Fatma S. Al-Qahtani, MBBS, KSUFPath
Hematology Division, Department of Pathology
King Khalid University Hospital, Riyadh, Saudi Arabia

Correspondence:
Fatma S. Al-Qahtani, MBBS, KSUFPath
Department of Pathology
King Khalid University Hospital
P.O. Box 2925, Riyadh 11461
Kingdom of Saudi Arabia
Tel: +966-1-4671617
Fax: +966-1-4672462
Email: Fatma.qahtani@yahoo.com / acisnanimd@yahoo.com

INTRODUCTION

Fever of unknown origin (FUO) in adults is defined as a temperature higher than 38.3ºC (100.9ºF) on several occasions that lasts for more than three weeks with no obvious source and failure to reach a diagnosis despite appropriate investigation.⁽¹⁾

FUO's are caused by infections (30-40%), neoplasms (20-30%), collagen vascular diseases (10-20%), and numerous miscellaneous diseases (15-20%). The literature also reveals that between 5 and 15% of FUO defy diagnosis, despite exhaustive studies.^(2-5) A thorough history, physical examination, and standard laboratory testing remain the basis of the initial evaluation of the patient with FUO. Newer diagnostic modalities, including updated serology, viral cultures, computed tomography, and magnetic resonance imaging, have important roles in the assessment of these patients.^(6,7) Much of the confusion in the literature concerning causes of FUO is due to the failure to define the criteria employed in classifying patients who have fever of unknown origin.

It has been observed that geographical factors are very relevant in the pattern of FUO. In 1989, Al-Mofleh et al⁽⁸⁾ prospectively presented FUO among 62 patients from 3 centers in Riyadh, Saudi Arabia and found that 71% of their cases were due to infection and neoplasm. However, in almost 2 decades after Al-Mofleh's report, no subsequent literature has been found from Saudi Arabia in particular on this subject. Therefore, this study was conducted to re-familiarize us with the epidemiological pattern of FUO, compare the results with previous literature both locally and from other parts of the world and investigate further underlying causes for undiagnosed cases through follow-up and subsequent admissions which may be related to the cause of FUO.

Between January 1983 and September 2008, all admitted patients with a diagnosis of FUO, according to the criteria of Petersdorf and Beeson⁽¹⁾ were retrospectively investigated for the causes and pattern. In this study, we excluded patients who had diagnosis of a specific clinical syndrome or had been diagnosed by a laboratory or radiological procedure within a week from admission. For cases with unconfirmed diagnosis, a further review of records was conducted to ascertain possible underlying causation of FUO during subsequent re-admissions or follow-ups to the hospital.

A total of 273 patients were diagnosed with FUO between 1983 and 2008. There were 109 (39.9%) males and 164 (60.1%) females. Mean age was 25.6 ± 19.9 years (range: 1-83 years). There were 174 (63.7%) patients who were 18 years old. Infectious inflammatory diseases were identified in 106 (38.8%), neoplasms in 66 (24.2%), connective diseases in 41 (15.0%) and others diseases in 18 (6.6%). Cause of fever could not be determined in 42 (15.4%) of cases. (Table 1)

Note: values expressed as n (%)

Infectious inflammatory diseases
Among the 106 cases with infective causes of FUO, tuberculosis was found in 36 (33.9%) patients, 21 (58.3%) among adult patients and 15 (41.7%) among pediatric patients as primary complex. Initial chest x-ray and laboratory investigations in these patients were remarkably normal. Diagnosis of tuberculosis was confirmed by mediatinoscopy, biopsy, laparoscopy and even percutaneous liver biopsy in two patients. All patients responded well to anti-tuberculous medications.

Brucellosis was found in 31 (29.3%) patients, 10 (9.4%0 with hydatid disease, 9 (8.5%) with enteric fever, 9 (8.5%) with meningitis, 7 (6.6%) with pyelonephritis and 4 (3.8%) with visceral infections. Confirmation of a diagnosis was reached in a mean of 32 ± 2.9 days.

Neoplasms
Among 66 patients who had FUO, 40 patients (60.6%) had lymphoma. Of these 40 patients with lymphoma 38 (85.0%) were adult patients. Thirty-six (90%) cases were confirmed by lymph node biopsy, the rest by exploratory laparotomy and biopsy. Leukemia was seen in 21 (31.8%) patients, confirmed by bone marrow examination. Carcinomas of the bladder, pancreas, renal cell carcinoma, breast and colon were seen in the remaining 5 (7.6%) patients. Confirmation of diagnosis was reached in a mean of 41 ± 7.2 days.

Connective tissue diseases
Collagen vascular disease was found in 41 (15.0%) patients, including 28 (68.3%) patients with systemic lupus erythematosus, 7 (17.1%) with mixed connective tissue diseases, 4 (9.8%) with rheumatoid arthritis and 2 (4.9%) with polyarteritis nodosa. Confirmation of diagnosis was reached in a mean of 28 ± 3.7 days.

Other diseases
There were 18 (6.6%) who had a variety of diseases including 10 (55.5%) patients with sarcoidosis, 3 (16.7%) with Crohn's disease, two patients with familial Mediterranean fever, one with secondary amyloidosis and one with subacute thyroiditis.

Undiagnosed cases
Despite extensive investigations diagnosis eluded physicians on the causation of FUO at the time of admission up to the time of discharge in 42 (15.4%) patients, 25 (59.5%) adults and 17 (40.5%) pediatric patients. Fever resolved spontaneously in all of these patients until they were discharged.

Among the 25 adult patients whose diagnosis was unconfirmed, 13 patients came back to the hospital in a mean of 4.2 ± 1.8 months after diagnosis of FUO. Of these, 8 patients were eventually diagnosed with sarcoidosis, 4 with extrapulmonary mycobacterial infection and 1 with giant cell arteritis. The 8 sarcoidosis patients presented with granulomas on subsequent follow-ups. The 4 patients with extrapulmonary mycobacterial infection included a case of tuberculous pericarditis, which did not present with pericardial pain or any cardiac manifestation at the time of fever and 3 cases of miliary tuberculosis, of which symptoms became recognizable 2 weeks after discharge from the hospital. The remaining 12 adult patients were not re-admitted nor had subsequent follow-ups to the hospital and causation of FUO remained obscure.

Among the 17 pediatric patients with undiagnosed causation of FUO, 12 subsequently followed-up to the hospital, of which 10 were eventually diagnosed with cyclic neutropenia and 2 with mucocutaneous lymph node syndrome. The remaining 5 patients never followed-up nor was re-admitted to the hospital.

Our study conforms to the epidemiological studies on FUO worldwide.^(2-7,9-14) As found in the literature, variations in FUO reflect the populations and periods studied. In children, infections are the most common cause of FUO.^(1,4-6) Our study showed 45.4% of our studied pediatric population revealed an infective focus. Among adults, neoplasms and connective tissue disorders are most common. Our study revealed a 24.2% neoplastic cause and 15% of collagen vascular disorder etiology, however, infection was seen in 38.8% of adult cases. In all of our patients, when summed up, the so called "big three" of FUO causation accounted for 78% of cases, 81.6% among adults and 71.7% among pediatric patients.

Comparing our results with previous studies, our percentage of an infective focus as causation of FUO was lower than that reported by Mansueto et al (68.1%)⁽⁹⁾ Zheng et al (49.1%)⁽¹⁰⁾ and Sipahi et al (47%)⁽¹¹⁾ but higher than that of Kucukardali et al (34.9%),⁽¹¹⁾ Zhiyong et al (31.73%)⁽¹³⁾ and de Kleijn (25.7%).⁽¹⁴⁾ (Table 2) Among the infective causes, tuberculosis remained the most common underlying cause of FUO together with Brucellosis in 2nd place. The relatively higher incidence of tuberculosis and brucellosis may be attributed to the growing population of expatriate workers and the continued herding of livestock in several parts of the Kingdom.

Source: Pubmed search (www.ncbi.nlm.nih.gov/pubmed/)
Note: Case reports excluded
* for comparison purpose

As a follow-up to the report of Al-Mofleh et al, a significant rise in the percentage of a neoplastic causation of FUO was seen (24.2% versus 12.9%) and a lower percentage for an infective causes (38.8% vs. Al-Mofleh's 58.1%).⁽⁸⁾ Neoplasms accounted for a higher percentage compared to the report done by Al-Mofleh two decades ago. This is considerably due to the increasing emergence of neoplasm among the Saudi population despite the advancement of technology. Noteworthy is the fact that the rapid modernization of Saudi Arabia may have contributed to the increasing incidence of cancer especially Hodgkin's, non-Hodgkin's Lymphoma, colorectal cancer and even breast cancer. Several reports of increasing incidence of cancer in Saudi Arabia have been reported substantially.
The magnitude of an unconfirmed diagnosis for FUO remained the same. Our study showed that in 15.4% of our patients, no diagnosis was reached. In most studies, this subgroup represents slightly more than our results, from 15.6%⁽¹²⁾ to as much as 31.8%.⁽⁹⁾ However, in such cases where diagnosis remains obscure, important clues towards identification of an underlying cause may appear subsequently. Various medical conditions exhibit variable symptomatologies and fever is just one of those. A careful follow-up and correlation of a patient's medical history and course of disease will eventually give clues for a diagnosis to be reached.

FUO remains a challenge despite the advent of more advanced technologies. With the continuing evolution of inciting factors for causation behind FUO, a keen clinical eye, and meticulous history taking coupled with exhaustive investigative procedures and follow-ups are needed.

1. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine 1961; 40:1-30.
   
2. American Family Physician 2003; 68: 2223-8.
   
3. Cunha BA. Fever of unknown origin. Inf Dis Clin North Am 1996; 10: 111-27.
   
4. Durack DT, Street AC. Fever of unknown origin. In: Macowiak PA, ed. Fever: basic mechanism and management. 2nd ed. Philadelphia: lippincott-Raven, 1997: 237-49.
   
5. Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis 1997; 24: 291-300.
   
6. Mackowiak P, Durack D. Fever of unknown origin. In Mandell GL, Douglas RG, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and practice of infectious diseases. 5th 3d. Philadelphia: Churchill Livingstone; 2000: 623-31.
   
7. Arnow PM, Flaherty JP. Fever of unknown origin. Lancet 1997; 350: 575-80.
   
8. Al-Mofleh IA, Al-Aska AI, Al-Nozha MM. Fever of unknown origin: experience in Saudi Arabia. Annals of Saudi Medicine 1990; 10: 620-5.
   
9. Mansueto P, Di Lorenzo G, Rizzo M, Di Rosa S, Vitale G, Rini G et al. 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). Intern Emerg Med. 2008; 3: 219-25.
   
10. Zheng M, Lin H, Luo S, Xu L, Zeng Y, Chen Y. Fever of unknown origin in the elderly: nine years experience in China. Trop Doct. 2008; 38: 221-2.
    
11. Sipahi OR, Senol S, Arsu G, Pullukcu H, Tasbakan M, Yamazhan T et al. Pooled analysis of 857 published adult fever of unknown origin cases in Turkey between 1990-2006. Med Sci Monit 2007; 13: CR318-22.
    
12. Kucukardali Y, Oncul O, Cavuslu S, Danaci M, Calangu S, Erdem H et al. The spectrum of diseases causing fever of unknown origin in Turkey: a multicenter study. Int J Infect Dis. 2008; 12: 71-9.
    
13. Zhiyong Z, Bingjun L, Xiaoju L, Xinjian F, Ping F, Wenya Y. Fever of unknown origin: a report from China of 208 cases. Int J Clin Pract 2003; 57: 592-6.
    
14. de Kleijn EM, Van Lier HJ, Van der Meer JW. Fever of unknown origin (FUO). II. Prospective multicenter study of 167 patients. The Netherlands FUO study group. Medicine (Baltimore) 1997; 76: 401-14.