origin (FUO) admitted to our clinic between 1994 and 1998 were evaluated prospectively. A group of 50 consecutive non-uremic patients with FUO followed up during the same period was used for comparison. The causes of FUO found in the uremic and non-uremic groups, respectively were as follows: infectious diseases, 69 vs. 44% (p = 0.03); collagen vascular diseases, 6.9 vs. 6%; neoplasms, 3.4 vs. 26%; miscellaneous causes, 3.4 vs. 16%; and undiagnosed, 17.2 vs. 8%. Tuberculosis was the most common cause of FUO in both groups. The spectrum of underlying conditions for FUO in our uremic patients differed from that in the non-uremic patients and the uremic patients had a very high propensity for infectious diseases, especially tuberculosis.     

Evolution of the incidence and aetiology of fever of unknown origin (FUO), and survival in HIV-infected patients after HAART (Highly Active Antiretroviral Therapy)

BackgroundFever of unknown origin (FUO) is common among HIV-infected patients with a CD4+ T-lymphocyte cell count below 200 cells/ml. The use of HAART has transformed the evolution of AIDS and related diseases.Design and methodCase-control study, nested on a historical cohort of 3777 HIV-infected patients who were attended at “12 de Octubre” University Hospital in Madrid, Spain, between 1994 and 2000.Results276 FUO episodes were recorded, 58 of which occurred in patients receiving HAART. The significant decrease on the accumulated FUO incidence along the study period of 7.3 episodes per 100 HIV-infected patients after 1997 corresponded with the introduction of HAART. FUO was more frequent in patients who did not receive HAART. The aetiological spectrum of FUO was transformed by the introduction of HAART: the incidence of tuberculosis decreased while that of leishmaniasis increased. The four year survival in the non-FUO group increased when compared to that of patients who had had FUO. Similarly, this four year survival increased in patients who received HAART at the time of FUO versus those not receiving it.ConclusionsOur results confirm that the incidence of FUO has significantly decreased with the introduction of HAART. HAART has also transformed the aetiological spectrum related to FUO considerably. The most frequent cause of FUO in non-HAART patients on this study was the disseminated infection by Mycobacterium avium intracellulare (MAI), followed by tuberculosis, while leishmaniasis was its most common cause in patients receiving HAART. Survival decreased in patients who developed FUO; however, patients who received HAART at the time of FUO had longer survival than patients who did not.     

Infektionen als Ursache von Fieber unklarer Genese

Infectious diseases are important causes of fever of unknown origin (FUO). The spectrum of infectious agents is broad and diagnosis depends on careful evaluation of individual risk factors. Infectious diseases presenting as FUO are frequently atypical presentations of well known infections, e.g. tuberculosis or infectious endocarditis. In this review we present an overview of infectious causes of FUO classified into community acquired infections, nosocomial infections, and infections in immunocompromised hosts.     

A case of paraneoplastic syndrome mimicking adult-onset Still’s disease

A 49-year-old woman was admitted to our hospital because of fever of unknown origin. The patient had long-lasting spiking fever, hepatosplenomegaly, pleural effusion, and skin rash. Laboratory tests showed marked leukocytosis and an extremely high serum ferritin level (240000ng/ml) accompanied by disseminated intravascular coagulation and hemophagocytic syndrome. Most of the patients features were compatible with a diagnosis of adult-onset Stills disease (AOSD), the rash, however, was not a typical rheumatoid rash but multiforme erythema. Biopsy of a breast nodule revealed breast cancer, leading us to a diagnosis of paraneoplastic syndrome mimicking AOSD. Although this is a rare disorder, cases resembling the present one have been reported, indicating the importance of including paraneoplastic syndrome in the differential diagnosis of AOSD.     

Etiología del derrame pleural: análisis de más de 3.000 toracocentesis consecutivas

Objective

To investigate the etiology of pleural effusions (PE) in adults and the accuracy of pleural fluid (PF) cytology and cultures in malignant and infectious PE, respectively.

Patients and methods

Retrospective analysis of all consecutive patients with PE undergoing diagnostic thoracentesis during the last 19 years in a university hospital.

Results

The leading causes of PE among the 3,077 patients were: cancer (27%), heart failure (21%), pneumonia (19%), tuberculosis (9%), abdominal surgery (4%), pericardial diseases (4%) and cirrhosis (3%). Tuberculosis was the most common etiology in patients < 34 years of age (52%), whereas heart failure predominated in octogenarians (45%). The most common primary tumors in malignant PE were lung (37%) and breast (16%). The overall accuracy of PF cytology was 59%, although it was significantly lower in mesotheliomas (27%) and squamous cell lung cancer (25%). In infectious PE, only 30% of cultures yielded positive results, a percentage which increased two-fold (66%) in purulent fluids (empyemas). Viridans streptococci were the most commonly isolated pathogens (25.5%). The sensitivity of solid media cultures of PF for Mycobacterium tuberculosis was low (18.5%).

Conclusions

Three-quarters of patients with PE in whom a diagnostic thoracentesis was indicated had cancer, heart failure, pneumonia or tuberculosis. PF cytology and cultures give false negative results in a significant number of cases.     

Primary Cytomegalovirus Infection in Otherwise Healthy Adults with Fever of Unknown Origin: A 3-Year Prospective Survey

Abstract Background: Primary cytomegalovirus disease is probably still underestimated or missed in common clinical practice, and further prevalence studies should be performed, in particular in the setting of fever of underdetermined origin (FUO) in adults. Patients and Methods: In a 3-year prospective survey of 123 consecutive adult patients referred for FUO often associated with a broad spectrum of constitutional signs and symptoms, 18 patients (14.6%) were found to have a primary cytomegalovirus infection, after a clinical, instrumental and laboratory workup. Results: In the majority of cases, this syndrome was consistently associated with altered white blood cell count, abnormal T-lymphocyte subsets and ultrasonography-confirmed hepatosplenomegaly. On the other hand, altered white blood cell differential and serum hepatic enzymes, and constitutional signs and symptoms were absent in 11.1–27.8% of cases, and an initial laboratory cross-reaction with anti-Epstein-Barr IgM antibodies was detected in 44.4% of episodes. Non-specific signs and symptoms were the only features in 27.8% of patients with adult cytomegalovirus disease, thus, confirming that this disorder may be still clinically underestimated, until virologic assays are performed. A prolonged and varied spectrum of subjective disturbances (similar to those encountered in infectious mononucleosis), which often limited daily activities, involved nearly 30% of subjects, and lasted for 3–15 months after recovery of acute cytomegalovirus disease. Conclusion: In the clinical, laboratory, and instrumental workup for FUO, rapid recognition of a primary cytomegalovirus disease is useful to exclude alternative diagnoses, avoid non-necessary exposure to antibiotics, and reassure patients of their self-limiting, benign disorder.     

Successful treatment of refractory adult-onset Still’s disease with infliximab. A prospective,non-comparative series of four patients

In this prospective, non-comparative case series, four patients with severe and highly active adult-onset Stills disease (AOSD), refractory to high doses of corticosteroids (which had been combined with methotrexate in three of them) and methotrexate were treated with infliximab (initial dose 3–5 mg/kg, continuing at intervals depending on the patients individual disease activity). Resolution of their symptoms, which was evident within few days after the first infusion, and a parallel rapid improvement of the acute inflammatory response indices were observed in all. Concomitant corticosteroid treatment was reduced after the first courses of treatment with infliximab, which was well tolerated, and complete disease remission was sustained during a 5–18-month follow-up period. Although further studies to confirm long-term efficacy and safety in larger numbers of patients are needed, we suggest that administration of infliximab with observation for objective improvement is the treatment of choice in cases of AOSD refractory to conventional treatment.Abbreviations AOSD Adult-onset Stills disease - CRP C-reactive protein - ESR Erythrocyte sedimentation rate - LDH Lactic dehydrogenase - MTX Methotrexate - NSAID Non-steroidal anti-inflammatory drugs     

Fever of unknown origin (FUO) caused by multiple myeloma: the diagnostic value of the Naprosyn test

Fever of unknown origin (FUO) remains a difficult diagnostic problem. The causes of FUO have changed over the years. Neoplastic disorders have now displaced infectious diseases as the most common cause of FUOs. Most neoplasms are associated with no or low-grade temperatures, with some important exceptions. Hypernephromas and lymphomas are neoplasms typically associated with high spiking fevers or may present as FUOs. Hematologic malignancies, that is, the acute and chronic leukemias, myeloproliferative disorders, and multiple myeloma, do not usually present with acute fevers or as FUOs. We present an elderly male patient who presented with an FUO, whose history is significant for multiple myeloma in remission. Differential diagnostic possibilities in this patient included plasma cell leukemia, relapse of multiple myeloma, secondary/superimposed malignancy, or opportunistic infection. The main differential diagnosis for his FUO was between neoplastic and infectious disorders. As part of the diagnostic workup, a Naprosyn test (naproxen 375 mg [by mouth] every 12 hours for 3 days) was used to differentiate neoplastic from infectious causes of FUO in this patient. The Naprosyn test was positive, which indicated a neoplastic explanation for the patient's FUO and eliminated, along with the infectious disease workup, an infectious explanation for his FUO. The patient's FUO was finally determined to be the result of a relapse of multiple myeloma and not of a secondary malignancy or malignant transformation of myeloma into plasma cell leukemia. We conclude the Naprosyn test remains a valuable diagnostic test to use to narrow differential diagnostic possibilities in patients with FUOs when a malignancy is a diagnostic consideration.     

Fever of unknown origin due to preleukemia/myelodysplastic syndrome: the diagnostic importance of monocytosis with elevated serum ferritin levels

Fever of unknown origin (FUO) is a common clinical diagnostic dilemma. In the elderly, causes of FUO most commonly include malignancy or infection, and less commonly include collagen vascular diseases. Among the collagen vascular diseases causing FUO in the elderly, polymyalgia rheumatica/temporal arteritis, and adult Still's disease (adult juvenile rheumatoid arthritis) are difficult diagnoses to prove. Among the infectious causes of FUO in the elderly are subacute bacterial endocarditis, intra-abdominal abscesses, and extrapulmonary tuberculosis. In the elderly, neoplastic causes of FUO include lymphomas, hepatomas, renal cell carcinomas, and hepatic or central nervous system metastases. Acute leukemias, particularly during "blast" transformation, may present as acute fevers in the absence of infection, but are rare causes of FUO. Preleukemia/myelodysplastic syndromes are exceedingly rare causes of FUO. We present a case of an elderly man who presented with findings that initially suggested adult Still's disease. Prolonged and profound monocytosis provided the key clue to his subsequent diagnosis of preleukemia/myelodysplastic syndrome. In this patient, a positive Naprosyn test result also suggested a neoplastic cause for his FUO. After months of prolonged fevers, myelocytes/metamyelocytes were eventually demonstrated in his peripheral smear during hospital evaluation. These findings, in concert with the persistent monocytosis, highly elevated ferritin levels, polyclonal gammopathy on serum protein electrophoresis, and eventual presence of myelocytes/metamyelocytes on peripheral smear, prompted a bone marrow test that demonstrated blast cells confirming the diagnosis of preleukemia myelodysplastic syndrome as the cause of this patient's FUO.