Introduction

The term fever of unknown origin (FUO) indicates febrile illnesses with a temperature above 38.3 °C for which an etiological diagnosis has not yet been formulated after 3 days of hospitalization or after three specialist visits. Certainly, in this context, the clinical laboratory provides essential elements to guide the etiological diagnosis.

Definition of Fever

Fever is defined as an increase in body temperature associated with an increase in the hypothalamic set point (e.g., from 37 to 38 °C). The control of body temperature occurs by thermoreceptors, located on the skin and defined as peripheral thermoreceptors, which, together with the deep thermoreceptors in the hypothalamus and the large veins, send information to the temperature control centers, present at the level of the hypothalamus itself. The maintenance of body temperature occurs by the implementation of mechanisms aimed at balancing circadian variations; the excess of heat is balanced with dissipation through cutaneous vasodilation and sweating, while the lowering of temperature is balanced with the increase of heat production, mainly at a muscular level through shivering and the reduction of heat loss through vasoconstriction.

It is essential to distinguish between fever and hyperthermia, which are characterized by elevated body temperature.

Hyperthermia is a condition in which the uncontrolled increase in body temperature exceeds the body’s ability to disperse heat and is potentially fatal. Furthermore, in hyperthermia, there is no alteration in the regulation of the thermoregulatory center at the level of the hypothalamus. Hyperthermia may be due to a primitive increase in endogenous heat production, as in the case of hyperthyroidism or heat stroke, or to an altered ability to disperse heat, as, for example, in the case of anhidrotic ectodermal dysplasia.

On the other hand, fever is defined as an elevation of body temperature beyond normal circadian variations due to alterations in the hypothalamic regulatory center. Fever is generally due to the action of pyrogens (any substance that causes fever) and, rarely, to cerebral alterations (brain tumors that compress the hypothalamus). Pyrogens can be of exogenous or endogenous origin. Most exogenous pyrogens are microorganisms, and their products, including toxins, bacterial endotoxins, and substances that form the cell membrane of bacteria, are the most important exogenous pyrogens. Most exogenous pyrogens induce fever by stimulating the synthesis of endogenous pyrogens by monocyte-macrophages. Specifically, endogenous pyrogens are specific cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), ciliary neurotrophic fac tor (CNTF), and interferon alpha (IFN-alpha). Cytokines play a crucial role in the pathophysiology of fever by inducing the synthesis of prostaglandin E2 (PGE2) in specific brain areas and inducing metabolic, endocrinological, and immunological changes characteristic of fever. PGE2, through interaction with specific receptors present in the preoptic nuclei of the anterior hypothalamus, which are physiologically deputed to the control of thermoregulation, induces an increase in the equilibrium point (set point) of the hypothalamic thermostat; the production and loss of heat adapt to this new set point. The fever is, generally, characterized by three phases:

1. Prodromal or ascending phase: this coincides with the start of the production of prostaglandins which induce an alteration in the hypothalamic setpoint, which, in turn, triggers a series of reactions that lead to an increase in body temperature (chills, vasoconstriction, increased basal metabolism).

2. Acme or fastigium phase: lasts throughout prostaglandin production. Hypothalamic neurons maintain the new setpoint temperature, and the subject will have a warm sensation with hot skin, sweating, tachypnea, tachycardia, and headache.

3. Defervescence phase: it begins with a reduction in prostaglandins production. The hypothalamic setpoint returns to the normal temperature value, and a series of mechanisms are activated to lower body temperature (sweating, vasodilation). The defervescence phase can be gradual (by lysis) or immediate (by the crisis).

Based on the temperature value (measured by axillary method), fever can be classified into:

 • Low-grade: 37–37.6 °C

• Moderate: 37.7–38.9 °C

• High: 39–39.9 °C

• Hyperpyrexia: > 40 °C

In addition, according to the course of the fever over time, we distinguish:

• Continuous fever: the fever remains high with slight variation.

• Intermittent fever: Characterized by wide fluctuations. In particular, there are one or two rises in temperature during the day, followed by a drop in temperature below 37 °C. This trend is typical of abscesses and sepsis.

 • Remitting fever: characterized by daily fluctuations in temperature which, however, remains constantly >37 °C, typical of bacterial and viral infections.

• Recurrent fever: characterized by periods of continuous fever and intervals of days of normal temperature (pyrexia). This pattern is typical of quartan and tertian fever associated with the malaria parasite.

• Undulating fever: periods of 7–10 days alternate with periods without the fever of 7–10 days. This pattern is typical of brucellosis.

Definition of Fever of Unknown Origin (FUO)

Although bacterial and viral infections are the leading causes of fever, many factors can induce it, including neoplasms, rheumatologic diseases, drug treatment, etc. When the cause of fever cannot be identified in a patient who has had an elevated body temperature for several days, it is referred to as a fever of unknown origin.

In particular, the first definition of FUO dates back to 1961 by Petersdorf and Beeson and is based on the following criteria:

 1. Fever with body temperature >38.3C° detected on several occasions

2. Duration of fever >3 weeks

3. Inability to make a diagnosis after a week of investigations in an inpatient

About 30 years later, due to the spread of the human immunodeficiency virus (HIV) and the use of immunomodulatory therapies, Durack and Street proposed a new classification of FUO into four categories:

1. Classic: fever with T ≥ 38.3C° that persists for >3 weeks without a recognized etiological cause after 3 days in a hospital or at least three outpatient visits.

2. Hospital or nosocomial: fever with T ≥ 38.3C° occur ring on more than one occasion in a patient hospitalized in intensive care in which there was no infection, present or incubating, at the time of admission and which, after careful evaluation, remains undiagnosed after 3 days.

3. Neutropenic: fever with T ≥ 38.3C° found on repeated occasions in a patient with less than 500 neutrophils/μl for which the diagnosis remains uncertain after 3 days of appropriate investigations, including negative microbiological cultures after 48 h.

4. HIV-associated: Fever with T ≥ 38.3C° found on repeated occasions in an HIV-infected patient, for a period >4 weeks in an outpatient or > 3 days in an inpatient, if the diagnosis remains uncertain after case evaluation.

Causes of FUO

Table 1 summarizes the leading causes of FUO, which can be divided into four groups: infections, neoplasms, noninfectious inflammatory diseases, and mixed diseases. In approximately 10% of adults, no cause of FUO is identified. The most frequent cause of FUO is infection; in patients with HIV infection, the possibility of opportunistic infections (e.g., tuberculosis, atypical mycobacterial infection, disseminated mycosis, and cytomegalovirus) should also be evaluated. However, FUO causes may differ geographically based on regional exposures, economic development, and available diagnostic tools. For example, infection may predominate in developing countries, whereas noninfectious inflammatory diseases and cancer are more common in developed countries.

Table1. Main causes of fever of unknown origin (FUO)

Diagnosis

 The initial evaluation is based on a careful history to identify focal symptoms and associated factors (such as travel, work, family history, exposure to animal vectors, and dietary habits) and on physical examination to identify potential diagnostic clues.

The history should investigate:

• Family history of infectious diseases (TB, HIV, viral hepatitis, etc.), autoimmune or inflammatory diseases, onco- hematological diseases, hereditary causes of fever (familial Mediterranean fever), etc.

• Personal history of infections (consider any signs of immunodeficiency, especially for children <1 year old)

• Rule out a recurrence of the episode

• Evaluate associated signs and symptoms

• Duration and type of fever (periodic or continuous)

 • Concomitant drug therapies (drug fever)

• Travel to an endemic area

The physical examination should include:

• Evaluation of auxological parameters

• Apparatus examination

• Inspection of the skin and mucous membranes (mucositis, aphthosis, condition of teeth, etc.) and all explorable lymph node stations

 After a thorough history and physical examination, there are three different situations:

 • Localizing symptoms or signs that were not present at previous visits, were not detected, or were not treated. Therefore, proceed with specific tests to confirm the diagnostic suspicion (Table 2).

• In most cases, the initial assessment identifies risk factors that may direct subsequent examinations, such as travel to an endemic area or exposure to possible disease vectors or weight loss not accompanied by anorexia, which could be indicative of infection (Table 2).

• If the initial assessment does not reveal clues but only nonspecific information, a series of laboratory investigations should be performed to identify potential diagnostic clues.

Table2. Examples of diagnostic approach in case of suggestive findings

Following the initial assessment, nonspecific laboratory tests should be performed:

• Complete blood count

• Erythrocyte sedimentation rate (ESR)

• C-reactive protein (CRP)

 • Liver and kidney function tests (ALT, creatinine)

• Blood cultures

 • Tuberculin skin test or interferon-gamma release test

• Urine test and urine cultures

A chest X-ray may also provide vital information to identify a possible infection or neoplasm. The evaluation of preliminary laboratory results could help to formulate a differential diagnosis and direct toward more specific investigations to confirm the diagnostic suspicion, such as specific serological investigations (anti-HIV, HBV, HCV, Epstein- Barr, cytomegalovirus antibodies research, etc.), peripheral blood smear, electrophoresis of serum proteins, thyroid function tests, imaging studies (magnetic resonance imaging or computed tomography), echo cardio, scintigraphy with marked leukocytes, and endoscopy or biopsy (liver, lymph nodes, pleura, pericardium, bone marrow). In general, computed tomography (CT) is helpful in delineating abnormalities localized to the abdomen or chest. Magnetic resonance imaging (MRI) is more sensitive than CT to detect most causes of fever of unknown origin involving the central nervous system and should be performed if a central nervous system etiology is suspected.

Figure 1 describes the diagnostic approach of FUO.

Fig1. FUO diagnostic pathway (Copyright EDISES 2021. Reproduced with permission)

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم شؤون المعارف يصدر كتابًا حول قصيدة الفرزدق في مدح الإمام زين العابدين (عليه السلام)

الأمين العام للعتبة العباسية المقدسة يشارك في حفل افتتاح مشروع تجديد الإيوان الذهبي بحرم أمير المؤمنين (عليه السلام)

المجمع العلمي يطلق ورشًا تطويرية لقرّاء الختمات الرمضانية في بابل

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المزيد

الآخبار الصحية

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ماذا يحدث للجسم عند قطع الكافيين فجأة؟

المزيد

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