Long-term follow-up of patients with undiagnosed fever of unknown origin.

BACKGROUND: A casual diagnosis cannot be established in 10% to 25% of the patients who are studied for fever of unknown origin (FUO). The long-term clinical outcome of these patients cannot be inferred from the literature. This study describes the results of a 5-year follow-up of 61 patients studied for FUO and discharged from the hospital with no causal diagnosis being established. METHODS: Patients meeting the classic criteria for FUO who were studied in the 1980s and discharged from the hospital without a casual diagnosis were followed up for at least 5 years or until death. Follow-up was performed by review of the patients' medical records or by consulting the treating physician and occasionally the patients themselves. The final diagnosis, clinical course (resolution of the fever and required treatments), and morality rate were studied. RESULTS: Of a cohort of 199 patients with FUO, 61 individuals (30%) were discharged from the hospital without a final diagnosis being established. A definite diagnosis could be established in 12 cases, mostly (eight of 12) within 2 months after discharge. Thirty-one individuals became symptom free during hospitalization or shortly following discharge. Eighteen patients had persisting or recurring fever for several months or even years after discharge, but 10 of them were considered to be finally cured. Four patients were treated with corticosteroids and six patients required intermittent therapy with nonsteroidal anti-inflammatory agents. Six patients died, but the cause of death was considered to be related to the disease that caused FUO in only two cases. CONCLUSION: No single disease, particularly not tuberculosis, was found to be a cause of undiagnosed FUO. Most cases resolved spontaneously, and corticosteroids were seldom required. Most symptomatic patients could be treated with nonsteroidal anti-inflammatory drugs. The mortality rate in patients with undiagnosed FUO who were followed up for 5 years or more was only 3.2%.

Fever of unknown origin in the 1980s. An update of the diagnostic spectrum.

OBJECTIVE: To determine the relative proportions of the diagnostic categories in patients with fever of unknown origin who were examined in the 1980s. STUDY DESIGN: Prospective case series. SETTING: General Internal Medicine Service based at University Hospital, Leuven, Belgium. PATIENTS: One hundred ninety-nine consecutive patients meeting the classic criteria of fever of unknown origin who were treated in the 1980s. MAIN OUTCOME MEASUREMENT: The final diagnosis established at discharge or during follow-up. RESULTS: Infections were found in 45 patients (22.6%), tumors were found in 14 (7%), multisystem diseases were found in 42 (21.5%), drug-related fever was found in six (3%), factitious fever was found in seven (3.5%), habitual hyperthermia was found in five (2.5%), miscellaneous diseases were found in 29 (14.5%), and no diagnosis was reached in 51 (25.6%). CONCLUSIONS: Tumors were a less important cause of fever of unknown origin in the 1980s. The same holds true for some infectious diseases, such as abscesses and hepatobiliary disorders. Multisystem diseases were more frequently found, and the number of undiagnosed cases increased. Although these shifts in the disease spectrum in fever of unknown origin most probably resulted from a constellation of factors, we suspect that these changes are mainly due to easy and early diagnosis by new diagnostic modalities, such as ultrasonography and computed tomography, of previously common causes of fever of unknown origin.

Recurrent or episodic fever of unknown origin. Review of 45 cases and survey of the literature.

We describe a series of 45 patients with episodic fever of unknown origin (FUO) who meet the classic criteria for FUO. Recurrent or episodic fever is defined as cyclical fever with seeming remission of the disease and fever-free intervals of at least 2 weeks. The traditional mix of infections, malignancies, and inflammatory diseases (multisystem diseases) represent only 20% of the causes of episodic FUO, in contrast to 60 to 70% in cases of continuous fever. The "miscellaneous" group of patients with episodic FUO is the most numerous and about half of the cases remain undiagnosed. This spectrum of causative diseases resembles the spectrum of so-called "prolonged" FUO, i.e., a feverish illness lasting at least half a year. Follow-up of the undiagnosed cases revealed a good prognosis. Only 1 patient died and only 1 more required continuous treatment with corticosteroids. Seven of the 21 undiagnosed cases required intermittent short-term treatment with either nonsteroidal anti-inflammatory drugs or corticosteroids. The remaining 14 seem to be "cured". Diagnosis was frequently based on the clinical course and on exclusion of other diseases. Gastrointestinal investigation was useful, but serologic and immunologic tests yielded only minimal benefit. Ultrasonography, computerized tomographic scans, and gallium scintigraphy were diagnostically useful. Invasive procedures are rarely required, and careful ambulatory follow-up is probably the best approach in cases of unresolved episodic FUO.

Comparison of premortem clinical diagnoses in critically iII patients and subsequent autopsy findings.

OBJECTIVE: To determine whether our practice of requesting an autopsy for patients who die in the medical intensive care unit (MICU) continues to be a valid approach to obtain clinically and educationally relevant findings. METHODS: In this retrospective study conducted in an adult MICU population of a university hospital, the clinical diagnoses and postmortem major diagnoses of 100 patients who died in 1996 (autopsy rate of 93%) were compared. RESULTS: Eighty-one percent of the clinical diagnoses were confirmed at autopsy. In 16%, autopsy findings revealed a major diagnosis that, if known before death, might have led to a change in therapy and prolonged survival (class I missed major diagnoses). The most frequent class I missed major diagnoses were fungal infection, cardiac tamponade, abdominal hemorrhage, and myocardial infarction. Another 10% of autopsies revealed a diagnosis that, if known before death, would probably not have led to a change in therapy (class II error). CONCLUSIONS: Autopsy remains an important tool for education and quality control. In contrast with historical series of 1 to 2 decades ago, there is a clear shift in the type of class I missed major diagnoses toward opportunistic infections. Bedside-applicable techniques such as electrocardiography with supplemental posterior leads, echocardiography, and meticulous abdominal ultrasonography might improve the outcome in selected MICU patients.

Fever of unknown origin in elderly patients.

OBJECTIVE: To describe the spectrum of diseases that may give rise to fever of unknown origin in elderly patients and to delineate the diagnostic approach in these patients. DESIGN: Subgroup analysis of a prospectively collected case series followed more than 2 years. SETTING: General Internal Medicine Service based at University hospital, Leuven, Belgium. PATIENTS: Forty-seven consecutive patients, older than 65 years, meeting the classic criteria of fever of unknown origin. MEASUREMENTS: The final diagnosis established and the clinical value of diagnostic procedures. RESULTS: Infections, tumors and multisystem diseases (encompassing rheumatic diseases, connective tissue disorders, vasculitis including temporal arteritis, polymyalgia rheumatica, and sarcoidosis) were found in 12 (25%), six (12%) and 15 patients (31%), respectively. Drug-related fever was the cause in three patients (6%), miscellaneous conditions were found in five patients (10%), and six patients (12%) remained undiagnosed. Microbiologic investigations were diagnostic in eight cases (16%), serologic tests yielded one diagnosis, immunologic investigations had a diagnostic value in four cases, standard X-rays yielded a diagnostic contribution in 10 cases, ultrasonography and computed tomography were diagnostic in 11 cases, Gallium scintigraphy had a diagnostic contribution in 17 cases, and biopsies yielded the final diagnosis in 18 cases. CONCLUSIONS: Multisystem diseases emerged as the most frequent cause of fever of unknown origin in the elderly, and temporal arteritis was the most frequent specific diagnosis. Infections, particularly tuberculosis, remain an important group. The percentage of tumors was higher in our elderly patients than in the younger ones but still clearly lower than in other recent series of FUO in adults. The number of undiagnosed cases was significantly lower in elderly patients than in younger individuals (P < or = 0.01). The investigation of elderly patients with FUO should encompass routine temporal artery biopsy and extensive search for tuberculosis if the classic tests such as blood count, chemistry, urinalysis, cultures, chest X-rays, and abdominal ultrasonography do not yield any clue. Gallium scintigraphy should be considered as the next step and not as a last-resort procedure.

Coronary involvement in the Churg-Strauss syndrome.

The Churg-Strauss syndrome (CSS) is a rare systemic disease characterised by vasculitis and peripheral eosinophilia in patients with an atopic constitution. Cardiac involvement is an important cause of morbidity and mortality yet coronary involvement is very rarely documented. We report the case of a 38 year old man presenting with fulminant heart failure. Coronary arteriography demonstrated extensive focal vasculopathy consistent with vasculitis. The diagnosis of CSS was established based upon the classical diagnostic criteria and corticosteroid treatment resulted in a spectacular remission of disease activity.

SLE and acute Addisonian crisis due to bilateral adrenal hemorrhage: association with the antiphospholipid syndrome.

This report describes a 68-year-old woman with SLE and positive antiphospholipid antibodies who developed an acute Addisonian crisis due to bilateral adrenal hemorrhage. We suggest that adrenal bleeding can be part of the thrombo-embolic complications seen in the secondary antiphospholipid syndrome.

Giant cell arteritis can be associated with T4-lymphocytic alveolitis.

We describe three patients with histologically proven giant cell arteritis who presented with respiratory complaints. In one patient, dry cough and dyspnoea dominated the clinical picture. In the other two patients, a diagnosis of giant cell arteritis was readily suspected by the presence of typical complaints, although both patients spontaneously mentioned a persistent cough and dyspnoea, respectively. Radiographs of the chest were normal. Lung function tests, including a carbon monoxide (CO)-diffusion capacity measurement, were always normal. Broncho-alveolar lavage fluid examination showed a normal cell count but an increased number of lymphocytes (16-61%) with a predominance of T4-lymphocytes (65.5-84.5%). We conclude that respiratory complaints and T4-lymphocytic alveolitis can be associated with giant cell arteritis.

Ankylosing spondylitis. An unusual manifestation of familial Mediterranean fever. Report of a case complicated by amyloidosis and polyneuropathy.

We report a case of familial Mediterranean fever (FMF) with typical clinical and roentgenological findings of ankylosing spondylitis. The spinal involvement in FMF is discussed. A second unusual feature of this case is the occurrence of polyneuropathy which could possibly be ascribed to the slowly evolving amyloidosis during continuous colchicine treatment.

Microscopic haematuria in giant cell arteritis.

Giant cell arteritis (GCA) is traditionally considered to spare the kidney, although an uncontrolled study reported microscopic haematuria in 10 out of 30 patients with GCA. To study the frequency and the characteristics of microscopic haematuria in GCA, we retrospectively studied 42 patients with biopsy-proven GCA, 39 patients with polymyalgia rheumatica (PMR) and 62 control patients >or=60 years of age, admitted to the general internal medicine unit. Patients with pyuria, significant bacteriuria or a known haematuric disorder were excluded. Microscopic haematuria was defined as the presence of >5 red blood cells (RBC) per high-power field (sediment counts) or of >8 RBC/microl (direct counting). Microscopic haematuria was present at presentation in 47.6% of the GCA patients, versus 17.9% of the PMR patients (P = 0.005) and 21.0% of the control patients (P = 0.008). Urinary RBC were predominantly dysmorphic in all GCA patients in whom RBC morphology was assessed (n = 7). Presenting symptoms, renal function, arterial blood pressure and degree of leukocyturia did not differ significantly between GCA patients with or without haematuria. After the initiation of corticosteroid therapy, microscopic haematuria was no longer detectable in 25 of 35 GCA patients (71.4%). Microscopic haematuria of renal origin is frequent but generally benign in patients with GCA. Its presence, if unassociated with blood pressure elevation or renal function deterioration, helps to rule in rather than to rule out the diagnosis of GCA. In the typical setting invasive urologic and nephrologic work-up may not be warranted.

Cauda equina syndrome complicating ankylosing spondylitis: role of computed tomography and magnetic resonance imaging.

We present two cases of cauda equina syndrome in ankylosing spondylitis. Cauda equina syndrome is a rare complication of ankylosing spondylitis, the pathogenesis of which is not well understood. The onset is insidious with pain and sensory symptoms; sphincter disturbances are common. After a period of increasing neurological symptoms, the condition tends to stabilize. The degree of nerve involvement is variable and can be accurately defined by electromyography. The diagnosis has to be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI); myelography must be avoided. There is no specific treatment, except for pain control. The different clinical presentations and the role of new imaging techniques, CT and MRI, are demonstrated.

Infectious osteitis pubis.

One month after a Burch operation, performed because of urinary stress incontinence, a 65-yr-old woman developed progressive suprapubic pain and a characteristic waddling gait. Initial treatment with bed rest, non-steroidal antiphlogistics and corticosteroids was unsuccessful. Six months later, a biopsy of the symphysis performed because of persisting disabling pain yielded a positive culture of Pseudomonas aeruginosa. A longlasting treatment with intravenously administered antibiotics followed by ofloxacin orally, resulted in complete clinical cure and progressive radiological improvement. The distinction between noninfectious osteitis pubis and infectious symphysitis or osteomyelitis of the pubis is discussed.

Linear IgA dermatosis: a new cause of fever of unknown origin.

We describe a 60-year-old patient who presented with prolonged fever, weight loss, adenopathies and malaise. Two months later, an aphthous stomatitis and pharyngitis developed, together with ulcerations bilaterally in the groin. Two separate skin biopsies revealed the diagnosis of linear IgA dermatosis. This entity, which is well known to dermatologists but not to internists, should be added to the extensive list of disorders than can provoke the syndrome of fever of unknown origin.

Prenalterol in the treatment of orthostatic hypotension in Shy-Drager syndrome.

The effects of prenalterol, a selective beta 1-adrenoreceptor agonist, were studied in a patient with the Shy-Drager syndrome, presenting with incapacitating orthostatic hypotension. The main haemodynamic defect was an impressive postural fall in stroke volume and cardiac output pointing to denervation of the capacitance vessels. Prenalterol 4 X 30 mg orally produced a marked increase in supine and standing blood pressure, along with substantial symptomatic improvement. Notable positive chronotropic and inotropic effects were observed. Association of fludrocortisone 0.5 mg/day resulted in further haemodynamic and symptomatic improvement, presumably due to plasma volume expansion. Haemodynamically, prenalterol and fludrocortisone resulted in a substantial increase in standing cardiac output, primarily due to the chronotropic effects of prenalterol. In addition to the haemodynamic effects, prenalterol stimulated the renin-aldosterone system and restored the normal diurnal pattern of water and sodium excretion, the latter may have contributed to the improvement of orthostatic tolerance. Prenalterol could be a valuable adjunct to the existing treatment schedules of neurogenic orthostatic hypotension.

Bacterial meningitis: diagnostic and therapeutic considerations.

In this review the epidemiology of bacterial meningitis and the new insights in the pathophysiology are thoroughly discussed. The different diagnostic steps are described and the present day antibiotic strategy and adjunctive inflammation-modulating therapy are delineated.

Chest pain in the emergency department: the broad spectrum of causes.

We performed a prospective study to describe the broad spectrum of causes of chest pain in patients presenting to the emergency department and to compare the diagnoses in referred patients, self-referred patients and patients rushed in by ambulance. The final diagnosis in a consecutive case series of 578 chest pain patients was established after discharge from the hospital. The underlying disorders were grouped into cardiac, respiratory, gastro-oesophageal disorders, musculoskeletal pathology, somatization disorders, other diseases and unknown. For comparison of the frequencies of the disease categories the Chi-squared test was used. Out of 578 patients, 161 (27.9%) were self-referred, 369 (63.8%) were referred by the general practitioner and 48 (8.3%) were rushed in by ambulance. Cardiac diseases represented 51.7% of the cases, myocardial infarction and unstable angina 19% and 12.8% respectively Cardiac diseases were statistically significantly less common in self-referred patients (p<0.0005). Pulmonary diseases encompassed 14.2% of the population, followed by somatization disorders (9.2%), musculoskeletal pathology (7.1%) and other causes (4.3%). In 11.1% of the cases no definite final diagnosis could be established. Somatization disorders were significantly more frequent in self-referred and ambulance patients. Cardiac and pulmonary problems are the most frequent underlying disorders in acute chest pain patients in the emergency department. Somatization disorders and musculoskeletal pathology represented respectively 19.1% and 14.8% of the non-cardiac causes. The referral pattern influenced significantly the distribution of the disease categories with more cardiac and less psychiatric disorders in referred patients.

Emphysematous pyelonephritis: no longer a surgical disease?

Emphysematous pyelonephritis is a rare, life-threatening infection of the kidney characterized by the presence of gas within the renal parenchyma, the renal collecting system and the perinephric tissue. It usually develops in diabetic patients and often presents abruptly with bacteraemia, septic shock and acute renal failure. Diagnosis can be delayed because the symptoms mimic a classical upper urinary tract infection. Aggressive management, including parenteral antibiotic therapy, treatment of septic shock and control of the glycaemia, is mandatory. Immediate nephrectomy has been considered to be essential to increase the chance of survival. Recently, percutaneous drainage has been reported as a kidney-saving and life-saving alternative to surgery. We present a case of severe emphysematous pyelonephritis in which there was full recovery after antibiotic treatment combined with temporary percutaneous drainage. The therapeutic options in this rare, life-threatening condition are discussed.

Imported malaria in the 1990s: a review of 101 patients.

Imported malaria remains a difficult problem in nonendemic areas of the world. We describe the clinical presentation of 101 cases of malaria diagnosed at the Leuven University Hospital between 1 January 1990 and 31 December 1999. Ninety-three patients (92%) presented initially at the emergency department. Diagnosis was initially not suspected by the referring physician in 48 patients (47%). Plasmodium falciparum was the commonest species, accounting for 67% of the cases. All but three patients had fever as the presenting symptom, but only 10 had a typical tertian fever pattern. Haemolytic anaemia, thrombocytopenia and hyponatraemia represented a typical triad in 20% of the cases. Only 13% of the malaria patients had taken correct chemoprophylaxis according to WHO recommendations. Eighty-three per cent of the patients were admitted to the hospital with a median duration of hospitalization of 4 days. All complications occurred in cases with P. falciparum. All patients were cured.

[Septic sacroiliitis]. / Septische sacroiliitis.

Three patients are described with septic sacroiliitis caused by Staphylococcus aureus, two occurring spontaneously and a third following septic thrombophlebitis. The diagnosis and treatment of this rather rare disease are discussed based upon our findings and the literature data.

Tackling fever and inflammation of unknown origin: the do's and don'ts.

Fever and inflammation of unknown origin continue to challenge the clinician. The differential diagnosis is broad and potential diagnostic pitfalls abound. To guide the approach, the authors discuss the do's and don'ts.