Fever of unknown origin R50.80

Fever ofunknown origin (FUO) is not a separate disease entity (Berner 2013). According to Weihrauch (2022), FUO occurs when temperatures ≥ 38.2 degrees C are measured repeatedly and persist for 2 - 3 weeks, the cause of which cannot be clarified despite one week of intensive clarification according to Petersdorf and Beeson (1961).

Nowadays, a revised version also refers to the following febrile conditions as FUO:

- FUO in neutropenic patients

- FUO without neutropenia

- Nosocomial FUO

- HIV-associated FUO

- FUO in malignancies, collagenoses, after drug intake, etc. (Herold 2022).

Kasper (2015) defines FUO as:

1. Fever of > 38.3 degrees C occurring on at least two occasions.
2. Duration of illness ≥ 3 weeks
3. No known immunocompromised state
4. Diagnosis remains uncertain after a thorough history, physical examination, collection of certain specified laboratory parameters (see d.), chest x-ray, abdominal ultrasonography, and tuberculin skin test.

Patients with weakened immune systems are excluded from FUO because their treatment requires a completely different diagnostic and therapeutic approach (Kasper 2015).

FUO is classified into:

- Classical FUO

- FUO in neutropenic patients

- FUO without neutropenia

- Nosocomial FUO

- HIV-associated FUO

- FUO in malignancies, collagenoses, after drug intake, etc. (Herold 2022).

In Western countries, FUO is due to infection in about 20-25%, second most often due to neoplasms and non-infectious inflammatory diseases (NIID), the latter including: collagen-related and rheumatic diseases, vasculitis syndromes and granulomatous diseases (Kasper 2015).

Outside of Western countries, up to 43% FUO is found due to infections, of which up to 50% is due to tuberculosis (Kasper 2015).

There are more than 200 known causes of FUO. The most important causes are infections, malignancies, inflammatory systemic diseases, drug-induced fever, and artificial fever (Michels 2012).

• Classical FUO:

Classical FUO is caused in approximately:

- 25 % by infections

- 10 - 15 % by malignancies

- 40 % by autoimmunopathies, collagenoses or others

- 20 - 25 % ultimately remain unexplained (Weihrauch 2022)

In children, the cause is found to be:

- 51 % by infection

- 6 % by malignoma

- 9 % by autoinflammatory / autoimmunological processes

- 23 % no cause could be found (Kallinich 2014).

In hospitalized patients, infected intravascular catheters, urinary tract infections, pneumonia, sinusitis, pulmonary embolism, deep vein thrombosis or reactivation of a herpes simplex infection or cytomegalovirus infection can be found in particular (Herold 2022).

• FUO in neutropenic patients:

In this case - predominantly during or after cytostatic therapy - the number of neutrophil granulocytes drops to values between 500 - 1,000 / µl. This is found in up to 75 % of patients treated with chemotherapy. However, in about 50 % the cause remains unclear. Even in these unexplained cases, one should suspect an infection (Herold 2022).

Germs such as staphylococci, streptococci, gram-negative bacteria, or fungi are most commonly the causative agent (Herold 2022).

• FUO without neutropenia:

This is often found in abscesses, endocarditis, HIV- infections, opportunistic infections, and tuberculosis (Herold 2022).

• Nosocomial FUO:

Cause of nosocomial FUO can be: infected catheters, pneumonia, sinusitis, urinary tract infections, deep vein thrombosis, pulmonary embolism, reactivation of herpes simplex infection (HSV), cytomegalovirus infection (CMV), postoperative in response to postaggregation metabolism or due to p. o. complications (see also fever after surgery), etc. (Herold 2022).

• HIV-associated FUO:

In this case, fever ≥ 38 degrees C occurs with proven HIV- infection. As soon as the CD4- lymphocytes are < 200 / µl, opportunistic infections can occur such as mycobacteria, Pneumocystis jirovecii, etc. (Herold 2022).

In addition, herpesvirus infections or cryptococcosis caused by cryptococci can occur not infrequently (Michels 2012).

• FUO due to malignancies, collagenoses and drugs:

In this case, no cause is found in up to 15% of cases (Herold 2022).

- Malignancies: A FUO is found especially in acute leukemias, lymphomas (especially Hodgkin's disease), liver tumors, atrial myxomas, inflammatory pseudotumors, brain tumors, neuroblastomas (Berner 2013).

- Collagenoses / autoimmune diseases: Here, a FUO occurs especially in vasculitides and systemic lupus erythematosus, juvenile idiopathic arthritis, pyogenic autoinflammatory processes such as chronic osteomyelitis, in granulomatous diseases such as sarcoidosis, Crohn's disease, granulomatous hepatitis (Berner 2013).

- Medications: Almost all medications can induce fever. Fever often occurs after taking allopurinol, barbiturates, captopril, quinidine, erythromycin, heparin, ibuprofen, nifedipine, penicillin, phenytoin, sulfonamides, etc (Frantz 2006).

• Peak fevers occurring daily or every 2 days are found especially with:

- Abscess

- malaria

- M. Still

- systemic lupus erythematosus (Huppertz 2021)

• Fever for days to weeks with periods of no symptoms:

This speaks for the rare but well treatable monogenetic episodic fever syndromes (Huppertz 2021).

Body temperature is controlled by the hypothalamus. Neurons in the preoptic anterior and posterior hypothalamus receive signals for temperature control from:

- Peripheral nerves (these transmit information from the cold and heat receptors of the skin).

- Blood circulating around the region (Kasper 2015).

Exogenous pyrogens and pyrogenic cytokines can lead to a change in the set point (Smid 2018).

- Exogenous pyrogens:

These are derived from microbacterial toxins such as Gram-positive and Gram-negative bacteria as well as viruses, etc.

- Pyrogenic cytokines (obsolete term: endogenous pyrogens):

These are produced in the body during inflammatory processes (Smid 2018).

They include, for example, IL- 1, IL- 6, tumor necrosis factor (TNF), interferons (especially interferon alpha) (Kasper 2015).

The cytokines lead to an elevation of the hypothetical set point in the hypothalamus. This activates neurons in the vasomotor center and leads to a reduction in heat loss through the skin via vasoconstriction in the extremities. Shivering may occur at this stage to thereby increase heat production by the muscles. The liver also contributes to heat production, as does putting on warmer clothing, hot water bottle, etc. when shivering. The processes of heat production and heat maintenance continue until the blood flowing through the neurons of the hypothalamus is at the temperature of the new thermostat setting. Once this temperature is reached, the hypothalamus maintains the intended temperature (Kasper 2015).

Diagnostic clues to possible causes of FUO are already provided by the height of the fever, type and course of the fever curve, etc. (Weihrauch 2022).

It is also important to objectify the fever, since some patients only feign it. In addition, a detailed (repeated) history should be taken including questions about family history, medication history (Michels 2012), country of origin, recent travel, sexual history, animal contacts, hobbies (Kasper 2015), drug abuse, any foreign material present in the body such as plates, nails, heart valves, catheters, shunts (Huppertz 2021).

Kasper (2015) recommends looking for "potentially diagnostic clues (PDCs)" as the most important step in the workup. Further diagnostics should be decided depending on these potentially diagnostic clues.

In addition, antibiotics and glucocorticoids should be discontinued prior to initiating diagnostic testing, if medically justifiable, as these can confound laboratory chemistry tests. Likewise, all nonprescription medications and dietary supplements should be discontinued to rule out drug-induced fever. If fever persists 72 h after discontinuation, it is unlikely that the medication is the cause (Kasper 2015).

Basic diagnostics for FUO consist of:

- Laboratory tests (see d.)

- Inspection of mouth, ano and genital region.

- X-ray thorax

- Abdominal sonography (Herold 2022)

- Sonography of lymph node stations, especially in the neck region (Michels 2012).

Other examinations should be decided depending on the "potentially diagnostic clues (PDCs)". Certain examinations, such as a possibly required scintigraphic diagnosis, should be performed exclusively during a fever episode (Kasper 2015).

Cave:

- In V. a. a hyperthyroidism as a cause of fever (lowered TSH), no X-ray examination with contrast medium should be performed (Herold 2022).

- In collagenoses/vasculitides, a specimen excision may be inconclusive if corticosteroid therapy was previously administered (Herold 2022).

- Negative serological tests for antibodies at the onset of a disease and in the case of immunosuppression do not rule it out (Herold 2022).

- Differential blood count

- Determination of erythrocyte sedimentation rate (ESR)

- C- reactive protein

- hemoglobin

- electrolytes

- Creatinine

- total protein

- alkaline phosphatase

- alanine aminotransferase

- aspartate aminotransferase

- lactate dehydrogenase

- creatine kinase

- ferritin

- antinuclear antibodies

- rheumatoid factors

- protein electrophoresis

- urinalysis

- blood cultures (n = 3)

- urine cultures

- Tuberculin skin test (Kasper 2015)

- HIV serology

- EBV serology in adolescents and young adults

- Hepatitis serology (Michels 2012)

The differential diagnoses are too numerous to list here. However, it should be noted that FUO is more often caused by an atypical expression of a common disease than by a rare disease (Kasper 2015).

If medically justifiable, all foreign bodies such as probes, drains, central venous catheters, bladder catheters, etc. should be removed as early as possible (Schwenk 2019).

Routine lowering is not indicated in cases of unclear fever because it may prevent adequate therapy or start it late (Weihrauch 2022).

However, there are situations in which lowering body temperature may be of vital importance, such as:

- malignant hyperthermia

- heat stroke

- grand mal epilepsy

- other diseases of the CNS

- elderly patients

- patients with existing:

- heart failure

- coronary heart disease

- pregnancy

In this group of patients, fever reduction has not yet been shown to have a detrimental effect on infection resistance (Frankincense 2022).

• Symptomatic Therapy:

In all patients with fever (see d.), symptomatic measures should be taken in the form of:

- adequate fluid substitution (Runge 2018). Fluid requirements increase by 0.5 - 1.0 l / 24 h for every 1 degree C (Herold 2022).

- Removal of warming blankets and excessive clothing (Weihrauch 2022).

• FUO in neutropenic patients:

Treatment with a broad-spectrum i. v. antibiotic should be started as soon as possible because the earlier therapy is started, the greater the chance of success (Herold 2022).

If no multidrug resistance bacteria (MDR) bacteria have been detected, i. v. administration of Pseudomonas-active betalactam is recommended. If there is no improvement after 72 h, antibacterial antifungal therapy should be initiated, possibly including a presentation to an infectiologist (Herold 2022).

• FUO in case of positive tuberculin test:

Because miliary tuberculosis in particular is difficult to diagnose, an attempt at therapy for tuberculosis should be initiated if the tuberculin skin test is positive or if granulomatous disease is present with anergy and sarcoidosis seems unlikely. If fever persists after 6 weeks of empiric antituberculous therapy, another diagnosis should be considered (Kasper 2015).

• Colchicine:

Colchicine is an effective drug for familial Mediterranean fever. However, it is not necessarily effective in the acute attack, showing marked improvement in symptoms only within weeks or months (Kasper 2015).

• Glucocorticoids:

These lead to an impressive improvement in symptomatology in giant cell arthritis and polymyalgia rheumatica (Kasper 2015).

• NSAIDS:

NSAIDs can cause significant improvement in adult-onset Still 's disease (Kasper 2015).

• Anakinra:

Anakinra is an interleukin- 1 cytokine that is very effective in autoinflammatory syndromes in increasing numbers, local and systemic infections, and febrile response. A therapeutic trial may be considered in patients whose diagnosis has not been clarified despite extensive investigations. In addition, anakinra may be considered for patients with severe side effects on glucocorticoid therapy (Kasper 2015).

• FUO without neutropenia:

Unless patients show threatening symptoms, they should initially be observed for 2 - 3 days. During this period, fever can be objectified. If fever persists after this time, a detailed diagnostic workup should be initiated (Herold 2022).

If no cause for the fever can be found during diagnostics, the patient should be treated symptomatically with antipyretic therapy, e.g., metamizole 1 g as a single dose, under close observation (Schwenk 2019).

In fever of unclear origin, several studies indicate a good course with spontaneous recovery between 51 - 100 % (Mourad 2003).

Especially in recent years, the FUO-related mortality rate has decreased. Most deaths are due to malignant disease. For non-malignant causes of FUO, the mortality rate is very low. In developing countries, however, infectious diseases are still the main causes of lethal FUO (Kasper 2015).

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