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.     

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。     

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.     

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.     

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.     

Diagnostic usefulness of percutaneous liver biopsy in HIV-infected patients with fever of unknown origin.

OBJECTIVES: to determine the value of percutaneous liver biopsy (PLB) in the diagnosis of fever of unknown origin (FUO) in HIV-infected patients and establish a prediction model for its usefulness to enable diagnosis of FUO in these patients to be standardized. METHODS: a total of 58 HIV-infected patients who underwent PLB for the evaluation of FUO were studied at 'Carlos Haya' Hospital in Malaga, Spain. The patients were classified into three groups, according to the results of the PLB: (a) diagnostic PLB (when a definitive diagnosis was obtained); (b) helpful PLB (the tissue sample showed suggestive, but not definitive, findings); and (c) normal or non-specific PLB (no contribution to diagnosis, the findings being normal or irrelevant). Multivariate analysis was made to establish a prediction model for the diagnostic usefulness of PLB, calculating the positive (PPV) and negative (NPV) predictive values. RESULTS: PLB was carried out in 58 HIV-infected patients during diagnosis of FUO. Risk factors for HIV infection included intravenous drug use (72.4%), homosexual or bisexual activities (12.1%), and heterosexual transmission (15.5%). Fifty-two out of 58 patients (89.6%) had previous AIDS-defining illnesses. The mean CD4 lymphocyte count +/-SD was 56.4+/-80.9/mm3. The mean duration of fever was 43 days. Diagnosis could be established in 51 (87.9%) patients, with tuberculosis (50%) and leishmaniasis (20.7%) being the most common. The PLB was diagnostic in 25 cases (43.1%), helpful in 13 (22.4%), and normal or non-specific in the remaining 20 (34.5%). Biopsy-associated complications occurred in two cases. The presence of hepatomegaly or splenomegaly were the most useful factors in predicting the usefulness of the PLB, with a PPV of 86.1% and NPV of 68.2%. In patients with tuberculosis, an increased alkaline phosphatase and hepatomegaly had a PPV of 86.4% and a NPV of 71.4%. CONCLUSIONS: PLB is a useful technique for the diagnosis of FUO in HIV-infected persons. Early PLB should be considered in those patients with hepatosplenomegaly and increased alkaline phosphatase levels.     

Fever of unknown origin in North Jordan

This is a retrospective study of all patients admitted to Basma Teaching Hospital with a diagnosis of fever of unknown origin (FUO). The study took place from January 1995 to December 2001. Fifty-two patients fulfilled the criteria of FUO. Infections were responsible for 26 cases (50%), malignancy for eight cases (15%), connective tissue disorder for six cases (12%) and others for 12 cases (23%). Infections remain the most common causes of FUO in Jordan, mainly tuberculosis, brucellosis and typhoid fever.     

Fever of undetermined origin in patients with the acquired immunodeficiency syndrome in Brazil: report on 55 cases.

The medical records of patients with AIDS admitted to a general hospital in Brazil from 1989 to 1997 were reviewed retrospectively with the aim at defining the frequency and etiology of fever of undetermined origin (FUO) in HIV-infected patients of a tropical country and to evaluate the usefulness of the main diagnostic procedures. 188 (58.4%) out of 322 patients reported fever at admission to hospital and 55 (17.1%) had FUO. Those with FUO had a mean CD4+ cell count of 98/ml. A cause of fever was identified for 45 patients (81.8%). Tuberculosis (32.7%), Pneumocystis carinii pneumonia (10.9%), and Mycobacterium avium complex (9.1%) were the most frequent diagnoses. Other infectious diseases are also of note, such as cryptococcal meningitis (5.5%), sinusitis (3.6%), Salmonella-S. mansoni association (3.6%), disseminated histoplasmosis (3.6%), neurosyphilis (1.8%), and isosporiasis (1.8%). Four patients had non-Hodgkin's lymphoma (7.3%). We conclude that an initial aggressive diagnostic approach should be always considered because biopsies (lymph node, liver and bone marrow) produced the highest yield in the diagnosis of FUO and the majority of the diagnosed diseases are treatable. The association of diseases is common and have contributed to delay the final diagnosis of FUO in most cases. In our study area the routine request of hemocultures for Salmonella infection and the investigation of cryptococcal antigen in the serum should be considered.     

Human immunodeficiency virus-associated fever of unknown origin: a study of 70 patients in the United States and review.

To characterize the clinical features of human immunodeficiency virus (HIV)-associated fever of unknown origin (FUO) in the United States, we performed a retrospective analysis of cases that fulfilled specific criteria (published by Durack and Street in 1991) at two medical centers in the United States between 1992 and 1997. Seventy cases met criteria for HIV-associated FUO; the mean CD4 cell count was 58/mm3, and the mean duration of fever was 42 days. A cause of FUO was found in 56 of the 70 cases; 43 were of a single etiology, and in 13 cases multiple conditions were established. The most common diagnoses were disseminated Mycobacterium avium infection (DMAC; 31%), Pneumocystis carinii pneumonia (13%), cytomegalovirus infection (11%), disseminated histoplasmosis (7%), and lymphoma (7%). In this United States series, FUO occurs most often in the late stage of HIV infection, individual cases often have multiple etiologies, and DMAC is the most common diagnosis.     

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     

A retrospective study of hospitalized patients with fever of unknown origin (FUO) past six years

We analysed retrospectively 48 hospitalized patients with fever of unknown origin (FUO) from 1982 through 1988. The criteria of FUO were (1) temperature of more than 38.3 degrees C documented on several occasions (2) overall duration of illness more than three weeks, (3) uncertain diagnosis till one week after hospitalization. Of this group of FUO, 25 patients (52.1%) were found to have infections, 8 patients (16.7%) had collagen disorders, 7 patients (14.6%) had neoplastic disorders, 3 patients (6.3%) were crohn disease and 5 patients (10.4%) were undiagnosed. Among infectious diseases, chronic tonsillitis was the most frequent (5 patients: 20%) and they were diagnosed by the provocative examination. Non bacterial meningitis and cervical lymphadenitis were diagnosed in all 3 patients (12% in all), Adult Still's disease was found in 3 patients (37.5%) and systemic lupus erythematosus (SLE) in 2 patients (25%) in collagen disease. Immunoblastic lymphadenopathy was diagnosed in 3 patients (42.9%) of malignant diseases. Three cases of Crohn disease were revealed in all the patients of the miscellaneous group. Duration of fever was relatively short in infection diseases compared to malignant and Crohn diseases. The most common laboratory abnormality is an elevated erythrocyte sedimentation rate (89.6%). As the final diagnosis of FUO are changing with the development of diagnostic techniques, a new criteria of FUO is necessary.     

Fever of Unknown Origin in Turkey

Abstract. Background: The etiology of fever of unknown origin (FUO) includes primarily infectious, collagen-vascular and neoplastic diseases. The distribution of the disorders causing FUO may differ according to the geographic area and the socioeconomical status of the country. Moreover, the developments in radiographic and microbiologic methods have changed the spectrum of diseases causing FUO. Materials and Methods: We reviewed 117 cases that fulfilled the criteria of FUO followed in our department during the period 1984 to 2001. Results: The etiology of FUO was infectious diseases in 34% of the patients, collagen-vascular diseases in 23%, neoplasms in 19% and miscellaneous diseases in 10%. In 14% of the cases the etiology could not be found. The three leading diseases were tuberculosis (24%), lymphomas (19%) and adult-onset Stills disease (11%). Tuberculosis was found to be a more common cause of FUO than reported in studies in developed countries. Invasive procedures helped to establish the diagnosis in 50 out of 92 patients (43%). As a final diagnostic procedure, laparotomy aided the establishment of a diagnosis in 15 out of 20 patients (75%). Conclusion: Although the relative rate of infectious disease as etiologic category is less commonly encountered, infectious disease, especially tuberculosis, remains a common cause of FUO. Although several diseases may lead to FUO, lymphomas, adult-onset Stills disease and particularly tuberculosis should be considered in the differential diagnosis of a patient admitted with FUO.     

Fieber ungeklärter Ursache

Fever of unknown origin (FUO) is defined as sustained unexplained fever despite intensive diagnostic evaluation and represents a particular diagnostic challenge. It can be classified into different categories, e.g. classical, nosocomial, neutropenic and HIV-associated FUO, which is based on the patient-specific clinical and immunological situation. Infections, malignant diseases and non-infectious inflammatory diseases have to be considered as the most important causes of FUO; however, no definitive diagnosis can be established in a substantial number of FUO patients despite an extensive diagnostic work-up. The present review focuses on the important diagnostic aspects as well as therapeutic options in FUO patients.     

Fever of unknown origin: a review of 20 patients with Adult-onset Still's disease

 In this study we aimed to investigate the findings in patients with adult-onset Still's disease (AOSD) admitted with fever of unknown origin (FUO) during the last 18 years in our unit, in order to discover the ratio of such patients to all patients with FUO during the same period, and to determine the clinical features of AOSD in FUO. The number and the aetiologies of the patients with FUO diagnosed between 1984 and 2001, and the clinical features of those with AOSD, were taken from the patient files. The diagnosis of AOSD was reanalysed according to the diagnostic criteria of Cush et al. [11]. The presumed diagnoses before a diagnosis of AOSD was established were also noted. The χ² and Fisher's exact tests were used for statistical analysis. We studied 130 patients with a diagnosis of FUO, 36 (28%) of whom had collagen vascular diseases. Of these 36 patients, 20 (56%, 12 female, 8 male, mean age 34 years, range 16–65) had AOSD. Clinical and laboratory findings were as follows: fever (100%), arthralgia (90%), rash (85%), sore throat (75%), arthritis (65%), myalgia (60%), splenomegaly (40%), hepatomegaly (25%), lymphadenopathy (15%), anaemia (65%), neutrophilic leukocytosis (90%), increased erythrocyte sedimentation rate (100%), elevated transaminase levels (65%), a negative RF (100%), and a negative FANA (80%). Antibiotics had been prescribed in 18 (90%) of cases. The presumed infectious diagnoses were streptococcal tonsillitis/pharyngitis (50%), infective endocarditis (four patients), sepsis (two patients) and acute bacterial meningitis (two patients). The presumed non-infectious diagnoses were acute rheumatic fever (three patients), seronegative rheumatoid arthritis (two patients) and polymyositis (two patients). Sixteen patients were followed for a mean duration of 30 months (range 2–59). A remission was obtained with indomethacin in three cases (19%), and with prednisolone in the remainder. Relapse was detected in three cases (19%). AOSD is one of the most frequent aetiologies of FUO. During the diagnostic course of a patient with FUO, a maculopapular rash and/or arthralgia and/or sore throat should raise the suspicion of AOSD. Because the disease has heterogeneous clinical findings, certain bacterial infections (e.g. streptococcal pharyngitis and sepsis) are generally considered and the prescribing of antibiotics is common. Received: 3 May 2002 / Accepted: 2 October 2002     

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.     

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.     

Fever of unknown origin in adults: 40 years on

A revision of the criteria of fever of unknown origin (FUO), established in 1961, is desirable because of important evolutions in medical practice and the emergence of new patient populations. The development of rapid laboratory tests and powerful diagnostic tools, such as ultrasonography, computed tomography and magnetic resonance imaging often makes hospitalization unnecessary and new categories of patients such as those with HIV infection, neutropenia, immunosuppression and nosocomial illness require an approach different from classical FUO. The more then 200 reported causes of FUO can be classified into four diagnostic categories; infections, tumours, noninfectious inflammatory diseases (NIID) and miscellaneous. A uniform classification system is highly wanted to allow comparison between different series. The reports of the 1990s show slight changes in the distribution of causes, namely less infections, less tumours, more NIID and more undiagnosed cases. A uniform diagnostic strategy cannot be determined. The initial investigation should be directed by potentially diagnostic clues revealed by extensive history, meticulous physical examination and a standard set of laboratory tests. 18Fluoro-deoxy-glucose-positron-emitted-tomography is a new valuable total body scintigraphy in the search for the site of origin of the fever. In view of the rather good long-term prognosis, a wait-and-see strategy may be more appropriate than a systematic staged approach. Elderly patients and patients with episodic fever represent two specific groups of classical FUO that require a distinct approach. HIV-associated, nosocomial and neutropenic FUO should be considered as separate clinical entities.     

Revised definition of 'fever of unknown origin': limitations and opportunities

AIM: The limitations and opportunities of revised definition of fevers of unknown origin (FUO) in comparison to conventional definition were investigated, and prehospital characteristics of the patients were detailed. METHOD: The patients were grouped according to both revised and classic definitions of FUO. RESULTS: Fifty-nine of the 80 patients (74%) met the conventional definition of FUO. Before their admissions, all patients had at least one course of antibiotic therapy. The aetiology was infectious in 52%, autoimmune in 19%, and neoplastic in 17%. In 12% of the cases, the reason for high fever could not be explained. The most common infectious aetiologies were various forms of tuberculosis (12%), brucellosis (12%), salmonella (7%) and malaria (5%). The revised definition inflated the rate of infectious aetiology. CONCLUSION: A standardized set of diagnostic tools used in this study was suggested. The subjects of FUO series have to be screened for endemic infections.     

Clinical analysis of 130 patients with fever of unknown origin

Hospital records of 130 patients with fever of unknown origin (FUO) from 1985 to 1989 were studied. Etiologic diagnoses were made in 117 (90%) patients, 60 (46.1%) patients had infections, 22 (16.9%) neoplasms, 19 (14.6%) connective tissue diseases, and 16(12.3%) various diseases grouped under "miscellaneous", 10% of the FUO cases remained undiagnosed and the death rate was 13.8%. This clinical analysis showed that infection was the most frequent cause of FUO in this series.     

Fever of unknown origin in a Mediterranean survey from a division of internal medicine: report of 91 cases during a 12-year-period (1991–2002)

Despite the availability of all advanced diagnostic tools, fever of unknown origin (FUO) remains a diagnostic challenge for physicians. The objective was to define, through a retrospective study, the categories of the diseases of Sicilian patients admitted at the Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy, for classical FUO. Using the registration system for patients admitted from 1991 to 2002, 508 charts of patients admitted because of fever were reviewed. Of these, only 91 patients fulfilled the criteria for classical FUO. The origin of FUO was diagnosed in 62 (68.1%) patients. Infection was the most common cause of FUO with 29 cases (31.8% of total of FUO), neoplasms accounted for 13 cases (14.2%), collagen vascular disease for 11 cases (12.0%), and miscellaneous for 9 cases (9.8%). Undiagnosed FUO were 29 (31.8%) and, of them, 22 cases were followed-up for 2 years. A definite diagnosis could be established only in 8 cases, 13 subjects completely recovered and 4 of them died. In the 73.4% of cases, the FUO have been the result of misleading factors in the diagnostic approaches as made by the physician. The results of our study are similar to those already reported by other authors in other populations, with infections as first, neoplasm as second, and collagen vascular diseases as third most important causes of FUO. In our study the prognosis for undiagnosed FUO cases was good, but a definite diagnosis could be established only in few cases. Therefore, further multicentric, prospective studies of good design are required.